ANALYSIS OF FRDCRAM AaiVrrjIS, NATIONAL INSTfTUTES OF HEALTH V'ATIONA)-, HEART INSTniJll X)LUME MTICWI, INSTiTUTES OF HEALTH PIJBIiC HEALTH SERVICE H. S. WrPASBOW OF HEALIIJ, EDIKAIIKW, AND WILFAK Librsry^ Natic ', Suit Unit ' Health Form Ho. CSSP-1 ^ ^^ Calendar Year 1956 FUBUC HEAIOS SERVICE - - HATIONAL INSTITUIES OF HEALTH INDIVSXJAL PROJECT REPORT Part A. Project Description Sheet 1. NHI-87 SERIAL NUMBER 2. National Heart Institute 3. Chemical Pharmacology INSTITOlg ^ DIVI^(!^ LABORATORY, BRANCH, OR DEPARTMEINT Ij., Pha rmac odynamic s 5, SECTION OR SERVICE LOCATION (IP OTHER IHAN BE'IUESUAT 6. studies on Antiarrhythmic Drugs PROJECT TITI£ 8. 7. Harriet M. Maling PRINCIPAL mVESTIlATOR OOBER mVESnOATORS 9' IF THIS PROJECT RESEMBLES, COMPIEMENTS, OR PARALLELS RESEARCH DONE ELSEWHERE IN THE PUBLIC HEALTH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACILITIES OR fUNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Objectives t To screen drugs for antiarrhythmic activity. Methods -Qnfiployeds Selected drugs have been screened against petroleiun ether-epinephrine induced arrl^hmias in the anesthetized, vagotomized cat and against the "spontaneous" ectopic activity vtiich is prominent in unanesthetized dogs the first day after ligation of the anterior descending coronary artery. Major Findings; Dilantin has antiarrhythmic action in unanesthetized dogs against ventricular arrhythmia due to coronary artery ligrtion, but does not show artiarrhythmic action in anesthetized vpgotomized cats against petroleum ether-epinephrine arrhythmias. This variabij.ity demonstrates the desirabilit of several types of tests. NHI-87 Serial Nimber VJIN 8568 (2-diethylaininoethyl l;=ainino=2-"hexoxybenzaraide hydrochloride) shows Eintiarrhythmic activity against ligation=induced ectopic activity in a very low dose (0<,32 ingmo/kgm,)c Antiarrhythmic activity of WIN 8^68 has also been demonstrated by Grumbach (personal communication) in isolated rabbit hearts and against aconitine-induced auricular fibrillation in anesthetized dogSs Significance to Heart Research; Two methods of testing drugs for anti- arrhythmic activity have been developed,, These methods can be used to determine whether new antiarrhythmic drugs deserve trial in human beings« Proposed Course of Project g Occasional testing of driigs reported by others to have antiarrhythmic action will be done against the spontaneous ectopic activity occurring in unanesthetized dogs on the first day following coronary ligatioHo Form No. ORP-1 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. IIEI-87 SERIAL NUMBER 12, BUDGET DATA; ESTIMATED OBLIGAnONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FI'57 $5,000 $2,046 BUDGETED POSITIONS 17,046 o3 o2 o5 PATIENT DATS PROF OTHER TOTAL FI'57 0 G 0 0 13. BUDGET ACTIVITT; RESEARCH FTl REVIEW & APPROVAL /~7 BIOLOGIC STANDARDS /~7 ADMINISTRATION EJ PROFESSIONAL & TECHNICAL ASSIST- ANCE LJ U. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957o IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S): None Form No. OHP-1 Calendar Year 1956 October 1956 (Attachment I) PDBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Anards & Publications 15.NHI-87 SERIAL NUMBER 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS FROM TEES PROJECT DURING CALENDAR YEAR 1956: Sjoardsmaj A., Mallng, H.^ Prattj H.W.j, Axelrodp J.^ Kayden, H.J. 5 and Terry, L.A. The antiarrhythmic action of Ambonestyl (2-diethyl- aminoethylisoniGotinainidej MC-lill2), New England Journal of Medicine 5 255s 213-216, 1956 17. LIST HONORS AND AWARDS TO PERSONNEL RELATING TO THIS PROJECT DURING CALENDAR YEAR 1956: None Form Ho. <»P-1 October 1956 (Attachment l) Calendar Year 19^6 PUBLIC HEALIH SERVICE - - NATIONAL HJSTITUTES OP HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. NHi^ga SERIAL NUMBER 2. Kstional Heart Institute INSTITUTE OR DIVISi6n 3 . Chemical Fharmacology LABCeAT(»y, BRANCH, GR DEPAREMENT Ij., CI ideal rharmscolcgy 6. SECTION OR SERVICE Studies vith Muscular relsxants PROJECT TITLE 5, Goldvjater Memorial Hospital; LOCAnON (IF OTHER THAN BEIHESDA) New York,? N- Yo 7. Bernard B, 3nd John Jo Burns 8. PRINCIPAL INVESTIGATOR OTHER INVESTIGATORS 9. IF THIS PROJECT RESEMBLES, COMn^MBNTS, OB PARALLELS RESEARCH DONE EL8EUHERE IN THE PUBLIC HEALTH SERVICE (VflTHOUF INTERCHANOE OF PER- SONNEL, FACILITIES OR FUNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Cbj_ecti_vej drug , To deveioD a lons; actinp; and effecti^/e muscular relaxant Ii§ili2^_-i^™£loZM^ " Micro methods for drug analysing^ micro techniques for isolation of metsboliteL'.^ clinical evaluation of the m^uscular relaxant effect of various drugs » Ma .lor Findings; Recently Flexin (McKeil 4-85) has been introduced as a new drug for the treatment of multiple sclerosis, » cerebral palsy, poliomyelitis and other conditions associated v;ith peripheral muscular spasm. Studies of its physiological disposition sho^^f that the drug has one inherent disadvantage in being slowly and incompletely absorbed mi-88 SERIAL NOo when given orally,, This property of Flexin explains some of the difficulty in controlling therapeutic response o Further studies have shown that the drug is metabolized in patients to a compound formed by the substitution of a hydroxyl group for the amino group in the molecule o This metabolite is as active a muscular relaxant as the parent drug and it has the added advantage of being rapidly and completely absorbed when given orallyo These observations have initiated studies in several clinics to evaluate this metabolite as a new drug for the treatment of patients with spastic diseaseso Significance to HEART Research; A long acting and effective muscular relaxant drug would be of great value for the treatment of various spastic diseases o Proposed course of pro.ject; No further study planned. Form No. ORP-1 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. KHI-38 SERIAL NUMBER 12. BUDGET DATA; ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOT&L FI' 57 $9,300 1499 BUDGETED POSITIONS $9,799 ok o7 lol PATIENT DATS PROP OTHER TOTAL FT' 57 0 1 1 0 13. BUDGET ACTIVITI; RESEARCH /j? REVIEW & APPROVAL /~7 BIOLOGIC STANDARDS /~7 ADMINISTRATION £7 PROFESSIONAL & TECHNICAL ASSIST- ANCE /~7 14.. IDENTIFY ANT COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IF COOPERATING UNIT IS UITHIN NIH INDICATE SERIAL NO.(S); None Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15. NHI-88 SERIAL NUMBER 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: None 17. LIST HONORS AND AWARDS TO PERSONNEL REUUNG TO TEES PROJECT DURING CALENDAR YEAR 1956: None Foxm No. GRP-l Calendar Year I936 October I956 (Attachment l) PUBLIC HEALIH SERVICE - - NATICSIAL mSTITUIES OF HBALOB INDIVUXJAL PROJECT REPCBT Part A. Project Description Sheet 1. NHI-89 SERIAL NUMBER 2. National Heart Institute 3, Chemical Pharmacology INSKITUIE. OR DIVISIGN LABORATORY^ BRANCH, OR DEPARIME31T U, Pharmacodynamics 5» SECTION OR SERVICE LOCATION (IF OTHER 1SAN BEIUESDAJ o. Relationships Among Ventricular Stroke Work; Contractile Force and PROJECT TITZS Systemic Output ?• Marion deV. Gotten and Harriet K. Maling 8. PRINCIPAL INVESTIGATOR OIHER INVESnOATORS 9« IF OHIS PROJECT RESEMBLES, COMPIEMENTS, OR PARALLELS RESEARCH DONE EISEMHERE IN THE PUBLIC HEALTH SERVICE (WIIHOUF INTERCHANGE OF PER- SONNEL, FACILITIES OR RJNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Ob.jecti-ves; The objective of this project was to study the inter- relationships which exist among the ventricular stroke work, con- tractile force and systemic output. Methods Employed; The experiments were conducted in heart-lung prepara- tions of the dog. The systemic output was measured with a Shipley- Wilson rotameter and the atrial pressures were controlled by a venous reservoir connected to the superior vena cava. The aortic resistance was controlled with a Starling resistance and the heart rate was maintained constant by keeping the temperature of the blood at 37° C. Atrial and aortic pressures were measured with electronic pressure transducers. Stroke work was cal- culated in the usual manner from the aortic pressures? left atrial pres- sures and stroke volume. The force of ventricular contraction was measured with a system of heart-levers which permitted measurements of contractile force at the initial diastolic fiber length existing at the time the measurements were made. NHI-89 SERIAL NO. Major Finilngs; Increasing the left atrial pressure resulted in increases in the left -ventricular stroke work, the left ventricular contractile force and the systemic outputo There was a linear rela- tionship between the increases in the stroke work and the increases in the contractile force, between the increases in stroke work and systemic output and between the contractile force and systemic outputo laical ventricular function curves resulted from plotting the stroke work against the atrial pressure o Increasing the aortic pressure resulted in increases in the left ventricular stroke work and contractile force which were related linearly. In the latter experiments, the systemic output diminished as the aortic pressure was elevated so that there was no linear relationship between the stroke work and systemic output or between the contractile force and the systemic output. The adminis- tration of norepinephrine produced a marked increase in the stroke work, contractile force and systemic output.. As in the previous experiments iu which the atrial and aortic pressures were Increased, there was a linear relationship between the stroke work and contractile force « There was a linear relationship between the stroke work and systemic output and the contractile force and systemic output with norepineph- Significance to HEART Research; Previously, there has been no defini- tive information a\ailable regarding the relationship which exists among the stroke work, contractile force and systemic outputo These ejqDeriments provide such information and demonstrate that, under the conditions studied, changes in the stroke work of the heart are related linearly to concomitant changes in the ventricular contractile force while the systemic output is related linearly to these two functions only under certain circumstances » Proposed Course of Project? These experiments are completed and no additional studies are planned «• Form No. ORP-1 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. imi-89 SERIAL NUMBER 12. BUDGET DATA; ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FT' 57 $8,500 13,533 BUDGETED POSITIONS $12,033 .4 »5 .9 PATIENT DAYS PROP OTHEK TOTAL FY' 57 0 1 1 0 13. BUDGET ACTIVITY; RESEARCH 777 REVIEW & APPROVAL £0 BIOLOGIC STANDARDS /~7 ADMINISTRATION nj PROFESSIONAL & TECHNICAL ASSIST- ANCE n 14.. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OIHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S); None Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITOTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15. NHI-89 SERIAL NUMBER 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: None 17. LIST HONORS AND AWARDS TO PERSONNEL HEUTING 10 TEES PROJECT DURING CALENDAR YEAR 1956: None (Attachment I) nsuQ m/dim service - - naticmm. instituies op healoh IHDIVIBaAL PROJECT REPORT Fart A. Project Description Sheet 1. ri-I-pO SERIAL NIMBER 2. national Heart Institute INSTITUTE Or DIVISK^ 3. Chemical Fharmeeology LABORATORY, BRANCH, OR DEPARTMEaiT *♦■• Fharmacodvnaiaics SECTION OR SERVICE 5. LOCATION (IF OIBER TOAN BE!IfiESDAj 8. Comparison of Adrenergic Elocki " -o:r ,-js \'i Irl- i-;itir' - C-F^visc Actions PROJECT TITI£ of Sympathomimetic ar-ines Karion ceV. Gotten PRINCIPAL INVESTIGATOR OOBER DiVESTIQATQRS 9' IF THIS PROJECT RESEMBLES, CCMPI£MBNTS, OR PARAUiELS RESEARCH DONE ELSQfflERE IN THE PUBLIC HEALTH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACIUTIES OR RJNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Objectives: The objective of th's project vas to compare the effective- ness of five adrenergic blocking agents in inhibiting the increases in cardiac contractile force produced by epinephrine, norepinephrine and iconroterenol. I-ietho:t- J'ii' ve.ve C'^noMcte: ■IZi measured in the usual manner v;ith ^u tlsc'^i- i i.;: ':■-■■■ :u:-. .;l ; ucr and the force of cardisc contrax.t"l o:: was ;.:Gat'iai-ed kit:, a ftrain i:au,-;e arch, ^^a_2or_Fi.idin2S : Phsntolemi'^o en'- dibenzyline mfrkedly inhibited the incx':.; ; p;; ca.'iec coni-rac^,ile ["'orce ' -ochJC'^c 'v rrint^ hrinej nor- opi'^eihiine and i; or re Le:ei:ol. r'-tn; ■.olaifti- o si; o r- o:"'uGed a partial liock;;de o"" the increase ir con '.'i-'sc tile force poducad hy eleclrical stimulation of the cardiac r:y.:r -:,";_-?: i.ic rerve fibers. lu yd<'ition to inhibiting the contracl.ile force effect: of the three sympathomimetic NHI-90 SERIAL NO. amines, the phentolamine and dibenzyline also reversed the pressor response to epinephrine and virtually abolished the pressor response to norepinephrine o The blockade of the cardiac stimulant effects of the three sympathomimetic amines was not related to the development of hypotension produced by phentolamine and dibenzyline since the blockade was equally effective when the blood pressure was kept at control values by partial compression of the aorta. The blocking action also was not due to an insensitivity of the heart to all cardiac stimulant drugs since ouabain produced typical increments in cardiac contractile force after complete blockade of the cardiac stimu- lant effects of epinephrine, norepinephrine and isoproterenol. The blockade was also not related to a diminished effectiveness of the sympathomimetic amines with repeated injections since control experi- ments have shown that the responses to the amines are quantitatively UTialtered with frequent repeated administrations. In contrast to the marked inhibition of the cardiac actions of the sympathomimetic amines by phentolamine and dibenzyline, three other adrenergic blocking drugs had only slight to moderate inhibiting effects. These three included hydergine, azapptine and piperoxan. The latter three blocking agents did, however, produce a reversal of the pressor response to epinephrine and a moderate reduction of the pressor response to norepinephrine. Significance to ESA.RT Research; Previous investigators, using isolated heart muscle preparations, had reported that the adrenergic blocking drugs did not inhibit the cardiac stimulant effects of epinephrine or norepinephrine. The present findings using Intact animals show that two of these blocking drugs do effectively block the contractile force effects of epinephrine, norepinephrine and isoproterenol and illustrate the necessity for employing intact animals for such experi- ments . Proposed Course of Pro,iect; The project is completed and no further experiments are planned. Form No. ORP-1 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NAnONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. NHI-90 SERIAL NUMBER 12. BUDGET DATA; ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FI' 57 111,500 14,835 BUDGETED POSITIONS $16,335 o3 lo2 le5 PATIENT DATS PROF OTHER TOTAL FT' 57 0 2 2 0 13. BUDGET ACTIVITT; RESEARCH /Tl REVIEW & APPROVAL HI BIOLOGIC STANDARDS /~7 ADMINISTRATION no PROFESSIONAL & TECHNICAL ASSIST- ANCE n 14.. IDENTIFY ANT COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S): None Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment I) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Airards & Publications 15. KHI-90 SERIAL NUMBER 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: None 17. LIST HONORS AND AWARDS TO PERSONNEL RELATING TO THIS PROJECT DURING CALENDAR YEAR 1956: None Form Ho. C»P-1 Calendar Year 1956 October 1956 (Attachment l) PUBLIC HEALm SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVUXTAL PROJECT REPORT Part A. Project Description Sheet 1. NHI°91 SERIAL NUMBER 2. National Heart Institute 3, Chemical Pharmacology INSTITtfE^ (A DinSLiXl LABi^ATORY, BRANCH, OR DEPARTMEWT l^, Pharmacodynamic s 5« SBCTKlM OK SKKVlClfi LOCATIOM (IF OTHER THAN BETHESDAJ 6. Contrast Between the Effects of Increased Cerebrospinal Fluid Pressure PROJECT TITLE and Augmented Reflex Sympathetic Activity on the Cardiac Contractile Force 7. Marion deV. Gotten PRINCIPAL INVESTIQATOR 8. Neil C._ Moran OTHER INVESnOATORS 9. IF THIS PROJECT RESEMBLES, COMPLEMENTS, OR PARALLELS RESEARCH DOSE ELSEWHERE IN THE PUBLIC HEAimi SERVICE (WITHOUT INTERCHANOE OF PER- SONNEL, FACILITIES OR RJNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO*(S) IF WITHIN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Objectives; The objective of this project was (1) to confirm results obtained previously in dogs on the effects of increased reflex sympathetic activity on the cardiac contractile force and blood pressure and (2) to compare the effects of increased reflex sympathetic activity in the cat with the effects of increased cerebrospinel fltiid pressure. Methods ^gployedg Anesthetized cats with intact circijlatory systems were used. The force of ventricular contraction was measured with a strain gauge arch sutured directly to the ventricular muscle while the blood pressure was measured in the usual manner with an electronic pressure transducer. Increases in reflex sympathetic activity were produced by teirqjorarily occluding the common carotid arteries and by electrically stimvilating the cut central end of a sciatic nerve. Increased cerebrospinal fluid pressure was obtrined by competing a needle in the subdural space to a saline-containing oressure bottle connected to a mercury manometer. NHI-91 Serial Number Major Findings 8 Increased reflex sympathetic activity prcxiuced a marked increase in the blood pressure with only a moderate direct increase in the cardiac contractile force. Thus, these results obtained in the cat are in agreement with similar findings in the dog. In contrast to the effects of increased reflex sympathetic activity, the administration of norepinephrine, in doses which produced increase.*" in blood pressure comparable to those produced by reflex sympathetic stimulation, produced significantly greater direct increases in cardiac contractile force. Elevation of the cerebrospinal fluid pressure also provoked marked rises in the blood pressure associated with marked increases in the cardiac contractile force. The latter findings demonstrate ihat the sympathetic rervous system may be stimulated in such a fashion as to produce marked increases both in blood pressure and contractile force. In contrast, reflex sympathetic stimulation prodioces a marked increase in blood pressure, but only a moderate direct increase in cardiac contractile force. Significance to HfiABT Research^ These experinsnts represent an extension of t a project aimed at stuc^ing the reflex control of the cardiac contractile force. There is relatively sparse information regarding the central and reflex sym= pathetic control of the contractility of the heart and it is anticipated that such experiments may provide data regarding these functions. Proposed Course of Projects No additional experiments similar to those describee above are planned. Other experiments will be conducted with cats along the lines described in the accompanying Individual Project Report for 1956 entitled "Reflex Control of Cardiac Contractile Force**, Form No. ORP-1 October 1956 (Attachment I) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. lJHI-91 SERIAL NUMBER 12. BUDGET DATA; ESTIMATED OBLIGATIONS MAN lEARS DIRECT REIMBUBSMENT TOTAL PROP OTHER TOT&L PI' 57 $5,100 $2,232 BUDC^TED POSITIONS $7,332 o3 .2 .5 PATIENT DAYS PROP OTHER TOTAL FT' 57 0 0 0 0 13. BUDGET ACTIVITT; RESEARCH /Tl REVIEW & APPROVAL jZJ BIOLOGIC STANDARDS /~7 ADMINISTRATION CJ PROFESSIONAL & TECHNICAL ASSIST- ANCE n U. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IP COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S): None Ponn No. ORP-1 Calendar I^ar 1956 October 1956 (Attachment I) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OP HEALTH INDIVIDUAL PROJECT REPORT Fart C: Honors, Awards & Publications 15. NHI-91 SERIAL NUIIBEE 16. LIST PDBLIGATIONS OTHER THAN ABSTRACTS IBOH TEES PROJECT DDRIHG CALENDAR TEAR 1956: None 17. LIST HONORS AND AWARDS TO PERSONNEL REUUNG TO TEES PROJECT DURING CALENDAR YEAR 1956: None Foim No. OBP-1 Calendar Year 19^ October 1956 (Attachment l) FUBLEC HEALTH SERVICE - '- IIATICIIAL IKSHTUIES OF BEALOH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. JCXSE ELSEWHERE IN THE PUBLIC HEALTH SERVICE (WITOOUT INTERCHANGE OF PER- SOMNEL, FACILITIES OR RJNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Objectives; In the course of a study of the effects of antiarrhythmic drugs on the delayed ventricular ectopic activity in dogs following coronary artery ligation, it was noted that intravenous injections of epinephrine produced marked ventricular tachycardia, even after the arrhythmias induced by the ligation had disappeared. The present investigation is a study of "the electrocardiographic responses to several selected sympathomimetic amines in unanesthetized dc^s before and for several weeks after coronary artery ligation to determine the intensity of the sensitization and its time-course. Methods Employed; The anterior descending coronaiy artery was ligated. in anesthetized dogs, using aseptic precautions, and folloi^ing the two-stage occlusion technique of Harris. Most experiments were conducted on un- anesthetized dogSo Electrocardiograms were recorded, sometimes simultaneously with femoral arterial pressure. Drugs were tested by intravenous injection before and at varying times after coronary artery occlusion. NHI-93 Serial Nvmiber Major Findings; Epinephrine and norepinephrine, in doses which cause little ectopic activity in unanesthetized nonnal dogs, produced ventricular tachQTcardia after coronary arteiy ligation,. This hypersensitivi-ty was particularly apparent about the fourth day after ligation, when the arrhythmias caused by the ligation per se had subsided, and gradually disappeared with time so that the responses were again normal 12 days after ligation. Sensitization was slightly greater for norepinephrine than for epinephrine over a wide range of doses. Observations with methoxamine, isoproterenol, methacholine, and atropine indicate that combined iH7ocardial stiraiolation and vagal slowing are necessary for demonstration of this sensitization. Significance to HEART Research; The hypersensitivity of the heart after experimental coronary artery occlusion is probably closely related to the "spontaneous" ectopic activity induced in dogs by coronary ligation per se. The duration- of the hypersensitivity corresponds closely with the clinical observation that the first two weeks following myocardial infarction in man is ■Uie most likely period for the development of paroxysmal ventricular tachycardia. The sensitization to norepinephrine suggests a possible risk of inducing arrhythmias by the use of large doses of norepinephrine in the treatment of shock resulting from myocardial infarction in man. Proposed Coiirse of Research; Experiments are now in progress on anesthetized normal dogs and on anesthetized dogs h days after coronary artery occlusion to clarify the role of the vagus in these sensitized responses.5 Buring peripheral vagal stimulation in anesthetized dogs, it is possible to demonstrate sensitization to isoproterenol after coronary artery ligation. This sensitization to isoproterenol is impossible to demonstrate in unanesthetized dogs because of the marked sinus acceleration after the drixg. Form No, ORP-1 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. I'IHI-93 SERIAL NUMBER 12. BUDGET DATA; ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FT' 57 $6,300 $2,603 BUDGETED POSITIONS $8,903 o4 o2 .6 PATIENT DAIS PROP OTHER TOTAL FT' 57 1 0 1 0 13. BUDGET ACTIVITY; RESEARCH /T? REVIEW & APPROVAL /~7 BIOLOGIC STANDARDS HI ADMINISTRATION EJ PROFESSIONAL & TECHNICAL ASSIST- ANCE n 14. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S): None Form No. ORP-1 Calendar Tear 1956 October 1956 (Attachment l) PDBLIC HEALTH SERVICE - - NATIONAL INSTIiaTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15.MI°93 SERIAL NUMBER 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR lEAR 1956: Maling^ Harriet M., and Neil C Mo ran. Hypersensitivity of the Heart to Spinephrine and Norepinephrine Following Experimental Coronary Artery Occlusion, submitted to Circulation Research. 17. LIST HONORS AND AWARDS TO PERSONNEL REUTING TO THIS PROJECT DURING CALENDAR YEAR 1956: None Form Ho. C»P-1 Calendar Year 1956 October 1956 (Attachment I) PUBLIC HEALlfi SERVICE - - NATIONAL INS^ECTlfEES OF HEALTH IHDIVnKJAL PROJECT REPORT Part A. Project Description Sheet 1. NHI-9^ SERIAL NUKBER 2. National Heart Institute 3. Chemical Fharinacology INSTITUTE OE^ DIVISION LABORATORY, BRANCH, OR DEPARTMENT '^. Fharmacody ramj C3 5» SECnOW OR SERVICE LOCATION (IF OTHER THAN BETHESDA) 6. Hypersensitivity of Heart to Small Doses of Norepinephrine Following PROJECT TITLE Large Intravenous Injections of Norepinephrine 7. Harriet M. Ma ling PRINCIPAL INVESTBIATOR 8. OTHER mVESTIQATORS 9. IF OHIS PROJECT RESEMBLES, CCMFI£MENTS, OR PARAII£L3 RESEARCH DGME ELSEWHERE IN THE PUBLIC HEALTH SERVICE (WIOHOUT INTERCHANOE OF PER- SONNEL, FACIUTIES OR RJNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). 10. PROJECT DESCRIPnCN (SEE INSTRUCTIONS): Objectives; These experiments have demonstrated a sensitization of the heart to small doses of norepinephrine for several days follov/ing the intravenous administration of large doses of norepinephrine to unanesthetized dogs. The present study is an investigation of the conditions necessary for the production of this sensitization, to determine the intensity and the duration of the sensitization and to correlate the sensiti 2ationj if possible? with changes in the myo- cardial concentration of catechol amines und with histological changes. Methods Bnployed; The sedimentation rate and the electrocardio- graphic responses to small test doses of norepinephrine are determined in unanesthetized dogs on a number of days before and after the intra- venous administration of large doses of noreplnephrire. aHi-9A SERIAL NO. Ka,ior Findings; The intra ■venous injection of a large dose of norepineph- rine (6 raicromoles/kgm. or approximately 1 mgm./lcgm., administered either in 6 doses of 1 micromole/kgm. each, 15 minutes apart, or by con- tinuous infusion over a period of 75 minutes) is followed by a period of sensitization to small test doses of norepinephrine. This sensitiza- tion continues for several days. During this period of sensitization, doses of norepinephrine which cause little ectopic activity before the administration of the large dose produce marked ventricular tachycardia. Significance to Heart Pcesearch; The sensitization to norepinephrine produced by large doses of nore-^i- ephrine resembles the hypersensitivity of the heart to small doses of norepinephrine after experimental coronary artery occlusion. The drug-induced sensitization supports the hypothesis that the ligation-induced sensitization may possibly be the result of the release of catechol amines from the damaged myocardium with subse- quent absorption by the adjacent normal cells. Determinations of myo- cardial concentrations of catechol amines will test this hypothesis further. Proposed Course of Research: The investigators hope to collaborate with Dr. Parkhurst Shore in correlating this sensitization with changes, if any, in the myocardial concentratior of catechol amines. The myocardial concentration of epinephrine and norepinephrine will be determined in normal dogs, and in dogs one, two, three, and four days after continuous infusion of a large dose of norepinephrine. The electrocardiographic responses to small test doses of norepinephrine will be determined immediately before sacrifice of each dog, as an indicator of the inten- sity of sensitization, if any, at that time. Form No. ORP-1 October 1956 (Attachment I) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. MI -9^ SEEIIAL NUMBER 12. BUDGET DATA: ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FT' 57 $4,000 11,726 BUDGETED POSITIONS $5,726 o2 o2 ,4 PATIENT DAIS PROF OTHER TOTAL FT' 57 0 0 0 0 13. BUDGET ACTIVITY; RESEARCH ITl REVIEW & APPROVAL /~7 BIOLOGIC STANDARDS /~7 ADMINISTRATION CD PROFESSIONAL & TECHNICAL ASSIST- ANCE / / H. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S): None Form No. GBP-l ^ Calendar Tear 1956 October 1956 (Attaehment I) PUBLIC HEALTH SERVICE HATICHIAL IBSTiniTES OP HEALTH INDnZBUAL F&OJEGT REPOEf Part C: Honors, Awards & Publications 15. BHI-9A ^BIAL HDllBEa 16. LIST FOBLIGATIOSS OTHEB TH&N ABSTRACTS FBOH THIS PROJECT GORIHG CAIENDAR lEAR 1956: None 17. II3T BCmSBS AHD AH&BD6 ID FBtSOHEL BEUHHG TO THIS FSOJBCT SDBI9B G&LEIDAR lEAR 1956: None Form No. ORP-l Calendar Year 19^ October 1956 (Attacbment l) POBIIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVUXJAL PROJECT REPORT Part A. Preset Description Sheet 1. mhI-95 8. AL SERIAL NIMBER 2- 5^^^°"fJL^^f^''^ Institute 3. Qh^jmigaJ, PharfflapQ3rOgy INSTITUTE OR DIVISION LABORATORY, BRANCH, OR DEPARTMENT 1^. 5. . SECTION OR SERVICE LOCATION (IF OTHER OBAN BETHESDAJ 6. The Preparation of Compounds with Anti-Digitalis 'ctivlty PROJECT TITUB ' 7. Elwood 0. Titus PRINCIPAL INVESTEATOR OTHER INVESnOATORS 9. IF THIS PROJECT RESEMBLES, COMFI£MBNTS, OR PARAII£LS RESEARCH DONE EISEHHERE IH THE PUBLIC HEALTH SBRVICE (WUHOUT INTERCHAIfQE OF PER- SONNEL, FACILITIES GR RJNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITSIIN NIH). 10. PROJECT DESGRIPnON (SEE INSTRUCTIONS): Objectives; Some biological evidence suggests that cardiac lactones hydroxylated in the 17 position might act as antagonists to digitalis- like steroids. An effort is being made to prepare these. Methods Employed; Microbiological hydroxylation of knovm steroids. Idehtification of products by conventionel chemical degradation. Ma.jor Findings; A method for the detection of 17-hydroxylated cardiac aglycones was desired. Cephalothesium roseum, a mo Id, can hydroxylate cardiac aglycones at carbon 17 and several other positions. Preliminary oxidation of the hydroxyl group at carbon 3 may be a necessary pre- requisite for hydroxylation. The 17 hydroxy derivative retained very slight digitalis-like activity in the frog heart. Sigroficance to HEART Research; Although no co: r-ouac'.'': are k.^ovn Epecifically to erjtagojize tVe effects of dlgi balls on heart niusclo, piich substances \vfould be of interest in theoretical studies of the mechanism of action of the cardiac steroids. They should be of use in both the diagnosis and treatment of digitalis intoxication. I ro posed 3cii: • of Project: ^'vince IT-bydroxj/lation did no'- cause any ar.parcnt qua!) ltc;ti\« chanf^es in activity, the project vas abandoned. Form No. OHP-1 October 1956 (Attachment I) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. MI -95 SERIAL NUUBER 12. BUDGET DAT/l: ESTIMATED OBLIGATIONS MAN YEARS DIRECT REBJBURSESJENT TOTAL PROP OTHER TOTAL FI' 57 $7,000 03,523 BUDGETED POSITIONS $10,523 .3 .5 o8 PATIENT DATS PROP OTHER TOTAL FT' 57 0 1 1 0 13. BUDGET ACTiyiTT; RESEARCH /t7 REVIEW & APPROVAL HI BIOLOGIC STANDARDS HI ADMINISTRATION EJ PROFESSIONAL & TECHNICAL ASSIST- ANCE n U. IDENTIFT ANI COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FT 1957. IP COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S): None Pora No. (fflP-1 Calendar Tear 1956 October 1956 (Attaefanent I) PUBLIC HEALTH SERVICE - - MTIOHAL IHSTITDTES OF HEALTH INDIVIDnAL PROJECT REPORT Part C: Honors, Awards & Publications 15. NHI--95 SEBIAL miUBER 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS PROH THIS PROJECT DURING CALENDAR TEAR 1956: Rone 17. ^ UST maSGBS ASD AW&BDS 10 FHtSOHHEL RELATIBQ TO THIS FROJEQT DURING CALENDAR lEAR 1956: None Pom Ho. ORP-l Calendar Year 19^ Octoiber 1956 (Attactaaent I) FOBLEC HEALIS SERVICE - - NATIONAL IHSTITUXES OF HEALTB mDlVUXJAL FROJBQT BEPCRS Part A. Project Descrlpticm Sheet 1. NHl-96 SERIAL NUMBER 2. Mational Heart Institute 3« Chemical Pharmacology INSTITWfi aft DlVI^ft* LABORATORY, BRANCH > OR DEPARTMENT ^. , 5. ^ SECnOR OR SERVICE LOCATION (IF OTHER IBAN BEIHESDA) 6, studies on Reserpine-Induced %-perglycemia and Release of Adrenal PROJECT TITLE Catechol Amines 7. Parkhurst A. Shore PRINCIPAL INVESTIGATE ----------—-—------_---_—---------—-—-—--, 8. OIHER IHVEUTIGAIORS 9* IF THIS PROJECT RESEMBLES, COMPLBCNIS^ CR PARAIUSLS BBSEARCH DOME ELSEUHERB IE THE FUBUC HEAUB SERVICE (WITHOUT INTERCHAIKIB OP PER- SONNEL, FACIUTIES GR FUNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL K0.(8) IFWI1HIM8IH). / 10. PROJECT DESCRIPTION (SEE INSIRUCnONS)/ Objectives; To determine reserpine-i:/duced effects on blood sugar, epinephrine release and the mechanism^' involved. Methods Employed; The effect of rese|>pine and other drugs on blood glucose levels and release of catechciL amines frtjm the adrenal glands is studied, ; Ma.ior Findings; It has been shown tljat the hyperglycemia folio vdng reserpine is a result of a centrally induced release of catechol amines from adrenal glands. Thus, tje release is blocked by adrena- lectongr but not by hypophysectony. ?'urthermore, the hyperglycemia NHI-96 SERIAL NO, may be blocked by a ganglionic blocking agent j hexamethoniuinj or by the adrenergic blocking agents ergotamine and dihydroergotamine. Direct analysis of sdrenal glands of rabbits has shovm that complete depletion of the catechol amine content occurs following large doses of reserpine. This is not a direct effect of reserpine on the adrenals as spinal transection blocks the release. It has been found that of the Hamjolfia alkaloids only the tranquilizing alkaloids effect epinephrine release and hyperglycemia. Chlorpromazine had no effect. Significance to HEART Research; This study is of significance in the further understanding of the action of reserpine, a drug used for control of hypertension and also of some mental diseases. Proposed Course of Pro.ject; It is planned to investigate possible mechanisms whereby reserpine, which causes a marked parasympathetic predominance, also causes sympathetic hyperactivity as reflected in centrally mediated activation of the adrenal medulla. Form No. ORP-1 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. NHI-96 SERIAL NUlfflER 12. BUDGET DATA; ESTIMATKD OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FI' 57 $12,000 $5,990 BUDGETED POSITIONS $17,990 .3 1..3 1-6 PATIENT DATS PROP OTHER TOTAL FT' 57 1 2 3 0 13. BUDGET ACTIVITY; RESEARCH /x7 REVIEW & APPROVAL HD BIOLOGIC STANDARDS /~7 ADMINISTRATION EJ PROFESSIONAL & TECHNICAL ASSIST- ANCE n U. IDENTIFI ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, PACIUTIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO. (S); None Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment l) PDBLIC HEALTH SERVICE - - NATIOHAL INSTITOTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Anards & Publications 15, NHI-96 SERIAL NDMBER 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: Taketomo, Y., Shore, P. A., Tomich, E. G., Kvintzman, R. , and Brodie, B. Studies on the Mechanism of Reserpine-Induced Epinephrine Release and Hyperglycemia, Journal of Pharmacology and Experimental Therapeutics, to be published. 17. LIST HONORS AND AWARDS TO PERSONNEL RELATING TO THIS PROJECT DURING CALENDAR YEAR 1956: None Foxn No. OilP-1 Calendar Year 19^ October 1956 (Attachment l) FUBUC HEALOH SERVICE - - NATIOIIAL mSTITUIES OF HEALIH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. NHI-97 SERIAL NUMBER 2. National Heart Institute 3. Chemical Phamacology INSnTOrg (A DIVISION laboratory, branch, or DEPARTMENT ^^. 5. , , SECTION OR SERVICE LOCATION (IF OTHER IHAN BEIHESDA) 6. studies on Central Autonomic Integrations PROJECT TIT| OR DEPARTMENT k. SECTION OR SERVICE 5. LOCATION (IF OOBER TBAN BEIHESDAJ 6. Physiologic Disposita.on and Fate of Reserpine PROJECT TITI£ 7. Sidney M« Hess PRINCIPAL INVESTEiATOR 8. OIHER INVESTIGATORS 9. IF raiS PROJECT RESEMBLES, CONFI£MENTS, OR PARAII£IS RESEARCH DONE ELSEWHERE IN THE PUBUC HEALTH SERVICE (WITHOUT INTERCHANQB OF PER- SONNEL, FACIUTIBS GR RJNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Objectivess Reserpine is of considerable iiqsortance in medicine as a tranquilizing and a hypotensive agent, and in physiology as a ^ool in elucidating the role of serotonin in the central autonomic nervoiis system. It is the purpose of this stucfy to determine the fate of administered reserpine. Methods Employed; Fluorescent meiiiods of analysis have been developed for this problem, Reserpine is a hit and run drugj its action persisting long after it has disappeared. Major Findings; Reserpine is metabolized differently in various animal species. For instance, rabbits do not Ynydrolyze reserpine readily, yet NHI-98 SERIAL MO, guinea pigs are able to hydrolyze the drug with facilityo The mechanism in rabbits is so far unknown. Among the compounds isolated after administering reserpine to guinea pigs are methyl reserpate, which has been fully identified, and reserpic acid, which has been indicated. Significance to HEART Research; The elucidation of the action of this hypotensive and tranquilizing drug improves our ability to understand and treat hypertension and mental disease. Proposed Course of Pro.ject: Efforts to learn how reserpine is handled after administration to animals and to humans are continuing. Studies to determine how reserpine enters the brain, how long it or its metab- olites persist in the body, and how it is finally eliminated from the body will be investigated. Form No. ORP-1 October 1956 (Attachment I) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. MHI-98 SERIAL NUIilBER 12. BUDGET DATA: ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSHUENT TOTAL PROF OTHER TOTAL FT' 57 $12,500 $6,272 BUDGETED POSITIONS $18,772 1.0 0 1.0 PATIENT DATS PROP OTHER TOTAL FT' 57 1 0 1 0 13. BUDGET ACTiyiTT; RESEARCH A7 REVIEW & APPROVAL HI BIOLOGIC STANDARDS /~7 ADMINISTRATION no PROFESSIONAL & TECHNICAL ASSIST- ANCE n 14-. IDENTIFT ANT COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING ITJNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FT 1957. IF COOPERATING UNIT IS WITHIN NIH INDICAOE SERIAL NO.(S): None Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment I) PUBLIC HEALTH SERVICE NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part Ci Honors, Aiiards & Publications 15.NHI°98 SERIAL NDHBER 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR TEAR 1956: Hessj Sidney M. , Shore, Parkhurst A,, and ^rodie, Bernard B, Persistence of Reserpine Action After the Disappearance of Drug from Brains JiCfect on Serotonino Joiornal of Pharmacology and Experimental Therapeutics llSsSUj, 1906, 17. LEST HONORS AND AWARDS TO PERSONNEL REUTING TO THIS PROJECT DURING CALENDAR YEAR 1956: None Fonn No. 0BP~1 Calendar Year 19^6 October 1956 (Attachment I) FUBUC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. NHI~99 SERIAL NUMBER 2. . National Heart InstitiAe 3« Chemical Pharmc-cology INSTITUTE (SA DIVISI^ LABORATORY, BRANCH, OR DEPARTMEaJT SECnCN OR SERVICE LOCATION (IF OOBER OBAN BEIHESDAJ 6, Pharmacological Studies on the Interrelationship Between the Cholinergic PROJECT TITI£ ~" and Adrenergic Nervous Systems 7. Neil C, Moran PRINCIPAL INVE3T2QAT0R 8. OTHER INVESnOATORS 9' IF THIS PROJECT RBSQffilES, CQNPI£MENTS, €R PARAII£Ifi RESEARCH DGNE ELSEWHERE IN THE PUBLIC HEAUEH SBRVICB (WITHOUT INTERGHANQE OF PER- SONNEL, FACILITIES OR FUNDS), IDQITIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WiraiN NIH). 10. PROJECT DESCRIPnON (SEE INSTRUCTIONS): Objectives; To study hitherto unrecognized interrelationships between the adrenergic ( synqjathetic) and cholinergic (parasympathetic) nervous systems by pharmacological and physiological means. Methods £hiployed; Standard physiological techniques for recording blood pressure^ blcod flow, cardiac contractile force, etc., in animals. NHI -99 yerial ijiunbdr Major Findings; Pilocarpine and otter cholinergic drugs inhibit the vasodepressor actions of acetylcholine and isoproterenol (an adrenergic drug), and inhibit the positive isotropic and chronotropic actions of isoproterenol and epinephrine « Adrenergic blocking drugs (phentolamine, azapetine and dibenzyline) inhibit the hyper salivation induced by pilocarpine and antagonize the inhibitory effect of pilocarpine on the vasodepressor effects of acetyl- choline and isoproterenol and on the positive inotropic and chronotropic actions of epinephrine and isoproterenol. This antagonism appears to be competitive in nature. Significance to HEART Research; The discovery of a more intimate inter- relationship between cholinergic and adrenergic systems is important to our knowledge to the autonomic nervous system and of the autonomic control of the cardiovascular ^stem. Proposed Course of Project? Completed at NHI, To be pursued by senior investigator at Qnory University* Form No. ORP-1 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part 6: Budget Data 11. mi-99 SEEOIAL NUMBER 12. BUDGET DATA; ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FT' 57 $3,500 $l,i^S8 BUDGETED POSITIONS I4,9S8 ol o3 .4 PATIENT DAIS PROF OTHER TOTAL FT' 57 0 0 0 0 13. BUDGET ACTiyiTT; RESEARCH /x7 REVIEW & APPROVAL /~7 BIOLOGIC STANDARDS /~7 ADMINISTRATION EJ PROFESSIONAL & TECHNICAL ASSIST- ANCE n H. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S): None Form No. ORP-1 Calendar Tear 1956 October 1956 (Attachment I) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDIIAL PROJECT REPORT Part C: Honors, Awards & Publications 15.NHI^99 SERIAL NDUBER 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS FROM TEES PROJECT DURING CALENDAR YEAR 1956: None 17. LIST HONORS AND AWARDS TO PERSONNEL RELATING TO THIS PROJECT DURING CALENDAR YEAR 1956: None Form No. <»P-1 Calendar Year 1956 October 1956 (Attachm^it I) HJBIIC HEAL1H SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. KHI-IOO SERIAL NUMBER 2. National Heart Institute 3* Gheraical Pharmacology INSTITWrS (^ DIVISldJN LABORATORY, BRANCH, OR DEPARTMENT k, 5. ^ SECadH OR SERVICE LOCATICN (IF OTHER THAN BETHESDA) 6. Isolation of Cardiotonic Substances from Mammalian Tissues PROJECT TITLE 7. Elv.'ood Titus. Stephen Hajdus, Herbert Weiss PRINCIPAL INVESTII3AT0R 8. OTHER INVESnOATOEiS 9. IF THIS PROJECT RESEKBI£S, COMPUBMBNTS, OR PARALl£LS RESEARCH DONE ELSEWHERE IN THE PUBLIC HEAIilH SERVICE (WITHOUT INTERCHANQfi OF PER- SONNEL, FACILITIES OR FUNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Objectives; The isolation and characterization of cardiotonic substances occurring in animal tissues. Methods Rmployed; Counter-current distribution, column and paper chromatog- raphy for isolation. Bioassays using effects on the Bowditch staircase phenomenon in the Isolated frog ventricle. Ma.jor Findings; Evidence for the existence of three cardiotonic sub- stances in Tarious mammalian tissues has been obtained in this and other laboratories. The most abundant of these, a factor occurring in the adrenal medulla jj has been isolated and characterized as P-palmitoyl KHI-100 SERIAL NOo glyceryl phosphoryl choline (palmitoyl lysolecithin) . Similar active material from beef heart appears to contain an unsaturated acid, prob- ably linoleic, in place of the palmitic. In the frog heart these sub- stances are about l/20 - l/60th es active as the digitalis steroids. The lysolecithins occur very largely as bound forms in i%'hich the hydro 5c/l of the a position of the glycerol is joined by a heiriiacetal linkage to a long chain aldehyde. These substances, although inactive in the frog heart, are very rapidly converted to Lhe active form by traces of acid^ Significance to HEA-RT Regoaroh; Tlvr; lysol ecithirc of marorrnlian tiecue may affect the permeability of cell nembranes to cations in a r-iairner similar to that of the digitalis steroids. -Either these substances or the as yet unidentified cardiotonic factors may serve as hormones : orrrally iiivolvod in control of "eort actibr. Prorio;;;.:': "Jourr.-^ ■:" I ro • ;: . .' ' ' "■ -• ■ ' " '.or ic prin- cipjo; I : - "■ Ian prepara- tio; n . i ' ■ . I • , ■ ^ Li.oiples Form No. ORP-1 October 1956 (Attachment I) FDBUC HMLTH SERVICE - - I1A.TI0ML INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. MHI-lOO SERIAL NUMBER 12. BUDGET DAT&; ESTIMATfcU) OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FT' 57 $14,000 $7,047 BUDC^TED POSITIONS $21,047 1«2 0 1,2 PATIENT DATS PROF OTHER TOTAL FI'57 1 0 1 0 13. BUDGET ACTIVITT: RESEARCH A7 REVIEW & APPROVAL HI BIOLOGIC STANDARDS HI ADMINISTRATION o PROFESSIONAL & TECHNICAL ASSIST- ^ ^ ANCE n H. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING lUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IF COOPERATING UNIT IS VITHIN NIH INDICATE SERIAL NO. (S): None Pono Ho. GRP^-l Calendar Tear 1956 October 1956 (Attachment I) PlffiLIC HEALTH S^7I(S - - RATIONAL INSTITOTSS OF HRAT.m INDIVIDDAL PROJECT REPORT Part C: Honors, Awards & Publications 15. MHI-100 SERIAL NUMBER 16. UST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: The Isolation of a Cardiac Active Principle from Ifemmalian Tissue. Elwood Titus, Herbert Weiss and Stephen Hajdu. Science? in press, The Isolation of a Cardiac Active Principle from Mammalian Tissue. Stephen Hajdu, Herbert Weiss and Slwood Titus, Journal of Pharma- cology and Experimental Therapeutics s in press. 17. LIST HONORS AND AWARDS TO PERSONNEL REUTING TO KIS PROJECT DURING CALENDAR YEAR 1956: Pona Ho. CRP-1 Calendar Year 1956 October 1956 (Attactment l) POBIIC HEALTH SERVICE - - NATIGNAL INSTITUIES OF HEALTH INDIVIDOAL PROJECT BEPQBH Part A. Project Description Sheet 1. MHI-lQl SERIAL NIMBER 2> National Heart Institute 3» Chemical Fharraacology INSniUl^ Ot^ DIVISl^ LABORATORY^ BRANCH, CR DEPARTMENT »^. : 5. . , SBCTION GR SERVICE LOCATICN (IP OTHER MAN BETHESDA) 6. Application of _ &uectroT3hoto."luorometric Assay PROJBCT TITZ£ 7. Bernard b, grg^j^g PRINCIPAL INVESTIGATOR 8. OTHER INVESnOATORS 9. IF THIS PROJECT RESEMBLES, COMFI£MENTS, OR PARAII£L3 RESEARCH DONE EISEUHERE IN THE PUBLIC HEALTO SERVICE (WITHOUT INTERCHANQE OF PER- SONNEL, FACILITIES OR iUNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Ob;jecti-ves5 To explore in a general way, the applicability of spectro- photofluorometry to biochemical and pharmacological problems. Methods Employed; ■ Ma.jor Findings; A survey of pure samples of light-absorbing compounds of biochemical or pharmacological importance revealed fluorescence of sufficient intensity as to be utilized for their determination in tissues in the case of the majority of compounds screened, iSuantita- tive procedures for tryptophan, tyrosine and tocopherol have been developed. NHI-101 SERIAL No. Significance to HEART Research; This technique provides the necessary sensitivity required in certain assays employed in cardio"rascular studies. Proposed Course of Project; The exploratory program as outlined above is essentially concluded. Further study will be directed toward the application of spectrophotofluorometry to specific analytical problems. Form No. ORP-1 October 1956 (Attachment l) PDBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. IiHI-=101 SERIAL NUMBER 12. BUDGET DATA; ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FT" 57 ^14,400 ^7,1S8 BUDGETED POSITIONS 121,588 lo2 0 1«2 PATIENT DAYS PROF OTHER TOTAL PI' 57 1 0 1 0 13. BUDGET ACTIVITY; RESEARCH /x7 REVIEW & APPROVAL JZJ BIOLOGIC STANDARDS /~7 ADMINISTRATION EJ PROFESSIONAL & TECHNICAL ASSIST- ANCE n 14-. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING RINDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IP COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S): Dr. Daniel Duggan, Fellovr, American Instrument Go. Dr. Robert Bovflaan, Laboratory of Technical Development Form No. ORP-1 Calendar Tear 1956 October 1956 (Attaclunent l) PUBLIC HE&LIH SSIVICE - - fflLTIffllAL IHSTIIUfES OF EEkLTSL INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15. HHI-101 aSLEAL NDBBER 16. LIST PUBLICATIONS OTHER TH&N ABSTRACTS FROH THIS PROJECT DTJRING CALENDAR TEAR 1956: The Spectrophotofluorometric Determination of Tryptophan in Plasma and of Tryptophan and Tyrosine in Protein Hydrolysateso Do E. Duggan and So Udenfriendo Journal of Biological Chemistry, 22^; 313. 1956. 17. UST HONORS AND AWARDS TO PBiSOHHEL BEUTING TO THIS PROJECT DORUG CALENDAR TEAR 1956: Koneo Vorm Kb. OBP-l Calendar Year 19^ October 1956, (Attactaaent l) Public BEALm sbekvics - • matiohal msnTuiBS of health IMDIVIIXIAL PROJECT BEPGRF Part A. Mject DescrlpUon Sheet 1. NHI-102 SERIAL HIMBER 2. National Heart Institute 3» Chemical Pharmacology ixsniUM (Hk olvisi6M " laboratory^ branch , or deparenbnt h, 5. . SBCll^ OR SERVICE LOCAXIQN (IF OIHER THAN BEQIESUA) 5, The Effect of Varioxis Dietary Factors on Mici'oaomal Drug MJetabolism PROJECT TIIUE 8. 7. Dr« BeB. Brodie^ Dr. ^ert N. La Dug Jr. PRINCIPAL INVESTIQATOR Dr «^ Jjmes^ Rj,_ i^^Llett * OIHER IMVESnOATGRS 9' IF THIS PROJECT RBSBffiLES, CQNPI£MBnB, OR PARALUELB RESEARCH DOME ELSEWHERE IN THE FUBUC HEAIOH SBtVICE (WITHOUT IHTERGHANQE OF PER- SONNEL, FACIUTIBB OR FUNDS), IDEMTIFY SUCH RESEARCH: (BY SERIAL NO*(S) IF WITHIN NIB). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS)! Objectives g Preliminary results have shown th^t animals which have been starved or have a vitamin C deficiency metabolize drugs and other foreign compounds at a slower rate than normally well fed animals » Since the rate^-^ of metabolism of a drijg affects its duration of actionj it is important %/n, but peroxide may be involved. Some of these drugs can be oxidized to the same products by model catalysts and a study of these model systems may help our understanding of the microsomal enzyme systems. Methods iiimployed; Drug metsbolism is being studied using various model systems and these reactions compared with the liver micro- somal systems o The products are m.easured by specific micro- chemicrl methods. Major Findings; Various alkylaminfe drugs iidiich are dealkyla ted 1^ liver microsomes are also dealkyl-r- ted by hemoglobin or cj^ochrome c in the presence of 11202.''^ Normally occurring alkylamines, such as sarcosine or choline are not dealkylfsted by these systems, -^^Reina^xn and FeCl3 MHI°10U Serial Number Further studies are in progress with the other types of drug metabolism using simple model catalysts. Significance to HEART Research; Most drugs are extensively metabolized in the body and their pharmacologic effectiveness depends upon how effectively these detoxication mechanisms operate, A study of these model systems may help lis learn more about the mechanism of the liver detoxication enzyme sys terns » Propo^d Course of Projects During the coming year various other catalysts will be tested with drug substrates and the mechanism of these reactions will be determined. Form No. OBP-1 October 1956 (Attachment I) PUBLIC HT.AT.TH SERVICE - - NATIOML INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B; Budget Data U. MHI-10^ SERIAL NUMBER 12. BUDGET DATA; ESTIMATED OBaCATIONS MAN TEARS DIRECT REIUBURSEUENT TOTAL PROF OTHER TOTAL FT' 57 $6,600 $3,312 BUDCSTED POSITIONS 19,912 o3 o6 ,9 PATIENT DATS PROP OTHER TOTAL FY' 57 0 1 1 0 13. BUDGET ACTiyiTT; RESEARCH /t7 REVIEW A APPROVAL /~7 BIOLOGIC STANDARDS Fl ADHINIS!mATION £7 PROFESSIONAL ft TECHNICAL ASSIST- __ ANCE n H. IDENTIFT ANT COOProATING UHIIS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIOI^, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FT 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO. (S): None Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment l) PDBLIG HEALTH SERVICE - - NATIONAL INSTITOTES OP HEALTH DJDIVIDTIAL PROJECT REPORT Part G: Honors, Awards & Publications l5.NHI-10li SERIAL NUMBER 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956; None 17. LIST HONORS AND AWARDS TO PERSONNEL RELATING TO THIS PROJECT DURING CALENDAR YEAR 1956: None Form No. ORP-1 Calendar Year 19^ October 1956 (Attacbnent l) FOBUC HEALIS SERVICE - - NATIONAL INSHTUEES OF HEALTH INDIVUXTAL PROJECT BEPCRT Part A. Project Description Sheet 1. HHT-inq SERIAL NIMBER 2. hational Heart Institute 3« Cho'^ical Fharriacolo^'- li^ LABORATORY, BRANCH, OR DEPARTMEaiT h. 5. . SECTION OR SERVICE LOCATION (IF OOBER IBAN BETHESDAJ 6. Hicrosomal Drug Snzyiiies - Mechanism of ftction niOJECT TITLE ?• Bernard B. Brodie and Bert K. La Du, Jr. PRINCIPAL INVESTroATOR 8. _ James Gillette OIHER INVESTIGATORS 9< IF OHIS PROJECT RESEMBLES, COMPLEMENTS, OR PARALLELS RESEARCH DONE ELSl^fflERE IN THE PUBLIC HEAI/EH SERVICE (WIOBOUF INTERCHANQE OF PER- SONNEL, FACILITIES OR RJNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WIIHIN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Ob,-]' actives; To establish how \Qrious types of drugs are metabolized in the body and whether specific detoxication mechanisms exist. Methods Employed; Drug metabolism pathvays are studied in vivo and in vitro and enzyme systems catalyzing these reactions are studied in detail. Metabolic products are rieasured by specific raicrochemical methods o Ma^ior Findings: Many drugs are i.-.etabclized by liver niicrosoi.ies and require TFKH and oxygen, A study of these requirements has shovm HHI-105 SERIAL NO. that microsomes contain a TPNH oxidase which yields peroxide. The participa- tion of TPHH oxidase in drug metabolism is indicated since compounds which inhibit TPNH oxidase also inhibit drug metabolism. The possibility that the drug enzymes are a series of peroxidases is unlikely since enzymatically generated peroxide cannot replace TPNH. Significance to HEART Research; Most drugs are extensi"sely metabolized in the body and their pharmacologic effectiveness depends in part on how ef- fectively these detoxication mechanisms operate. Understanding these mech- anisms may be helpful in developing new drugs of longer or shorter duration. Since the detoxication mechanisms vary in different animal speciesj, the observed differences in toxicity and response to drugs in different species may now be explained on a biochemical level. Proposed Course of Project; During the coming year several problems to be in-«estigated are: (l) How many types of drug metabolism are present in liver microsomes, (2) are these special mechanisms for drugs and foreign compounds, and (3) how do they operate (mechanism)? Form No. ORP-1 October 1956 (Attachment I) PUBLIC HEALTH SERVICE - - NAnONAL INSTITOTES OF HEALTH INDIVIDDAL PROJECT REPORT Part B: Budget Data 11. NHl-105 SERIAL NUMBER 12. BUDGET DATA; ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FY' 57 -$7,200 $3,594 BUDGETED POSITIONS $10,794 .6 0 ,6 PATIENT DAYS PROP OTHER TOTAL FT' 57 1 0 1 0 13. BUDGET ACTIVITY; RESEARCH /Y7 REVIEW & APPROVAL HI BIOLOGIC STANDARDS /~7 ADMINISTRATION CJ PROFESSIONAL & TECHNICAL ASSIST- ANCE n 14.. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IP COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S): None Form No. ORP-1 Calendar Tear 1956 October 1956 (Attaehsent I) FD6LIC HEALTH SERVICE - - NATKfflAL TS^TLTOTES OF HEALIB ISDinOQAJj PROJECT BEPORT Fart Cj Honors, Awards & Publications 15. HHI-10$ SERIAL mniBER 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS FBOJECT DURING CALENDAR YEAR 1956: The Oxidation of Drugs by Liver Microsomes: On the Role of TPNH and Oxygen. J. R. Gillette, B. B. Brodie, and B. K. La Du. Journal of Pharmacology and Experimental Therapeutics, in press. 17. LIST BDiKSS AND Al&RDS TO PSSOHNEL RELATING ID THIS PBOJECT DQBIBG CALENDAR TEAR 1956: None Porn Mb. (»P-1 Calendar Year 1956 Octolier 1956 (AttEtctaBient I) PUBLIC HEALIH SERVICE - - NATIONAL INSTITlfCES OF HBALIH INDIVUXJAL PROJECT REPORT Part A. Project Description Sheet 1. nhi-i n6 SERIAL NIB4BER 2. Mational Heart Institute 3« Chemical Pharmacology INSTITOt^ (A DIVISION LABORATORY, BRANCH, OR DEPARTMEINT I*. Clinical Pharmacology 5. Goldwater Memorial Hospital, SECTION OR SERVICE LOCATION (IF OOBER OSAN BEIHESDAJ New Yorks New York 6, Studies with Intra -venous Anesthetics PROJECT TITLE 7. Bernard B. Brodie and J, Jo Burns 8. PRINCIPAL INVESTSIATOR OIUEK nVESnOATOBS 9. IF IBIS FROJBCT RESEMBLES, CQMFLBMENTS, OR PARAXIALS RESEARCH DONE ELSEHHERE IN THE PUBLIC HEALTR SERVICE (WITHOUT INTERCHANQE OF E^- 8CMNEL, FACIUTIES OR FUNDS), IlffiMTIFY SUCH RESEARCH: (BT SERIAL NO.(S) IF WmUM HIH). 10. PROJECT DESCRIPTION (SEE INSTOUCTIOlfS): Objectives; A study of the physiologic disposition and intermediary metabolism of various barbiturates is intended to derive fundamental information concerning the pharmacology of intravenous anesthetics and to provide direction for the development of better intravenous anesthetics. There is a need for a potent intravenous anesthetic which may be used in surgical procedures of long duration. In this respect, an effort is being made to find a nonbarbiturate anesthetic since it has become clear that barbiturates as a class are slowly metab- olized and exert a hypnotic and not a truly anesthetic action. NHI-106 SERIAL NO. Methods Employed; Chemical assay of drugs and their metabolites in blood and tissues. Ma.ior Findings; Previously we reported that the rapid onset of action of thiopental in anesthesia is due to the speed with which the drug passes into the brain. In fact, the only barrier appears to be the rate of cerebral blood flov;. It has now been found that other intra- venous anesthetics used in the operating room including Evipal, Surital, Kemithal, Dolitrone and K-Methyl Thiopental also owe their rapid onset of action to rapid penetration into the brain. These anesthetics all have a high degree of fat solubility which apparently accounts for their rapid passage into the brain, and determine their ultra short-acting properties in anesthesia due to their extensive localization in body fat. Significance to HEART Research; The action of anesthetics on the cardiovascular system in some instances is responsible for their toxicity. Better and safer anesthetics are therefore being sought. Proposed Course of Pro.iect; Further studies are planned to relate plasma levels of thiopental to electric activity of the brain as measured by EEC pattern. Preliminary results show that no correlation exists, presumably due to development of acute tolerance. These findings are of considera ble interest because they may afford an experimental procedure to study this phenomenon of importance to anesthetic agents in general. Form No. ORP-1 October 1956 (Attachment I) POBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. ^NHI-ig6 ll^ SERIAL NUUBER 12. BUDGET DATA; ESTIMATED OBLIGATIONS MAN YEARS DIRECT REBSBURSEUENT TOTAL PROF OTHER TOTAL FT' 57 $6,000 $309 BUDGETED POSITIONS 16,309 o4 o2 o6 PATIENT DATS PROF OTHER TOTAL FT' 57 1 0 1 0 13. BUDGET ACTIVITg; BESEARCH Rl BEVIEW & APPROVAL HI BIOLOGIC STANDARDS /~7 ADMINISTRATION £7 PROFESSIONAL & TECHNICAL ASSIST- ANCE n L4.. IDENTIFI ANI COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OIHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FT 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S): Drso Ee Ho Papper and Lo Mark, Department of Anesthesiology, College of Physicians and Surgeons, Colnmbia University, and New York University Research Service, Goldwater Msmorial Hospital o Form No. ORP-1 Calendar Tear 1956 October 1956 (Attaehment I) PUBLIC HEALTH SER7IGE - - HATIQKAL INSTITTTTES OF HEAL3H INDIVIDnAL PROJECT REPORT Part C: Honors, Awards & Pablications 15. HHI-106 SERIAL NDIBiE 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS FROU TEES PROJECT Waim CALENDAR YEAR 1956: Clinical Application of Studies on the Physiologic Disposition of Thiopental, L, C. Mark, Jc Jo Bimsp B. B. frodie, and E. Me Pappero No Y. State Journal of Medicine, 56s 2819-2822, 1956. The Passage of Thiopental into the Brain. Lo C. rferk^, Jo Jo Burnsj. C. lo CampomaneSi, S. Ho Ngai, No Trousof, E. Mo Papper and B. B. Brodie. Journal of Pharmacology and Experimental Therapeutics, in press. 17. nST HONORS AND Al&RDS TO PESSORNEL REL&TING TO THIS PROJECT DUBBR CALENDAR YEAR 1956: None Fozm No. GBP-1 Calendar Year 19^6 October 1956 (Attachment l) FOBLCC HEALIH SERVICE - - NATIONAL TSSflTimSS OF tOSAUm IMDIVOXJAL FROJECT BEPCRT Fart A. Project Description Sheet 1. NHI^IO? SERIAL NUMBER 2. National Heart Institute 3. Chemical Pharmscology INSTITblg (A DVnSL(m LABORATORY, BRANCH, OR DEPARTMEair k, 5. SBCmOH OR SERVICE LOCATION (IP OOSER IfiAN BBIHESDAJ 5, Comparative Biochemistry of Driig Metabolism KtOJECT TITI£ — — — 7. Dr. Bernard B, Brodie PRINCIPAL INVESTS3AT0R 8. J^«.JiSfl.JL^-Q.%i^%lLt§.. OIHER INVESnOAIORS 9> IF THIS PROJECT RE3Q4BIES, COMFl£MENTS, OR PARALLELS RESEARCH DONE EISEUHERE IN THE PUBLIC HEAUH SERVICE (WITHOUT INTERCHANQE OF PER- SONNEL, FACILITIES OR FUNDS), IDENTIFY SUCH RESEARCH: (BY Sm^AL NO.(S) IF WITHIN NIH). 10. PROJECT DESCPJFTION (SEE INSTRUCTIONS): Objectives To investigate the specificity of enzyme systems responsible for the metabolism of a variety of foreign alkylamine compoiinds snd their differentiation from the systems by which normally occurring alkj'-lamines are metabolized. Methods Employed g Isolation of particulate cell fractions by the method of Schneider and Hogeboom from various animal tissues. The oxidation of various alkylamine compounds was determined by me?isuring substrate or product by specific chemical methods « NHI-107 Serial Number Major Findings; The lack of specificity of dealkylation of foreign com= pounds , observed in mammalian liver micros ones may in part be e^lainsd by the presence of more than one enzyme. There are at least two dealkylating enzymes having the same requirements, active on a wide spectrum of alkyl- amine coinpounds, only one of which is sensitive to inhibition by SKF 525-A. A study of the distribution of the microsomal enzyme systems for oxidative dealkylation of drugs in various species of the phylogenetic scale indicates that the dealkylation systems first appear to any appreciable extent in lower foims of terreslrial life, with more efficient oxidation occurring in higher forms. In aquatic species, such as fish, frog and salamander, a mechanism of excretion exists, and the foreign compounds studied were excreted imchanged. The close association between the development of oxidative systems for the metabolism of foreign compounds and the needs of species for systems of water retention^ as well as tJie fact that the oxidative systems cannot be associr ted with normally occurring compounds, suggests the evolutionary developnent of detoxication, non-specific in character, for rendering water-soluble compounds which would otherwise be toxic to the species. Significance to HEART Researchg The accumulating evidence would suggest the presence in the body of oxidative systems evolved for the purpose of species preservation. A better understanding in the use of drugs can be obtained in knowing the character and specificity of a syston evolved for its detoxication. Proposed Course of Projects The distribution of other microsomal enzyme systems, such as side-=>chain oxidation, hydroxylation and ether cleavage will be sou^t in various species of the phylogenetic scale, and other mechanisms of detoxication will be investigated in species failing to demonstrate de- alkylation and other oxidative processes associated with mammalian liver microsomes. Consideration will be given to the presence of detoxication systems in species which undergo metamorphosis, giving rise to a change from an aquatic to a terrestrial existence, as in the toad, for example. Form No. ORP-1 October 1956 (Attachment I) PUBLIC TTRAT.TH SERVICE - - MTIOSAL INSHTDTES OP HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. MHI-107 SMIAL NUUBER 12. BUDGET DATA; ESTnJAThO) OBLIO&TIONS MAN TEARS DIRECT REIMBURSEUENT TOTAL PROP OTHER TOTAL FY' 57 $13,300 $6,695 BUDGETED POSITIONS $19,995 1.1 0 lol PATIMT DATS PROP OTHER TOTAL FT' 57 1 0 1 0 13. BUDGET ACTIVITT; RESEARCH /T7 REVIEW & APPROVAL HI BIOLOGIC STANDARDS Fl ADMINISTRATION £7 PROFESSIONAL & TECHNICAL ASSIST- ANCE n H. IDENTIPT ANT COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FT 1957. IF COOPERATING UNIT IS T?ITHIN Hffl INDICATE SERIAL NO.(S): None Form No. ORP-1 Calendar Tear 1956 October 1956 (Attachment l) PDBLIC HEALTH SERVICE - - NATIONAL INSTITQTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15.NHI-107 SERIAL NUMBER 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: None 17. LIST HONORS AND AWARDS TO PERSONNEL RELATING TO TEES PROJECT DURING CALENDAR YEAR 1956: None row ». CRP-l Calendar Year 1956 October 1956 (AttackoMit I) FOBLIC SEALIH SERVICE - - NATiaUL IBSTITUIES OF HEALTH IHDIVIDDia. PROJECT BEPCBT Part A. Project Description Sheet 1. NHI-I08 SERIAL NIMBER 2. National Heart Institute 3. Chemical Pharmacology B^ffOKTSTMWSraS LABORATORY, BRANCH, OR DEPARTMENT 1^, Pharmacodynamics 5, ■ _^ mBHarSO^WCS LOCATIOH (if other OBAIf Biii'J'iMDA) 5 studies on Length-Tension CTirves for Cardiac Muscle in vivo IftOJBCT TITX£ •7, -Marion deV, Cotten PRINCIPAL INVESTIGATOR _— — , 8. OIHER INVESnOATORS 9. IF THIS PROJECT RESEMBIES, C0MFI£MEIIT8, OR PARALLELS RESEARCH DGNE EL3EUHERE IN THE PUBLIC HEALTH SERVICE (WITHOUT INTERGHANOE OF PER- SONNEL, FACILITIES OR RINDS ), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). PROJECT DESCRIPTION (SEE INSTRUCTIONS): Objectives g The objective of this project is to determine whether length- tension curves for cardiac ventricular muscle in vivo may possibly serve as a measure of the functional state of cardiac muscle under variovis conditions. Methods Eknployed; The experiments were conducted in anesthetized dogs with intact nervous and circiilatory systems. The blood pressure w*s measTired in the usual manner with an electronic pressure transducer. Length- tension curves for both the right and left ventricle were obtained by progressively stretching the segment of muscle directly between the two points of attach- ment of a strain gauge arch. Major Findings; Increasing the initial length of ventricular muscle in small increments results in a progressive increase in contractile force until lengths of between UO-60 per cent above the control initial length have been attained. Stretching the muscle segment beyond these limits results in a progressive HHI°108 .Serial Nomber decline in the contractile force » These length= tension curves are con= aidered to represent anothar expression of Starling's Law of the heart. Stretching muscle segments in four or more areas of .the ventricular muscle gave a series of length- tension curves with similar contours, but which showed moderate quantitative differences in height. These quantitative variations indicated that the use of length-tension. curves as a measure of the function state of cardiac muscle can only be of value when the responsiveness of the muscle is markedly altered. Temporary occlusion of a coronary artery supplying the area of heart muscle under test, resulted in the expected development of cyanosis and localized systolic bulging of the affected muscle. Progressive stretching of such ischemic muscle did not result in an increase in contractile force and, therefore, the length-tension curve was essentially flat. Restoration of the KLood supply within thirty minutes following occlvision resulted in a return to a •normal" length^ tens ion curve. Significance to HEART Research s Previously, it has been necessaiyto infer the functional state of cardiac muscle from its ability to operate against various stress loads. However, the function of the heart under conditions such as stenosis of an outflow tract may not present a reliable picture of the actual state of the myocardium. It is anticipated that measurement of length=tension, cirpves for ventricular. muscle may provide a more direct method for assessing the functional state of cardiac muscle under various abnormal circulatory states. Proposed Course of Projects Additional experiments will be conducted to determine whether cardiac muscle is altered sufficiently under various abnormal circulatory states to be detected from changes in length^tension curves. These conditions will include coronaiy artery constriction, hyper= thyroidism, acute and chronic anemia and heart failure produced both in the intact dog by pulmonary stenosis and in the heart=lung preparation of the dog. Form No. ORP-1 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NAnONAL INSTITOTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. Mil-1G3 SERIAL NUIUIBER 12. BUDGET DATA; ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FT' 57 13,800 $1,675 BUDGETliD POSITIONS $5,475 o2 o2 o4 PATIENT DAIS PROP OTHER TOTAL FT' 57 0 0 0 0 13. BUDGET ACTIVITY; RESEARCH HP REVIEW & APPROVAL / 7 BIOLOGIC STANDARDS Fl ADMINISTRATION EJ PROFESSIONAL & TECHNICAL ASSIST- ANCE n H. IDENTIFT ANI COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OH OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FT 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S): None Form No. OHP-1 Calendar Tear 1956 October 1956 (Attachment l) PUBLIC BEALICB SS17ICE - - HA.TIOR&L INSTITQTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Alardg & Publleatlona 15.NHI-IO8 SERIAL NUMBES 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS FROH THIS PROJECT DTJRING CALENDAR lEAR JL956i None 17. LIST HONORS AND AW&BOS TO FEBSOHNEL RELATING TO THIS PROJECT DURING CALENDAR lEAR 1956: Nona Foxn' No. <»P-1 Calendar Year 1956 Octobftr 1956 (Attachment I) FOBIIC HEALTH SERVICE - - HATIONAL INSTITUIES OF HBALOB INDIVIIXJAL PROJECT REPORT Part A. Frojact Description Sheet 1. NHl-109 SERIAL NUMBER 2. National Heart Institute 3- Chemical Pharmacology INSTITOtS (A DIVISldN ~ LABORATORY, BRANCH, OR DEPARTMEOT If, Pharmacodynamics 5« SECTION OR SERVICE LOCATICN (IP OTHER THAN BETHESDAJ 6, studies, on the Pharmacology of Alkaloids Derived from Ormosia Panamensis PROJECT TITLE 7. Gertrude P. Quinn and Keil C. Moran PRINCIPAL INVESTIQATOR 8. OIHER INVESnOATORS 9. IF OSIS PROJECT RESEMBLES, CONFI£MENTS, OR PARALLELS RESEARCH DONE ELSEUHERS IN HOB FUBUC HEALTO SBRVICE (WITOOUT INTERCHANQE OF PER- SONNEL, FACILITIBS OR FUNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WI1HIN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Objectives: Previous studies have shown that oxypanamire, an K-oxide, formerly referred to as IiHI-196, is a potent hypotensive agent In animals. The pharmacological actions and mechanism of action have been described by Moran, et al. During the course of study, panamine was found to be a neuromuscular and ganglionic blocking agent and this action \-ias attributed to the presence of the K-oxide in the molecule. During the interval covered in tiiis report, the study concerned with a characterization of oxypanamine as a neuromuscular and ganglionic blocking agent has been completed. Preliminary studies were made on the actions of the Darcnt alkaloid, pansmine, S-methyl panamine and the air oxidation product of N-methyl panamine. Their HHI-109 SERIAL RO. actions were compared to those of ojgrpanamine, the air oxidation product of panamineo Methods Employed; Conventioral physiological techniques for recording blood pressure^, respiration and reuromuscular and ganglionic transmission were employed. The rabbit head-drop assay was used as a further measure of neuromuscular blockade » Ma.ior Findings; In doses far exceeding the hypotensive dose, oxypanamine has been shovna to be a neuromuscular and ganglionic blocking agent in b)th cats and dogSo The mechanism of action of the neuromuscular blockade was demonstrated to be essentially similar to that of d-tubocurarine; i.e., a competitive inhibition of acetylcholine at the myoneural junction. The rabbit head-drop assay was used to compare the relative potencies of several derivatives of panamine. No effect was produced with 50 mgm/kgm panamine whereas 1 mgm/kgm of its M-oxide, oxypanamine, produced rabbit head -drop o The head-drop was produced with 22 mgmAgni K-methyl panamine and 1 mgm/kgm of the air oxidation product of K-methyl panamineo The cardiovascular actions of the air oxidation product of N-methyl paramine in a dog were similar to those described for oxypanamine and the effective doses were equivalent » Neither panamine nor N-methyl panamine exhibited the cardiovascular actions of their N-oxide derivatives. There is some e^Tidence to suggest that oxypanamine causes respiratory paralysis by a depression of the respiratory center as well as by neuro- muscular blockadeo Significance to HEART Research! Oxypanamine has been shown to be a potent hypotensive agent in animals » The pharmacological propertiesi, the toxicity and mechanism of action have been extensively studied in this and previous research periods o Preliminary studies were made with some derivatives of panamineo These compounds have been found either to be inactive or similar in action to oxypanamine and therefore are probably of no therapeutic value o All the pharmacological actions of oxypanamine may possibly be attributed to the presence of the N-oxide in the molecule. Studies with these drugs have been discontinued o Proposed Course of Pro.ject: The project has been completed and terminated. Form Ho. OBP-1 October 1956 (Attachment I) PUBLIC HEALTH SERVICE - - NATIOSAL INSTITUTES OF HEiLLTH INDIVIIJUAL PROJECT REPORT Part B: Budget Data li. NHI - 109 SEHIAL NUMBER 12, BUDGET DATki ESTIMATED OBLIO&TIONS M&NIEABS DIRECT REIMBURSEMENT TOTAL ^F 'OTHER TOXU. FI'57 $12,600 $5,207 BUDGETED POSITIONS $17,807 .4 l\2 1 patimtWis PROF 0TH51 TOTAL n'57 1 1 2 None 1.6 13. BUDGET ACTiyiTT; HWtRARBH /k/ REVIEW & APPROVAL /Z7 BIOLOGIC STANDARDS /~7 ADHIHISTRATIOI £J PROFESSIONAL & TECHNICAL ASSIST- ' ANCE /7 14. IDERIIFr ART GOOPERATEHG UNITS OF THE PUBLIC HEALTH SESVIGS, OS OTHER ORGANIZATIONS, FROVIDIMG ITJNDS, FACILinES, OR PERSONNEL FOR THIS PROJECT IN FT 1957. IF GOOFEBATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S}: Laboratory of Chesaisfery of Natural Products, NHI-77 Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITDTES OF HEALTH INDITUJUAL PROJECT REPORT Part C: Honors, Awards & Publications 15. KHI-109 SERIAL NUUBER 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS FROH THIS PROJECT DURING CALENDAR TEAR 1956: Manuscript in preparationo 17. LIST HONORS AND AWARDS 10 PERSONNEL RELATING TO THIS PROJECT DURING CALENDAR TEAR 1956: None Foxm No. ORP-l CcLLendar Year 19^ October 1956 (Attcudnent I) FOBLEC HEALIB SEEiVICE - - AAHCRAL XHSTITUIES OP HEALTH mmvnxiAL iIboscs.bespcbis Part A. Project Description Sheet 1. HKE-llQ SERIAL miBER 2. National Heart Institute 3» Chemical Pharmacology jHsmUM (Ht DlhriMda labqraxcry^ branch, cr M^AKiMbwr it. Clinical Pharmacology 5, Goldgater Memorial Hospital, N.Y.,N.Y. SBCfAtm OR SBRVI^ lOCMXCl (Z7 OSBER aSAN BE!IHESDAJ 6, studies on Anti-Rheumatic Drugs PROJECT fmjE 7. Bernard B. Brodie and John J, Bums PRINCIPAL INVE3T1DA3IOR 8 J'^Ji«ct Description Sheet 1. HHI~lli SERIAL NUMBER 2. National Heart Institute 3« Chemical Pharmacology iNsnTbtig CiA divis16n " laboratory, branch, or departmemt h, PhariLacodynamics 5« SkcnOK OR &ia« 1956. 17. LIST HONORS AND AWARDS TO PERSONNEL REUTING TO THIS PROJECT DURING CALENDAR YEAR 1956: None Form No. (BP-l Calendar Year 1956 October 1956 (Attachment l) FUBUC HEALm SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. NHI-^llij 8. SERIAL NUMBER 2. National Hem-t institute 3» Chenical Pharniacolo^'- INSTITUTE (H^ DIVISI6n LABORATORY, BRANCH, OR DEPARTMENT »^. 5. , _^ SECTION OR SERVICE LOCATICaj (IF OTHER THAN BETHESDA} 6. studies on the Mechanism of Action of Steroid Hormoneso Role of Steroids PROJECT TITLE in Cation Transport 7. filwood 0, TituSg Elliott ^chiffmann ^ PRIHCIPAL INVESTIGATOR ' """^ ' OIHER INVESTIGATORS 9 . IF THIS PROJECT RESEMBLES, COMPLEMENTS, OR PARALLELS RESEARCH DONE ELSEWHERE IN THE PUBLIC HEALTH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACILITIES OR lUNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Objectives g Certain adrenocortical hormones and related synthetic steroids profoundly affect the passage of cations and water through cell membra nese The cardiac glycosides appear to block the active transport of potassium into a variety of cells. Recent studies suggest that these transport phenomena may involve phospholipids and that the steroids may act by reason of their influence on the carrier function of the lipids. This project is designed to test this hypothesis. Serial Number Methods Eknployeds Paper and column chromatographic isolation of phospho- lipids and phosphorus containing degradation products thereof* Measurement of radioactivity of P^ containing stibstances. Flame photometric estimation of sodium and potassium. Studies of phospholipid turnover in isolated tissues under various conditions such as electrical stimulation, steroid intoxication, etc , Major Findings; The project is being initiated, A variety of phospho- lipids has been isolated from beef heart to serve as model substances. Significance of HE^RT Research; Both the mechanism of cation transport and the mechanism of action of the cardiac glycosides are presently obscure. It is possible that a study of the role of phospholipids in membranes may clarify both phenomena. Proposed Course of Projects If phospholipids are involved in cation transport across membranes, two types of mechanism may be conceived; (a) A dynamic role in which cations are transported as lipid complexes. Synthesis of carrier on one side of the mem= brane and degradation on the other would provide a trans- port mechanism, (b) A static role in -vAiich phospholipid remains inert in the membrane and functions somewhat in the manner of an ion exchanger. Other biochemical functions such as generation of hydrogen ion internally and exchange of H"*" for other cations would provide a transport mechanism.. Since con- dition (a) would require that the passage of cations and effect of steroids thereupon should be reflected in the turnover of specific phospholipids, it is the easier hypothesis to test. The project will be initiated with a study of the effects of steroids, therefore, on phos- pholipid turnover. Form No. ORP-1 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NAnONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. MI-ll^ SERIAL NUMBER 12. BUDGET DATA: ESTIMATKU OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL Py'57 113,300 $6,695 BUDGETED POSITIONS $19,995 .8 o5 lo3 PATIENT DATS PROF OTHER TOTAL FI' 57 1 1 2 0 13. BUDGET ACTIVITT; RESEARCH /~77 REVIEW & APPROVAL ZZ7 BIOLOGIC STANDARDS /~7 ADMINISTRATION ny PROFESSIONAL & TECHNICAL ASSIST- ANCE /~7 U. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S): None Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment I) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15.NHI"llii SERIAL NUMBER 16. LIST PUBLICAnONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: None 17. LIST HONORS AND AWARDS TO PERSONNEL RELATING TO THIS PROJECT DURING CALENDAR lEAR 1956: None Form No. ORP-1 October 1956 (Attachment l) Calendar Year 1956 PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. HHI-115 SERIAL NUMBER 2. National Heart Institute INSTITUTE (M DIVISION 3t Chemical Pharmacology LABORAT(»Y, BRANCH, OR DEPARTMENT k. SECTION OR SERVICE 5. LOCATION (IF OTHER THAN BETHESDAJ 6. studies on the Blood-Brain Barrier PROJECT TITLE 7. Dr. Steven E. Mayer PRINCIPAL INVESTKATOR 8. OTHER INVESTIGATORS IF THIS PROJECT RESE34BLBS, COMPLEMENTS, OR PARALLELS RESEARCH DONE ELSEWHERE IN THE PUBLIC HEALTH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACILITIES OR RJNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). 10. PROJECT DESCRIPTI(»I (SEE INSTRUCTIONS): Objectives s To determine some of the factors involved in the selective lack of permeability of the central nervous system to substances in the circulation. Consideration of such variables as protein binding? lipid solubl ity, etc., was indicated in order to permit a quantitative appraise] of the relationship between chemical structure and brain permeability o Methods Qnployed: In vivo animal experiments and determinations of physico-chemical constants o MHI-115 SERIAL No. Major Findings; The blood-pbfain barrier can be studied from two aspects: its action on impeding the rate of entrance of substances into the brain, and its influence on the final steady state concentration reached in the central nervous system. Any evaluation of brain permeability must involve a study of several different compartments between which inter- change occurs at different rates. One should not consider that the blood- brain barrier is merely a membrane which is less permeabLe than those found in the capillary walls of other tissues » Significance to HEART Research; Many drugs used in the treatment of cardiovascular diseases act on the central nervous system hit little is known of the requirements for a compound to pass through the blood- brain barrier. Proposed Course of Prciect; The project is being terminated. Form No. ORP-1 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. J^HI-115 SERIAL NUMBER 12. BUDGET DATA! ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL PI' 57 $6,500 $3,242 BUDGETED POSITIONS $9,742 .3 c5 .8 PATIENT DAYS PROF OTHER TOTAL FT' 57 0 1 1 0 13. BUDGET ACTIVITY; RESEARCH /77 REVIEW & APPROVAL ZZ? BIOLOGIC STANDARDS /~7 ADMINISTRATION no PROFESSIONAL & TECHNICAL ASSIST- ANCE nj H. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S): None Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment l) PDBLIC HEALTH SERVICE - - NA.TIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15. NHI-115 SERIAL NUMBER 16. UST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: The Permeability of the Central Nervous System to Some Pharmacologic Agents. S. E. Mayer and R. P. Maickel. Journal of Pharmacology and Experimental Therapeutics, to be publishedo 17. UST HONORS AND AWARDS TO PERSONNEL RELATING TO THIS PROJECT DURING CALENDAR YEAR 1956: None Form No. ORP-1 Calendar Year 195^6 October 1956 (Attachment l) PUBLIC HEALOH SERVICE - - NATIONM. INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. NHI-116 SERIAL NUMBER 2. National Heart Institute 3« Chemical Pharmacology INSTITUTE OR DIVISION LABORATORY, BRANCH, OR DEPARTMENT ^' ?» , SECnCW OR SERVICE LOCATION (IF OTHER THAN BETHESDA) 6. Role of Norepinephrine in the Central Nervous System PROJECT TITLE 7. Dr, P. A. Shore PRINCIPAL INVESTIGATOR ' ' 8. OOBER INVESTIGATORS 9' IF THIS PROJECT RESESffiLBS, COMPIEMENTS, OR PARALLELS RESEARCH DONE ELSEWHERE IN THE PUBLIC HEAURI SERVICE (WIIHOUT INTERCHANGE OF PER- SONNEL, FACILITIES OR RJNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Objectives g Norepinephrine has been implicated as a possible neurohumoral agent in the brain. The concept has been developed that serotonin and nor- epinephrine may be chemical transmitters of mutually antagonistic centers in the central autonomic nervous system, and that reserpine acts by an alteration of serotonin in one center while chlorpromazine may act by in- hibition of norepinephrine in the other. The action of many centrally acting drugs could conceivably be explained in terms of an interaction with norepinephrine in the brain. The development of a physico-chemical method for norepinephrine in brain has made possible studies, on a bio- chemical level, of possible interactions of drugs with brain norepinephrine. i;HI-ll6 Serial fvumber Methods ^ployed; Various drugs are administered to animals and the effects on norepinephrine in the brain are determined,, Major Findings s This is a new project made possible by the development of assay procedure for norepinephrine, It has already been found however, that administration of reserpine depletes rabbit brains of norepinephrine J confirming previous observations of othar investigators. Significance to llalART Research; This study is of significance and it will aid in understanding the role of norepinephrine, a substance believed to be implicated in many body functions including control of blood pressure* Proposed Course of Projects The effects of various drugs on brain catechol amines will be investigated, A correlation will be made of the pharmacologic effects of reserpine and the alteration of norepinephrine levels in brain > Form Wo. ORP-1 October 1956 (Attachment I) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. NHI-116 SERIAL NUMBER 12. BUDGET DATA! ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FT' 57 110,800 $5,426 BUDGETED POSITIONS $16,226 .2 1.3 1<.5 PATIENT DAIS PROP OTHER TOTAL FT' 57 0 2 2 0 13. BUDGET ACTIVITY; RESEARCH lYl REVIEW & APPROVAL HI BIOLOGIC STANDARDS HI ADMINISTRATION nj PROFESSIONAL & TECHNICAL ASSIST- ANCE n 14. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S): None Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment l) PDBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15 . NHI-II6 SERIAL NUMBER 16. LEST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: None 17. LIST HONORS AND AWARDS TO PERSONNEL REUUNG TO THIS PROJECT DURING CALENDAR YEAR 1956: None Form No. ORP-1 Calendar Year 19^6 October 1956 (Attachment l) PUBUC HEALOH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. NHI-117 SERIAL NUMBER 2. National Heart Institute 3» Chemical Pharmacology INSTITUTE 6R DIVISI6N LABORATORY, BRANCH, OR DEPARTMENT ^. , 5. , SECTION OR SERVICE LOCATION (IF OTHER THAN BEOHESDA) 6. The Metabolism of Toluene and Some Alkylbenzenes by Mammalian Liver PROJECT TITLE Preparationse 7. James Gillette PRINCIPAL INVESTIGATOR "^ ' 8. OTHER INVESTIGATORS 9 . IF THIS PROJECT RESE^ffiLES, COMPLEMENTS, OR PARALLELS RESEARCH DONE ELSEWHERE IN THE PUBLIC HEALTH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACILITIES OR RJNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Objectives; It is known that animals can oxidize toluene to benzoic acid. However, little is known about this biotransformation on an enzyme level. Since many foreign compounds are metabolized by enzyme systems localized in the microsomal fraction of liver, it is of interest to determine whether toluene is metabolized by a microsomal enzyme system. NHI-117 Serial Kuir.ber Iletbods jjmployed; Standard biochemical and chemical techniques will be uJv>loyed in this study.. Major Findings; The 9,000 x g supernatant frection of rabbit liver homogenate contains an enzyme systan which C'':talyzes the oxidation of toluene to benzoic acid . Since nicotin?inide, ijhich inhibits the destruction of DPN and TPII, is required for this biotransformation, it is probable that either one or both of these coenzymes are necessary. Significance to H!jIART Research; A number of alkylbenzene derivatives are used as drugs in medicinal practice. This study should help us to understand how these pharmacolop:ical agents are metabolized on an enzyme level. Proposed Course of Project; The pathway by which toluene is oxidized to benzoic acid will be studied. The intercellular localization and the requirements for the enzymes involved in this biotransforne tion will be determined. Other alkylbenzenes ^^rill be used as possible substrates for this enzyme system. Form No. ORP-1 October 1956 (Attachment I) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. ™I-117 SERIAL NUMBER 12. BUDGET DATA; ESTIMT]!!) OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTA.L PROF OTHER TOTAL FI'57 13,700 $1,332 BUDGETED POSIHONS 15,532 .3 0 .3 PATIENT DAYS PROP OTHER TOTAL FI'57 0 0 0 0 13. BUDGET ACTIVITY; RESEARCH ZZ7 REVIEW & APPROVAL fZJ BIOLOGIC STANDARDS /~7 ADMINISTRATION EJ PROFESSIONAL & TECHNICAL ASSIST- ANCE nj U. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S); None Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment I) PDBUC HEALTH SERVICE - - NATIONAL INSTITUTES OP HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15.NHI-117 SERIAL NUMBER 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: None 17. UST HONORS AND AWARDS TO PERSONNEL REUTING TO THIS PROJECT DURING CALENDAR YEAR 1956: None Form No. ORP-1 Calendar Year 19^6 October 1956 (Attachment l) PUBLIC HEALOH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. NHI-118 SERIAL NUMBER 2. National Heart Institute 3- Chemical Pharmacology INSTITUTE OR DIVISION LABORATORY, BRANCH, OR DEPARTMENT h. ^ 5. , ^ SECTION OR SERVICE LOCATION (IF OTBER THAN BETHESDA) 6. Mechanism of Action of Reserpine - Studies of the Biochemical Effects PROJECT TITLE of Reserpine Influencing Serotonin 7. Parkhurst A. Shore PRINCIPAL INVESTIGATOR ' ' 8. OOSER INVESTIGATORS 9' IF ^raiS PROJECT RESEMBLES, CCMPI£MENTS, OR PARALLELS RESEARCH DONE ELSEWHERE IN THE PUBLIC HEALTH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACILITIES OR RJNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WiraiN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Ob.iectives; To study the biochemical mechanisms whereby reserpine causes a prolonged pharmacological effect and effect on serotonin levels in the body. Methods Employed; Reserpine is administered to animals and the effects on serotonin in the body are studied. Ma.jor Findings; Previous reports have described the prolonged pharmacologic effects and depletion of serotonin in the brain, which persist after adminiatered reserpine is no longer detectable NHI-118 SERIAL NO. in the brainc Also described were experiments demonstrating that reserpine causes a marked deficiency in the ability of blood platelets and brain to take up added serotonin. This action may be the primary effect of the drug. It has been thought by other investigators that perhaps reserpine causes its prolonged pharmacological effects and depletion of serotonin by means of a metabolic product of the drug which might be undetectable by the usual analysiSo This has been shown to be unlikely as brain serotonin was observed to decline to the same extent whether 1 or 5 mg/kg of reserpine was administered to rabbits. The same intensity and duration of pharmaco- logic effects and the same time for the restoration of serotonin^ leTsels were seen fdHowingr the- two- different doses. It would be expected that the larger dose of reserpine would have resulted in the formation of more of a metabolic product than the smaller dose and therefore should have caused a more prolonged response o The structural specificity required for release of serotonin has been further emphasized. It has been found that none of the following drugs cause the release of serotonin. Central stimulants (leptazol, picrotoxin), other tranquilizing agents (chlorpromazine, meprobamate, benactyzine), or the serotonin analogue and anti-hypertensive agent, Benzjrl Anti-Serotonin o Experiments on the effect of reserpine on serotonin of various speicies have shown that serotonin is almost completely released follovdng adminis- tration of reserpine to rats and hamsters. In chickens, however, it has been found that only about 65-70 per cent of apparent serotonin can be released following even very large doses of reserpine. It is hoped that ly using the chicken, "free" serotonin following reserpine may be distin- guished from "bound" serotonino Significance to HEART Research? This study is of significance in two aspects: (l) an understanding of the action of reserpine, a drug used in the control of hypertension and mental disorders, (2) understanding the normal function of serotonin^ a substance which is implicated in many body functions including control of blood pressure » Proposed Course of Project; Studies on the mechanism whereby reserpine exerts its pharmacologic effects and effects on serotonin will be continued o Form No. ORP-1 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - KAnONAL INSTITDTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. HEI~118 SERIAL NUMBER 12. BUDGET DATA; ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL PI' 57 $5,600 $2,819 BUDGETED POSITIONS $8,419 .3 .3 «6 PATIENT DAIS PROP OTSER TOTAL FT' 57 0 1 1 0 13. BUDGET ACTIVITT; RESEARCH /Y7 REVIEW & APPROVAL £Z/ BIOLOGIC STANDARDS /~7 ADMINISTRATION /U PROFESSIONAL & TECHNICAL ASSIST- ANCE /~7 14.. IDENTIPI ANI COOPERATING UNITS OP THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN PI 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S): None Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment I) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15. NHI-118 SEELIAL NUI/BER 16. UST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: Shore, P. A., Platscher, A., Tomich, E. G,, Carlsson, fi., Kuntzman, R., and Brodie, B. B. Ann. N. Y. Acad. Scl., in press, Brodie, B. B,, and Shore, P. A., Ann. N. Y. Acad. Scl,, in press. Shore, P. A., Pletsdier, A., Tomich, E. G., Kuntzman, R., and Brodie, B, B., J. Pharmacol. Expt. Therap. ]JL7: 232, 1956. Brodie, B. B., Shore, P. A., and Pletscher, A., Science 121, 992, 1956. Brodie, B. B., Tomich, E. G., Kuntzman, R,, and Shore, P. Ac J. Pharmacol, Expt. Therap., in press. Shore, P. A. and Brodie, B. B. Proc. Soc. Exp. Biol, and Med., submitted for publication. 17. LIST HONORS AND AWARDS TO PERSONNEL REUTING TO THIS PROJECT DURING CALENDAR YEAR 1956: Travel award for Dr. Parkhurst A. Shore to attend the Twentieth International Physiological Congress, July 29 - August Us 1956* Brussels, Belgium, Form No. QEtP-1 Calendar Year 19^ October 1956 (Attachment I) PUBUC HEAI/m SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. NHI~119 SERIAL NUMBER 2. National Heart Institute 3- Chemical Pharmacology * INSTITUTE 6ii DIVISION LABORATORY, BRANCH, OR DEPARTMENT h. 5. . , SECTION OR SERVICE LOCATION (IP OTHER THAN BETHESDAJ 6. The Enzymatic Oxidation of Benzyl Alcohol and Other Aromatic Alcohols PROJECT TITLE 7. James R. Gillette PRINCIPAL INVESTIGATOR 8. OTHER INVESTIGATORS 9 • IF THIS PROJECT RESEMBLES, COMPLEMENTS, OR PARALLELS RESEARCH DONE ELSEWHERE IN THE PUBLIC HEALTH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACILITIES OR fVNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Objectives; It is well known that benzyl alcohol and other aromatic alcohols are oxidized in vivo to their respective acids. However, very little is known about the metabolism of these compounds on an enzyme level. The purpose of this investigation is to study the enzymes in- volved in these biotransf ormations « Such a study may help us to under- stand the metabolism of a number of drugs. MHI~119 Serial Number Metho'is Employed; Standard biochamicil and chamicnl methrxjs will be employod . Major Findings; Rabbit liver horaogenate contains an enzyme system locelized in the 9,000 x g supernatant fraction, which oxidizes benzyl alcohol to benzoic acid. This system is stimiila ted by the addition of either DPN or to a lesser extent TPN. Furthermore, the DPN supplemented system is stimulated even more by the addition of methylene blue. These data may indicate that a dehydrogenase may particir>ate in the oxidation of benzyl alcohol » Significance to HEART Research; A number of drugs have aromatic alcoholic groups as a part of their molecular structure. Since the oxidation of thase groups may affect the activity of the drugs, it is important to study this type of reaction* Proposed Course of Project; The possible pathways in the biotransformation of benzyl alcohol will be studied and the enzymes involved will be determined, The metabolism of some other alcohols will be investigated. Form No. ORP-1 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. ™I-119 SERIAL NUMBER 12. BUDGET DATA; ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FI'57 $8,000 $3,347 BUDGETED POSIHONS $11,347 .5 .3 .8 PATIENT DATS PROF OTHER TOTAL FI'57 1 0 1 0 13. BUDGET ACTiyiTT; RESEARCH /x7 REVIEW & 'APPROVAL A~7 BIOLOGIC STANDARDS CJ ADMINISTRATION CJ PROFESSIONAL & TECHNICAL ASSIST- ANCE l_/ U. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO. (S) : None Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment I) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15.NHI-119 SERIAL NUMBER 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: None 17. LIST HONORS AND AWARDS TO PERSONNEL REUUNG TO TEES PROJEO i: DURING CALENDAR YEAR 1956: None Form No. ORP-1 Calendar Year I956 October 1956 (Attachment l) PUBLIC HEALIH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. NHI-120 SERIAL NUMBER 2. National Heart Institute 3, Chemical Pharmacology INSTITUTE (^ DIVISl6h LABORATORY, BRANCH, OR DEPARTMENT »^. 5. , , SBCnCW CR SERVICE LOCATION (IP OTBER THAN BETHESDAj 6. The Pharmacological Actions of Oxypanamine, NHI-196a an Alkaloid Derived PfiOJECT TITLE from Ormosia panamensis 7. Neil C. Moran 8. PRINCIPAL INVESTIGATOR Gertrude P. Quinn OTHER INVESTIGATORS 9. IF THIS PROJECT RESEMBLES, COMPLEMENTS, OR PARALLELS I^SEARCH DCm ELSEWHERE IN THE PUBUC HEAI/EH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACILITIES OR RJNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Objectives; With the discovery of oxypanaraine (NHI-I96) as an oxidation product of pansinine, a new alkaloid from Ormosia panamensis, a study of the pharmacological actions of oxypanamine was undertaken. Methods iimployeds Standard physiologic and pharmacologic techniques were employed for measuring blood pressure, blood flow, cardiac function, etQ. NHI°120 Serial Number Major Findings g Oxypanamine produces in dogs a con^lex pattern of actions including a fall in blood pressure, hemoconcentration, broncho constriction^ rise in pulmonary artery pressure^ stimulation of the small intestinej, cutaneous erythema and urticaria and in high doses neuromuscular and ganglionic blockade. It does not release histamine, does not block the autonomic nervous system and is active in spinal dogs. No direct vasodilation occurs when oxypanamine is injected into the femoral artery. The fall in blood pressure, broncho constriction, rise in pulmonary artery pressure and hemoconcentration are partially or completely inhibited by antihistamine dinigs. It is concluded that oxypanamine acts through a histamine mechanism. The compound is virtually inactive in rabbits, rhesus monkeys and. man. Significance to HEART Research; Primary significance is in the basic study of mechanians of eliciting a fall in blood pressure and in furthering knowledge of biological significance of histamine. Proposed Course of Projects Completed, Form No. ORP-1 October 1956 (Attachment I) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OP HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. tlHI-i20 SERIAL NUMBER 12. BUDGET DATA; ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FI'57 $8,600 $3,573 BUDGETED POSITIONS $12,173 .5 ,4 .9 PATIENT DAYS PROP OTHER TOTAL FT' 57 1 0 1 0 13, BUDGET ACTIVITY; RESEARCH >^~7 REVIEW & APPROVAL HI BIOLOGIC STANDARDS /~7 ADMINISTRATION EJ PROFESSIONAL & TECHNICAL ASSIST- ANCE n 14.. IDENTIFY ANY COOPERATING UNITS OP THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S); None Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH ■ t INDIVIDUAL PROJECT REPORT '*■■ Part C: Honors, Awards & Publications 15. NHI-120 SERIAL NUIflBER 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING ^CALENDAR YEAR 1956: \. Neil C. Mo ran, 'Jertnide P, Quinn and William M. Butler , Jr. Pharmacological Actions of Oxypanaminej, an Alkaloid Derived from the Seeds of Ormosia panamansis. Manuscript in preparation for J. Pham. and J^xper, Therap. Neil C. Moran, Gertrude P. Quinn and William M. Butler, Jro An -Evaluation of the Hist amine -like Actions of Oxypanamine , Manuscript in preparation for J. Pharm. and Exper, Therap. 17. UST HONORS AND AWARDS TO PERSONNEL REUTING TO THIS PROJECT DURING CALENDAR YEAR 1956: None Form No. QBP-1 Calendar Year 19^6 October 1956 (Attachment I) FOBLIC HEALOH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. NHI°121 SERIAL NUMBER 2, National Heart Institute 3, Chemical Pharmacology INSTITUTE OR DIVISION LABC^TORY, BRANCH, OR DEPARTMENT h. . 5. ^ SECnCW OR SERVICE LOCATION (IF OTHER THAN BETHESDA) g Studies on the Biosynthesis of Cardiotonic Steroids PROJECT TITLE Y^ ELwood 0, Titus and Elliott Schiffraann PRINCIPAL INVESTIGATOR ~~ ' 8. OTHER INVESTIGATORS 9> IF THIS PROJECT RESEMBLES, COMPLEMENTS, OR PARALLELS RESEARCH DONB ELSEWHERE IN THE PUBLIC HEALTH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACIUTIES OR FUNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WimiN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Objectives; The presence of a cardiotonic steroid in the South American toad represents one of the few examples of the existence of digitalis- like materials in animals, ' The biosynthesis of this material might illustrate a general scheme of cardiotonic steroid formation. For these reasons it was of interest to investigate the biological production of the cardiotonic lactones. NHI-121 Serial Number Methods Jtaployeds Synthesis of radioactively labeled precursors for administration to animals and in vitro preparations. Preparation of enzyme systems capable of in vitro synthesis of cardiac lactones. Chromatographic isolation and determination of radioactivity of cardiac lac tones » Major Findings g Cholesterol is a precursor of cardiac lactones in toads e Because of certain unique structural features of tie se lactones their synthesis represents a type of metabolic pathway not hitherto demonstrated in animals « Significance to HEART Researchs The mechanism for biogenesis of cardiac lactones in toads may exemplify a general metabolic pathway used for synthesis of these substances. As yet unidentified cardiotonic substances in mammalian tissue may resemble the toad lactones chemically. Proposed CoTirse of Projects The experiment with tritium to determine initial transformations of cholesterol is being carried on. It appears from recent results with cholesterol metabolism that some poly-hydro:gr sterols are intermediates. Work is conten^jlated using some of these compounds^ depending on the results of the tritium experiment. It is also contemplated to investigate possible relations between steroids and lipids in transport processes. Form No. ORP-1 October 1956 (Attachment I) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. MI -121 SERIAL NUlilBER 12. BUDGET DATA; ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FT' 57 $8,600 $4,299 BUDGETED POSITIONS 112,899 .7 0 .7 PATIENT DAYS PROF OTHER TOTAL FT' 57 1 0 1 0 13. BUDGET ACTIVITY; RESEARCH A7 REVIEW & APPROVAL HI BIOLOGIC STANDARDS /~7 ADMINISTRATION EJ PROFESSIONAL & TECHNICAL ASSIST- ANCE IZJ U. IDENTIFy ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S): None Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment I) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OP HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15.NHI-121 SERIAL NUMBER 16. LIST PUBLICAHONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: Siperstein^ M.D., Murray, A.VI. and Titus, E.G. The Biosynthesis of Cardiotonic Sterols from Cholesterol in the Toad, Bufo marinus . Archives Biochemistry and Biophysics (1956), in presso 17. LIST HONORS AND AWARDS TO PERSONNEL RELATING TO THIS PROJECT DURING CALENDAR YEAR 1956: None Form No. (BP-1 Calendar Year 19^6 October 1956 (Attacbtment l) PUBLIC HEALIH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. nhI-122 SERIAL NUMBER 2. National Heart Institute 3. Chemical Pharmacology INSTITOt^ (B DIVISI6N LABORATORY, BRANCH, OR DEPARTMEaiT ^' 5. ^ , SECnCN OR SERVICE LOCATION (IF OTHER THAN BETHESDA) 6. De-velopment of a Phy si op -Chemical Assay Procedure for Norepinephrine PROJECT TITLE and Epinephrine in the Brain 7- Parkhurst A. Shore „._««_—___-__-__ PRINCIPAL INVESTIGATOR 8. OTHER INVESTIGATORS 9. IF THIS PROJECT RESEMBLES, COMPLEMENTS, OR PARALLELS RESEARCH DOm ELSEWHERE IN THE PUBLIC HEAI/IH SERVICE (WITHOUT INTERCHANOE OF PER- SONNEL, FACILITIES OR RJNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WimiN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Objectives: In order to examine the proposed role for norepinephrine in the brain (see report entitled "Role of Norepinephrine In the Central Nervous System"), a simple physico-chemical method for the estimation of this substance in tissues it needed. Methods Employed; Optimal conditions for extraction of catechol amines, oxidation to a fluorescent material and determination of this fluorescence are studied. NHI-122 SERIAL NO. Major Findings; A technique has been developed to extract norepinephrine and epinephrine from brain tissue. This procedure is far superior to past methods for extraction as it involves extraction of these amines into an organic solvent rather than simply a precipitation of proteins. Based on this extraction, an assay procedure has been developed by modifica- tion of the usual process of oxidation of these catechol amines to form fluorescent products. The method appears to bs specific for the catechol amines. Ultraviolet activation and fluorescent spectra of the oxidation products of the substances extracted from brain are identical with the spectra of the oxidation product of norepinephrine. It appears that the catechol amine in rabbit is mostly norepinephrine, as the pH requirements for oxidation of the substance from train most closely resemble norepinephrine rather than epinephrine. Preliminary experiments indicate that the administration of reserpine to rabbits causes a depletion of norepinephrine in rabbit brains. This repre- sents a further proof of identity of the train substance as it has been reported that reserpine causes the depletion in brain of a substance shovm by bioassay to be norepinephrine. It appears that as little as 0.5 microgm of catechol amine is needed for the physico-chemical assay which should be able to differentiate between epinephrine and norepinephrine. Significance to HEART Research; Norepinephrine and epinephrine are the mediators of sympathetic tone in the body^ and therefore are important in the control of blood pressure. Furthermore^, norepinephrine has been impli- cated in the central nervous system as a chemical transmitter in the central sympathetic component of the autonomic nervous system. Proposed Course of Pro.ject; Development of the method will be continued. It is planned to further determine the specificity of the method for catechol amines in train and other tissues by paper chromatography of counter-current distribution. It is also planned to estimate the content of catechol amines in various parts of the brain and in various tissues. Form No. ORP-1 October 1956 (Attachment I) PUBLIC HEALTH SERVICE - - NAHONAL INSnTOTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. NHI-122 SERIAL NUMBER 12. BUDGET DATA: ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FI' 57 18,200 $4,087 BUDGETED POSITIONS $12,287 .2 .9 1.1 PATIENT DAIS PROF OTHER TOTAL FT' 57 0 1 1 0 13. BUDGET ACTIVITT; RESEARCH fYl REVIEW & APPROVAL HI BIOLOGIC STANDARDS /~7 ADMINISTRATION ED PROFESSIONAL & TECHNICAL ASSIST- ANCE no U. IDENUFI ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S): None Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment I) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15.NHI-122 SERIAL NUMBER 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: None 17. LIST HONORS AND AWARDS TO PERSONNEL RELATING TO THIS PROJECT DURING CALENDAR YEAR 1956: None Form No. OBP-l Calendar Year 19^6 October I956 (Attachment l) PUBLIC BEAUm SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. NHI-123 2. 8. SERIAL NUMBER Natinml Hpart. Tnstitnte 3> gt^^ryijig^JL Pharmagplpgy INSTITUTE 6R DIVISION LABORATORY, BRANCH, OR DEPARTMENT i^. 5. , ^ SBCnCW OR SERVICE LOCATION (IF OTHER THAN BETHESDAj ^' Drug Enzyme Systems PROJECT TITLE T' Jam^s Fottts ,-—____— , , PRINCIPAL INVESTIGATOR OTHER INVESTIOAT<»S 9' IF THIS PROJECT RESE»fBLBS, COMPLEMENTS, OR PARALLELS RESEARCH DONE ELSEWHERE IN THE PUBLIC HEALTH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACILITIES OR RJNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). PROJECT DESCRIPTION (SEE INSTRUCTIONS): Objectives; A large number of drugs are oxidized along a -variety of pathways by liver microsomes in the presence of TPNH. This work stresses reductive enzymes which metabolize azo and nitro compounds. These reactions occur in soluble as well as microsomal fraction of cell and are TPNH dependent. They represent a new type of flavoprotein in mammalsj with so little specificity for substrate or for flavin that they may be perhaps regarded as "primitive" prototypes in the evolu- tion of enzyme systems. NHI-123 SERIAL NO. Methods Employed; Drug metabolism is being studied using various liver fractions. The products are measured colorimetrically and spectropho to- me trioall7. Significance to HEART Research; A knowledge of the metabolism of drugs is inpjrtant in the development of new therapeutic compounds and in under- standing of drug action; study of drug enzymes can lead to the discovery of fundamental mechanisms involved in the normal body econony. Proposed Course of Pro.ject; Studies on other types of reductive processes used by body to detoxify foreign compounds will be continued. The nature of the relationship of the prosthetic group to the protein enzyme will be studied. Form No. ORP-1 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITOTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. NHI-123 SERIAL NUKIBER 12. BUDGET DATA; ESTIMATliD OBLIGATIONS MAN YEARS DIRECT REIMBURSESIENT TOTAL PROF OTHER TOTAL Fy'57 $13,700 $6,836 BUDGETED POSITIONS 120,536 .6 1,0 1«6 PATIENT DATS PROF OTHER TOTAL FT' 57 1 1 2 0 13, BUDGET ACTIVITI; RESEARCH /x7 REVIEW & APPROVAL /~7 BIOLOGIC STANDARDS HI ADMINISTRATION EJ PROFESSIONAL & TECHNICAL ASSIST- ANCE n U. IDENnFI ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO. (S): None Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment I) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15.NHI-123 SEEIIAL NUMBER 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: On the Enzymatic Reduction of Pronto sil and Other Azo Compounds by Mammalian Liver Systems. J. R. Fouts, J. J. Kamm, and B. B. Qrodie. Submitted for publicationo On the Enzymatic Reduction of Aromatic Nitro ComDOunds. J. R. Fouts and B. B. Brodie. Journal of Pharmacology and Experimental Therapeutics, in press » 17. UST HONORS AND AWARDS TO PERSONNEL RELATING TO THIS PROJECT DURING CALENDAR YEAR 1956: None Form No. C»P-1 Calendar Year 1956 October 1956 (Attachment I) PUBLIC HEALIS SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. NHI-12U SERIAL NUMBER 2. National Heart Institute 3, Chemical Pharmacology INSTITUTE 61^ DIVISI6N LABORATORY, BRANCH, OR DEPARTMENT ^' ?» , SECnCW OR SERVICE LOCATION (IF OTHER THAN BETHESDA; 5^ The Fate of Substances Introduced into the Cerebrospinal Fluid PROJECT TITLE Y^ Steven E. Mayer PRINCIPAL INVESTIGATOR 8^ OTHER INVESTIGATORS 9' IF THIS PROJECT RESEMBLES, COMPIEMEatTS, OR PARALLEI^ RESEARCH DOSE ELSEWHERE IN THE PUBLIC HEAI/TH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACILITIES OR RJNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Objectives; To measure the rate of disappearance of organic compounds from the cerebrospinal fluid and their entrance into the solid matter of the central nervous system after administration into the cists rna magna. NHI-12U Serial Number Methods Snployedg In vivo animal experiments and standard radio- isotope techniques. Major Findings; Substances which enter the central nervous system rapidly frcm the circulation, Isave the cerebrospinal fluid at approximately the same rates, iidiile those which enter slowly also leave slowly. All the substances enter the brain in small amounts (about 1% of the injected dose) with the exception of N-acetyl-1;- aminoantipyrine which averages about 3% of the injected dose per gram of brain, A test of the possibility of active transport of conqjounds from brain to circulation was negative with one of these compoxmds. The results have suggested a different compartmentalization of the brain after intravenous and intracistemal administration. Significance to HEART Research s Almost nothing is known regarding the distribution of svibstances injected into the ventricles or subarachnoid space of the brain, although many pharmacologic agents are active when administered in this fashion. Proposed Course of Projects Project has been terminated. Form No. ORP-1 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. MEI-12^- SERIAL NUlkIB£3l 12. BUDGET DATA: ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FI'57 $8,500 $4,228 BUDGETED POSITIONS $12,728 .5 .4 .9 PATIENT DAYS PROP OTHER TOTAL FT' 57 1 0 1 0 13. BUDGET ACTIVITY; RESEARCH /x7 REVIEW & APPROVAL HI BIOLOGIC STANDARDS /~7 ADMINISTRATION no PROFESSIONAL & TECHNICAL ASSIST- ANCE n 14. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S): None Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15. NHI-'12l| SEEIIAL NUMBER 16. LEST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: None 17. LIST HONORS AND AWARDS TO PERSONNEL RELATING TO THIS PROJECT DURING CALENDAR YEAR 1956: None Form No. (KUP-1 CctLendar Year 19^6 October 1956 (Attachment l) PUBLIC HEALIB SERVICE - - NATIONAL INSOITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. NHI-125 SERIAL NUMBER 2. National Heart Institute 3» Chemical Pharmacology INSTITUTE Ot^ DIVISI6N LABORATORY, BRANCH, OR DEPARTMENT SBCnOH OR SERVICE LOCATION (IF OTHER THAN BETHESDAj 6. studies on the Role of Serotonin in the Ebdy - The Mechanism of Its PROJECT TITLE Storage and Release T • Parkhurst A. Shore PRINCIPAL INVESTIGATOR "~ ' 8 P§r^£§-§i-Si^si?f§-«. OIHER INVESTIGATORS 9. IF THIS PROJECT RESEMBLES, COMPLEMENTS, OR PARALLELS RESEARCH DONE ELSEWHERE IN THE PUBUC HEALTO SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACILITIES OR RJNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Objectives; Previous studies have suggested that serotonin is a neuro- humoral agent in the central autonomic nervous system, and that reserpine exerts its action primarily by an interaction with sites in the brain which normally bind serotonin in an inactive form., Of a fundamental nature is the question of the mechanisms whereby a proposed neurchormors is stored and released. The release of stored serotonin has been demonstrated in vitro by the addition of reserpine to a suspension of rabbit blood platelets, and it has been demonstrated that reserpine administration blocks the uptake of serotonin added to blood platelets in vitro and brain in vivo » NHI-125 SERIAL NO. Methods Employed i The process by which serotonin is released by reserpine and other agents is studied in vi"VD and in vitro. Also studied is the process by which added serotonin is taken up by various tissues o Ma.ior Findings? The presence of "specific" reserpine- sensitive binding sites for serotonin has been demonstrated., Thusj the administration of reserpine blocks uptake of serotonin, that results from administration of the precursor of serotonin, 5-hydro3cytryptophan, in brain, but does not Hock the uptake in liver, an organ which does not normally contain sero- tonin o Experiments designed to study the intracellular distribution of serotonin indicate that the amine is not bound to any definite particle of the cell. It has been found that, contrary to published reports, the parenteral administration of serotonin in mice causes a rise in train serotonin, indicating that the blood- train tsrrier is slightly permeable to sero- tonin. Significance to HEART Research; This study is of significance as it will aid in understanding the fundamental processes by which serotonin, a sub- stance implicated in many body functions including control of blood pressure, is bound and released o Proposed, Course of Pro.iect; Efforts will be made to reduce the serotonin content of brain t^ means other than Rauwolfia administration o It is hoped that a technique will be developed to differentiate between "free" and "bound" serotonin , Form No. ORP-1 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NAnONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. HHI-126 SERIAL NUMBER 12. BUDGET DATA: ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FT' 57 $7,000 $3,523 BUDGETED POSITIONS $10,523 .3 .6 .9 PATIENT DAIS PROF OTHER TOTAL FT' 57 0 1 1 0 13. BUDGET ACTIVITl! RESEARCH FT/ REVIEW & APPROVAL CJ BIOLOGIC STANDARDS HI ADMINISTRATION EJ PROFESSIONAL & TECHNICAL ASSIST- ANCE n 14-. IDENHFI ANI COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FT 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO. (S): None Form No. OBP-1 Calendar Year 1956 October 1956 (Attachment l) PDBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15. NHI-125 SERIAL NUMBER 16. LIST FOBLICAnONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: B. B. Ek'odie, E. G. Tomich, R. Kuntzman, and P. A. Shore, Journal of Pharmacology and Experimental Therapeutics, in press. 17. LIST HONORS AND AWARDS TO PERSONNEL REUTING TO THIS PROJECT DURING CALENDAR YEAR 1956s None {Att&ukmeXit I) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A, Project Description Sheet 1. NHI-126 SERIAL NUMBER 2. National Heart Institute 3. Lab, of Clinical Biochemistry INSTITUTEl (5R DIVISION LABORATORY, BRANCH, OR DEPARTMENT SECTION OR SERVICE LOCATI(»J (IF OTHER THAN BETHESDA) 6. studies on Phenylpyruvic Oligophrenia PROJECT TITLE Dr. Chozo Mitoma PRINCIPAL INVESTIGATOR 8. Mr, Herbert S. Posner OTHER INVESTIGATORS 9. IF THIS PROJECT RESEMBLES, COMPLEMENTS, OR PARALLELS RESEARCH DONE ELSEWHERE IN THE PUBLIC HEALTH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACILITIES OR JUNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS)'. Objectives; The association of dementia with a block in conversion of phenylalanine to tyrosine in patients with phenylpyruvic oligophrenia suggests a chemical etiology for the mental defect. These studies are designed to establish the exact nature of this chemical defect , Methods Employed; Chemical analysis of bloody urine^, and tissues in phenyl- ketonuric patients. Enzymatic studies with liver from these patients « Ma.jor Findings § In previous studies on animal tissues it has been shown that two protein fractions (enzymes) are needed to catalyze the conversion of phenylalanine to tyrosine; I - is found exclusively in the liver, II - is found in all organ tissues. Since hydroxylation of phenylalanine takes place only in the liver, enzyme I may be regarded as specifically involved in the conversion^ whereas enzyme II must be an aux:iliary enzyme involved in many other functions of the body. Using liver autopsy samples from phenyiketonuric patients it has been NHI-126 shown that enzyme II is present in normal amounts Since phenylketonuria liver does not carry out the hy^iroxylation it must be assimed then that the block is in a specific liver en.5yme. Thus, the mental defect may be secondary to liver disfunction. The o-hydroxyphenylacetic acid excreted such large amounts in patients with phenylketonviria (200-300 mgs as compared to 1-3 mg= in normal) has been shovm to be derived from phenylalanine. The suspected intermediate in the process, o- tyrosine, has been shovm to have marked central excitatory effects similar to d-amphetamine , These actions are apparently mediated by o-tyramine which appeared in the tissues following administration of the amino acid. This is further evidence of the production of a centrally "toxic" substance by the liver in phenylketonuric patients » Significance to Heai't Research; Aromatic amines are important humoral substances and profoxmdly influence the cardio-vascular system (adrenalin, noradrenalin, serotonin) ^ o-Tyramine may be a normally occxirring amine whose production is elevated in phenylpjTuvic oligophrenia making such patients valuable for this study. Proposed Course of i^o.ject; Patients with phenylketonuria will be admitted to the Clinical ilenter to continue studies on the enzymatic block in liver hydroxy lating enzyme, Tissues from these patients will also be used to look for o=tyramine and o-tyrosine, The proposed pathway leading from phenylalanine through o- tyrosine, o=tyramine and o-hydroxyphenylacetic acid will be investigated in vivo and in vitro. Form No. ORP-1 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. NHI - 126 SERIAL NUUBER 12. BUDGET DATA; ESTBJATbU) OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FI'57 $11,400 $5,708 BUDGETED POSITIONS $17,108 .3 .5 .8 PATIENT DAYS PROP OTHER TOTAL FY' 57 0 1 1 None 13. BUDGET ACTIVITY; RESEARCH FH REVIEW & APPROVAL [ZJ BIOLOGIC STANDARDS Fl ADMINISTRATION lU PROFESSIONAL & TECHNICAL ASSIST- ANCE n 14.. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S); Dr, Albert Sjoerdsma Form No. ORP-1 - Calendar Year 1956 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15. NHI-126 SERIAL NUMBER 16. LEST PUBLICATIONS OTHER TH/IN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: Diminished Phenylketonuria in Phenylpyruvic Oligophrenia after Administration of L-Glutamine, L-Glutamate or L-Asparagine, A, Meistery S, Udenfriend^ and S, Bessman, J. Clin, Invest, 21, 619 (1956). 17. LIST HONORS AND AWARDS TO PERSONNEL REUTING TO THIS PROJECT DURING CALENDAR YEAR 1956: None Form No. ORP-1 Cedendar Year I956 October I956 (Attachment l) PUBLIC HEALOH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Deecription Sheet 1. NHI-127 SERIAL NUMBER 2. National Heart Institute 3. Lab, of Clinical Biochemistry INSTITUTE OR DIVISION LABORATORY, BRANCH, OR DEPARTMEaiT SECTION OR SERVICE LOCATION (IF OTHER THAN BETEIESDA) 6. studies on Serotonin PROJECT TITLE 7. Herbert Weissbach and Sidney Udenfriend PRINCIPAL INVESTIGATOR ' 8. OTHER LJVESTIGATORS 9> IF THIS PROJECT RESEMBLES, COMPLEMENTS, OR PARALLELS RESEARCH DONE ELSEWHERE IN THE PUBLIC HEALTH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACILITIES OR RJNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS) Objectives s To investigate the biogenesis, disposition and metabolism of serotonin and to determine the functions of serotonin and its implications in certain disease states. Methods Employed; Prepsiration and purification of enzymes and evaluation of drugs and analogues as inhibitors of their activity. Determination of effects of drugs and various reactions on serotonin metabolismjin vivo» by measurement of serotonin disappesirance or increase in blood and tissues. Major Findings; It has now been shown that not only is serotonin present in the brain but that it can be formed and destroyed in the central nervous system, Furtherraorej, serotonin and the enzyme which forms itj, 5-hydroxytryptophar (5HTP) decarboxylase^ are concentrated in the brain stem areas suggesting that these areas are involved in its actions. When 5HTP is administered to animals NHI-127 the serotonin content of brain is markedly increased, the greatest increase being found in the brain stem areas. The marked pharmacologic effects following 5HTP administration to animals, which are no doubt due to its con- version to serotonin, resemble the effects produced by administering the hallucinagenic indole lysergic acid diethylamide. Resolution of D,L-5HTP has been achieved sind it has been shown that only the L antipode possesses pharma- cologic activity and that only this form can be decarboxylated enzymatically to serotonin. In man 5HTP has proved to have hypotensive activity and to produce marked gastro-intestinal motility when administered in doses of 25=75 mg. Because of these toxic effects no attempt has been made to evaluate the central effects of this compound in man. Direct demonstration of pyridoxal phosphate as a cofactor of 5HTP decar- boxylase has been achieved. Furthermore, marked serotonin depletion has been shown in brain, blood and tissues of pyridoxine deficient chickens. Isoniazid which has been widely used to produce acute pyridoxine deficiency does not inhibit the decarboxylation of 5HTP to any great extent. Administration of the monoamine oxidase inhibitor, iproniazid has been shown to produce a rapid increase in brain serotonin (threefold within five hours). However, this drug does not appreciably effect peripheral depots of serotonin, Iproniazid also increases the amounts of serotonin formed in brain following administration of 5HTP but has little effect on that formed in the carcass. Administration of iproniazid in vivo was found to abolish the activity of monoamine oxidase in homogenates prepared after sacrifice of the animals. The monoamine oxidase activity of slices was found to be unaffected. Since iproniazid does potentiate the central actions of serotonin it must do so by inhibiting serotonin destruction in a very specific portion of the brain. It has been shown that blood platelets absorb serotonin both ^ vitro and in vivo. This probably accounts for the high concentration of serotonin in platelets. This property of platelets is not limited to serotonin but extends to adrenaline, histamine, bufotenine, etc. Platelets may thus provide a mechanism for inactivating amines when they enter the circulation. Significance to Heart Research; Serotonin is known to be a vasoconstrictor substance. Furthermore, it seems to be involved in the functioning of those areas of the brain which regulate blood pressure, temperature, etc. Its signi- ficance to heart research is, therefore, obvious. Proposed Cotirse of Projects Attempts will be made to purify the enzymes tryptophan hydroxylase, 5HTP decarboxylase and monoamine oxidase and to study their mechanisms of action. Inhibitors of these enzymes will also be investi- gated in attempts to develop pharmacologic agents. Compounds which can inhibit peripheral actions of serotonin will be checked on malignant carcinoid patients. Form No. ORP-1 October 1956 (Attachment I) PDBUP HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH , INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. NHI - 127 SERIAL NDMBER 12. BUDGET DATA; OBLIGATIONS MAN YEARS DIRECT ItEIMBURSEMENT TOTAL PROF OTHER TOTAL FT' 57 $26,000 $13,037 BUDGETED POSITIONS $39,037 .8 .9 1.7 PROF t;;';;;, OTHER . |.i'»iii|i' .n>l. PATIENT DAYS FY' 57 '■ V %: V ■ 13. BUDGET ACTIVITY; RESEARCH /T? REVIEW & APPROVAL ZI7 BIOLOGIC STANDARDS ZZ? '.•'■2: None ADMINISTRATION n? PROFESSIONAL & TECHNICAL ASSIST- ANCE £Z/ U. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S): Dr. Albert Sjoerdsma Dro Bernard Wi-tkop Dr. Fred Leonard NHI •=■ 133 NIAMD Visiting Scientist, Geigy Pharmaceutical Co, Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment I) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: tlonors, Awards & Publications 15. NHI=127 SERIAL NUMBER 16. LIST PUBLICAnONS OTHER THAN ABSTHACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: 1. Studies on Tryptophan and Serotonin in Patients with Malignant Carcinoid^ So Udenfriendj Ho Weissbach and Ao Sjoerdsmaj, Science 123. 669 (1956), 2o A Clinicalj, Physiological and Biochemical Study of Patients with Malignant Carcinoid, Ao Sjoerdsraaj, S, Udenfriend and H„ Weissbach- American J. Mede s> 20p 520 (1956) o 3» Identification and Assay of Serotonin in Brain^, Do Bogdanskiy Ao Pletscherj Bo Brodie and So Udenfriend, Jo Pharmo Expero Therap, 117» 82 (1956) o 4,0 Increase in Tissue Serotonin Following Administration of Its Precursor 5=I^droxy tryptophan J, So Udenfriend,, Ho Weissbach and Do Bogdanskij, Jo Biolo CheiHo (in press) » 5. Biochemical and Pharmacological Studies with D= and L=3"Hydroxytryptophanj Ko Freter, Ho Weissbachp So Udenfriend and B, Witkopj ProCo Soc, Expero Biolo and Med, (in press) » 17. LIST HONORS AND AWARDS TO PERSONNEL RELATING TO THIS PROJECT DURING CALENDAR YEAR 1956: Dr, Sidney Udenfriend ■= Awarded Senior Research Fellowships, NIH March 1957 - September 1957 NHI=127 6c Biochemical Studies on Serotonin and Their Physiological Irapli cations jj S, Udijnfriendj H, Weissbach end Dc Bogdanski, Symposium on Neuro- endoc'inology, chap^ 7 (in press) , 7, The Dis :ribution of Serotoninj 5=Hydroxytryptophan Decarboxylase and Monoaiine Oxidase in Brain;, D^ Bogdsjiskij H, Weissbach and S^ Udenfr'iend, J. Neuro chemistry (in press), 8., The relitionship of Platelet Serotonin To Disturbances of Clotting and HemostasiSj, M, Weiner and S, Udenfriend, Blood (in press) , 9. Biochemistry and Metabolism of Serotonin as it Relates to the Nervous System, S, Udenfriend, D, Bogdanski and H, Weissbach, Proc, Second Internat'l, Neurochem^ Symp, (in press). 10, Biochemical, Physiological and Pharmacological Aspects of Serotonin, S, Udenfriend, P, A. Shore^ D, Bogdanski^, H, Weissbach and B., Brodie, Recent Progress in Hormone Research (in press), lie. Biochemical Findings Relating to Serotonin Action, S. Udenfriends, H. Weissbach and D» Bogdanski, Annals Nc Y, Acads Sci, (in press), 12. rUrther Observations on Patients with I'lalignant Carcinoid, A. Sjoerdsma, H= Weissbach, Ls Terry and S, Udenfriend, Amer» J.- Med s (in press) = Porxn No. ORP-1 Calendar Year I956 October I956 (Attachment l) PUBLCC BEALTB. SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. NHI=128 SERIAL NUMBER 2. National Heart Institute 3. Lab, of Clinical Biochemistry INSTITUTE Ofi DIVISI6N LABORATORY, BRANCH, OR DEPARTMENT ^' :, 5. ^ , SBCnCN OR SERVICE LOCATION (IF OTHER THAN BETHESDAj 6. Hydroxylation and Biogenesis of Aromatic Cbmpounds PROJECT TITLE DTo Oho 20 Mitoma PRINCIPAL INVESTIGATOR Mto Herbert So Posner OTHER INVESTIGATORS 8. 9* IF THIS PROJECT RESEMBLES, COMPLEMENTS, OR PARALLELS RESEARCH DONE EISEWHERE IN THE PUBLIC HEALTH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACILITIES OR IVNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Ob.i actives g The formation and hydroxylation of aromatic and cyclic compounds are important biochemical processes. Such reactions will be investigated with respect to histidine, tyrosine^ 5=hydroxytryptophan and hydroxyacetanilid. Methods Employed; Standard enzjmiatic procedures. Major Findings; Although the microsomal hydroxy la ting system of ratSj, rabbits and guinea pigs converts aniline exclusively to p-aminephenoi^ o=amino.= phenol is excreted in the urine appearing in very large amounts in cat andjiog. It is impossible to demonstrate that in dog and cat liver both the o- and p- hydroxy la ting system are present in the microsomes. NHI-128 It has been shovm that the major product of the action of liver micro- somes on naphthalene is the corresponding dihydrodiola This substance is readily dehydrated to yield naphthol and may be the intermediate in the hydroxy^ lation of naphthalene. Studies are vmder way to determine whether dihydrodiol intermediates occur in all aromatic hydroxylations and it has already been demonstrated that such a compottnd appears during the hydroj^r lation of quinoline to 3-=hydroxyquinoline, Significance to Heart Research; Aromatization of hydroxylation are important processes on the biosynthesis of the humoral agents which act on the car dio= vascular system and in the detoxication of drugSc Proposed Course of Projects Studies will be continued on the o- and p=hydroxylating enzymes of microsomeSe Mechanism of aromatic hydroxylation will be investigated particularly with due respect to dihydrodiol intermediates « Dihydrodiol analogues of acetanilide and other compounds will be synthesized and tested as intermediates in the hydroxylating system^ Studies on the mitochondrial system which converts cyclohexanecarboxylic acid to benzoic acid will be continued and comparison will be made between this system and the fatty acid oxidase system^ Form No. ORP-1 October 1956 (Attachment I) PUBLIC HEALTH SERVICE - - NAHONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. NHI - 128 SERIAL NUMBER 12. BUDGET DATA; ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FT' 57 $11,500 $5,778 BUDGETED POSITIONS $17,278 .3 .5 .8 PATIENT DAIS PROF OTHER TOTAL FI'57 0 1 1 None 13. BUDGET ACTIVITI; RESEARCH /x? REVIEW & APPROVAL /~7 BIOLOGIC STANDARDS /~7 ADMINISTRATION nj f~ PROFESSIONAL & TECHNICAL ASSIST- ANCE n 14.. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S): Dr. Bernard Witkop NIAMD Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment I) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15 . NHI°128 SEEIIAL NUMBER 16. UST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: lo studies on Partially Purified Phenylalanine H^drojcylassj, Co Mitomay Archo of Biochera„ and Biophys» 60s 4''76 (1956). 2b Enzymatic I^droxylation of Aromatic CompoundSj, C. Mitomay He Posner, Ho Co Reitz and S. Udenfriend, Arch, of Biochem, and Biophys. 6lj, 431 (1956). 3. Aromatic Ifydroxylating Enzymes, S, Udenfriendp C, Mitoma and Ho Posnery Amer. Chem. Soc, Symposiurap Sept, 1956j, (in press), 17. LIST HONORS AND AWARDS TO PERSONNEL REUUNG TO THIS PROJECT DURING CALENDAR YEAR 1956: None Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITOTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. NHI°I29 SERIAL NUMBER 2. National Heart Institute 3. Lab, of Clinical Biochemistry INSTITUTEl (Hk DIVISION LABORATORY, BRANCH, OR DEPARTMENT h. 5. , , SECTION OR SERVICE LOCATI(»« (IP OTHER THAN BETHESDA) 6, The Role of Serotonin in Anaphylaxis PROJECT TITLE 7. Herbert Weissbach PRINCIPAL INVESTKATOR 8. OTHER INVESTIGATORS 9. IF THIS PROJECT R£SEa4BLBS, COMPLEMENTS, OR PARALLELS RESEARCH DONE ELSEWHERE IN THE PUBLIC HEALTH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACILITIES OR FUNDS ), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WimiN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Objectives 8 To determine to what extent serotonin release is a factor in anaphylaxis and related coi.dltions and to determine whether some allergic mani- festations can be alleviatea by inhibitors of serotonin. Methods Employed g Standard procedures are used to sensitize animals to various antigens. The antigen is then administered and the changes in serotonin concentration in blood and various tissues is measured^ comparison is made with histamine, Ma.jor Findings; It has been shown that both serotonin and histamine are released from platelets of sensitized rabbit blood in vitro upon addition of the specific antigen. When antigen is administered to sensitized rabbits serotonin and histamine are released and are fou"d free in the plasma. NHI-129 Serotonin has been found to be present in the lung of many animal species. It was found that guinea pig lung contains histamine but little, if any, sero- tonin whereas mouse lung contains serotonin but little h'-Stamine, Since anti- histaminics completely protect guinea pigs from anaphylactic shock but have little effect on mice, serotonin may be a factor in the pulmonary aspects of anaphylaxis ^ Significance to Heart Research; It is recognized that in allergic mani- festations there are released agents having pronounced effects on the cardio= vascular system. Histamine relofso has been demonstrated and has led to development of antihistaminics drugs to alleviate some of these effects. Release of serotonin may be another factor in allergy and may lead to develop- ment of newer therapeutic agents. Proposed Course of Projects: Thro From such studies the turnover rate of noradrenaline in two pheochromocytoma patients was estimated to have a half life of about 8 hotirs. Enzymes involved in adrenaline formation and metabolism have been demonstrated in pheochromocytoma tumor itself. One patient with pheochromocytoma was shoim to have signifi- cantly lowered fasting tyrosine blood levels although tryptophan values were normal suggesting a serious' impairment of tyrosine metabolism in general. Methods for assaying noradrenaline in urine of normals and pheochromo=. cytoma patients were perfected. Significance to Heart Research; Noradrenaline and adrenaline are important regulatory substances of cardio-vascular function. Proposed Course of Project; Studies on the perfused calf adrenal will be completed^ Purification and study of enzymes involved in adrenaline for= mationo Further studies on pheochromocytoma patients to determine the magnitude of noradrenaline formation and its possible interference with other tyrosine pathways of metabolism.. Interrelationship of adrenaline formation with pigment formations requiring similar intermediates such as dihydroxyphenylalanine will be investigated in animals and in patients with albinism and melanoma-s. Form No. ORP-1 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NAHONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. NHI ~ 131 SERIAL NUMBER 12. BUDGET DATA: ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FI'57 $23,000 $11,557 BUDGETED POSITIONS $34,557 .5 1.2 1,7 PATIENT DAIS PROF OTHER TOTAL FT' 57 1 2 3 None 13. BUDGET ACTIVITY; RESEARCH /T? REVIEW & APPROVAL [~1 BIOLOGIC STANDARDS /~7 ADMINISTRATION EJ PROFESSIONAL & TECHNICAL ASSIST- ANCE n \k. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S): Dr. Albert Sjoerdsma - National Heart Institute Dr. George Rosenfelt - Naval Medical Research Center, Bethesda, Md. Form No. ORP-1 Calendar Year 1956 October 1956 (Attaohment I) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OP HEALTH INDIVIDUAL PROJECT REPORT Part Cj Honors, Awards & Publioationa 15. NHI-131 SERIAL NUMBER 16. LIST PUBLICAHONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: lo Precursors of Adrenal, Epinephrine and Norepinephrine in vivo, S. Udenfriend and J. Wyngaarden, Biochem. and Biophys. Acta 20, 48 (1956). 17. UST HONORS AND AWARDS TO PERSONNEL REUnNQ TO THIS PROJECT DURING CALENDAR YEAR 1956 1 None Form No. ORP-1 Calendar Year I956 October I956 (Attachment I) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. NHI-^132 SERIAL NUMBER 2. National Heart Institute 3' Lab, of Clinical Biochemistry INSTITUTE OR DIVISION LABORATORY, BRANCH, OR DEPARTMENT k, ^ 5. SECTION OR SERVICE LOCATION (IF OTHER THAN BETHESDA) 6. Studies on Indoleacetic Acid PROJECT TITLE 7. Herbert Weissbach PRINCIPAL INVESTIGATOR "^ ' 8. OOHER INVESTIGATORS 9. IF THIS PROJECT RESEMBLES, COMPLEMENTS, OR PARALLELS RESEARCH DONE ELSEWHERE IN THE PUBLIC HEALTH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACILITIES OR RJNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Objectives g To determine how indoleacetic acid is formed and what its significance may be in animal tissues in health and disease* Methods Employed g Enzyme studies on the conversion of precursors to indoleacetic acidj the use of C-^ labeled tryptophan in intact animals and in patients I measiirement of indoleacetic acid in urine and tissues after tryptophan administration in normals and in patients with various disorders « Major Findings? The normal excretion of indoleacetic acid in man averages about 6 mg/day. Only about 20 per cent of the normally excreted indoleacetic acid is conjugated,, One patient with cerebellar ataxia had a significantly elevated excretion (15 mg/day) o However ^ this was not very marked and is nowhere near the 100=200 mgo reported by Jepson et al» NHI-132 An unidentified water soluble indole compound has been found in large q^^antities in a number of urines. This may not be related to indoleacetic acid but will be investigated further ^ The extent of conversion of tryptophan to indoleacetic acid in homogenates has been found to vary considerably from tissue to tissue and from species to species ^ Significance to Heart Research s This project is part of the basic research program of the i^Jational Heart Institute = Although it does not relate directly to heart disease the knowledge gained relative to cellxilar metabolism^ in generals will further omt understanding of cardiovascular function^ Proposed CourMe of Project g Patients with cerebellar ataxia^ diabetes and other disorders in which indoleacetic acid is implicated will be studied to determine the extent of conversion from tryptophan and its significancej, if anyp in the pathology of the disorder. Enzymatic pathways leading to indoleacetic acid will be investigated. Comparisons will be made with comparable systems in plants. Form No. ORP-1 October 1956 (Attachment I) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OP HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. NHI ° 132 SERIAL NUMBER 12. BUDGET DATA; ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FY' 57 $11,600 $5,849 BUDGETED POSITIONS $17,449 ,3 ,5 .8 PATIENT DAYS PROF OTHER TOTAL FT' 57 0 1 1 None 13. BUDGET ACTIVITY; RESEARCH 777 REVIEW & APPROVAL CJ BIOLOGIC STANDARDS Fl ADMINISTRATION EJ PROFESSIONAL & TECHNICAL ASSIST- ANCE n lA. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S): Dr, Albert Sjoerdsma - NHI 137 Dr. James Do Solomon - St. Elisabeth's Hospital, on 3 D o G , Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment l) FDBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15. NHI^132 SERIAL NUMBER 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: None 17. LIST HONORS AND AWARDS TO PERSONNEL RELATING TO THIS PROJECT DURING CALENDAR YEAR 1956: None Form No. (SWP-1 Calendar Year 1956 October I956 (Attachment I) POBLIC HEALOH service - - NATIC^iAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. NHI-133 SERIAL NUMBER Clinic of General Medicine and 2. National Heart Institute 3« Experimental Therapeutics INSTITUTE flft DIVIS16N LABQRATQRY, BRANCH, OR DEPARTMENT If, Experimental Therapeutics 5« SECTION OR SERVICE LOCATION (IF OTHER THAN BETHESDA) 6. Studies on Vasoactive Substances PROJECT TITLE 7. Dr. Albert Sjoerdsma PRINCIPAL INVESTIGATOR Q Drs. J. Do Davidson, B. J. Haverback, and_Lj^ '-i..I®£Ei_. _»._.. -_--_-_- OTHER INVESTIGATORS IF a«IS PROJECT RESEMBLES, COMPUMENTS, OR PARALLELS RESEARCH DQNB EISEWHERE IN THE PUBLIC HEALTH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACILITIES OR RJNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Objectives^ Relate naturally occurring vasoactive substances to cardio- vascular disease and response to drugs. Methods Employeds Largely as described previously or published elsewhere in the literature. Nunerous problems have arisen in chemical assay of catechol amines in blood and urine. Major Findings; (1) Malignant Carcinoid Syndrome - Several patients were admitted for study during the past year and numerous analyses were done on specimens sent from elsewhere. Elevated blood serotonin and urine 5-OH indoleacetic acid (5-HIAA) are consistent findings and the total number of NHI-133 cases studied by us has now reached 30. It is of interest that at least 2 of the patients appeared to have their primary tumor in the lung. Findings of low fasting olasma tryptophan and urinary N'methylnicotinamide in some patients substantliate our previous suggestions of a disorder in tryptophan metabolism in this condition. A tracer study, in one patient, with the serotonin precursor, 5-hydroxytryptophan, enabled calculation of the tumor pool of serotonin (2800 mgra) , its turnover rate (Vz life of Si days), and the tunor m^ss (1-3 kgm) . No measurable difference was found in the serotonin content of mixed venous and arterial blood which, if present, might account for predominant right-heart involvement. However, measurements of plasma serotonin may be unreliable due to problems of separating it from the formed elements of blood, particularly platelets, in which the bulk of circulating serotonin is carried. The absence of serotonin from cerebrospinal fluid probably indicates that this substance does not penetrate readily into the central nervous system. Therapy with so-called serotonin antagonists, with the possible exception of chlor — promazine, has been disappointing. Heserpine therapy causes rapid depletion of platelet serotonin, but in a dosage as high as 10 mgm/day has not affected the serotonin content of the tumors. Chlorpromazine therapy has been shown to interfere with direct assay of 5-OH-indoles in urine, but as shown by our usual extraction procedure for 5-HIAA, serotonin production is actually unaffected. (2) Studies with Serotonin Precursor. 5-OH-tryptophan (5HTP) - Since serotonin is rapidly metabolized and does not readily penetrate the CNS, its precursor was administered acutely to man and chronically to rats. In man, in a dosage range of 25 to 125 mgm of the D-L compound, increased amounts of serotonin were found in the urine for several hours. It was anticipated that central effects might be observed but gastrointestinal stimulation and 3 instances of vascular collapse have prevented our achieving a dose-level at which this might occur. Twice daily injection of ^TP in a dosage of 200 mgm/kgm to rats was shown to result in sustained elevations of tissue serotonin. Chronic administration (4 months) failed to produce any cardiac or other tissue pathology of consequence. Considering the potency of serotonin, and the pathology in carcinoid patients, this was a surprising result. (3) Pheochromocytana - Using C^'^ label, both dihydroxyphenylalanine (DOPA) and dihydroxyphenylethylamine (DOPamine) have been shown to be precursors of nor-adrenaline in man. The calculated rate of nor-adrenaline turnover in two patients was about 8 hours, this being much more rapid than for adrenal catechol amines in experimental animals. In order to obtain patients for study, numerous assays have been done on blood and urine, and a few on pheochroraocytoma tissue. The precursor relationship of DOPA and DOPamine to nor-adrenaline has also been shown in pheochroraocytoma tumor tissue i_n vitro. (4) Miscellaneous - Since the vasoactive substances of concern to us are derived from amino acids (tryptophan and tyrosine) we have become interested in studying various amino acids which might be important in cardiovascular disease, (a) A specific and sensitive method for assay of indoleacetic acid (tryptophan metabolite) in tissue and urine has been developed and a condition found (hereditary ataxia) which is characterized by excessive excretion of I. A. A. (b) We have collaborated at the pre-clinical level with our colleagues in biochemistry in development of methods for studying the metabolism of hydroxy pro line, and amino acid found only in collagenous NHI-133 protein, (c) Members of our group have embarked on studies in hypersensi- tivity and intestinal function as a result of the studies, and observations on patients with malignant carcinoid (since these patients develop asthma, '^ailergic-like'V skin eruptions and hypeitmiotility of the gut). These studies are described in other reports. Significance -to Program of the Institute; The importance of studying conditions characterized by oveV-production of naturally occurring substances and associated cardiovascular disease is obvious. We feel that studies of amino acid metabolism in man will afford additional clues to the pathogenesis of C-V disease. Proposed Course of Project; (1) Study pulmonary A-V serotonin difference in the plasma of carcinoid patients whose platelet serotonin has been reduced to zero by adtninistration of reserpine. Some of the patients admitted to NHI will be transferred to NCI for use of anti-neoplastic drugs. We await the development by our associates in biochemistry of an agent wh^ch will inhibit serotonin foimation i|i vivo. (2) Additional studies of catechol amine metabolism in pheochromocytoma patients are planned, particularly with the idea of finding metabolites in urine which might be easily measured and afford a simpler means of diagnosis. We hope to extend our studies of nor-adrenaline turnover to patients with normal and high blood pressure in order to learn more about chemical evejits at sympathetic nerve endings. (3) Other patients to be admitted for study will be those with various abnormalities in amino acid inetabolism (e.g.. phenylketonuria, albinism, hereditary ataxia, urticuria pignentosa, hypersensitivity states, connective tissue disorders, etc.). Form No. OSP-1 October 19% (Attachment I) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. ITHI-133 SERIAL NUMBER 12. BUDGET DATA: ESTIMATED OBLIGAHONS MAN lEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FI'57 $30 J 000 $93,36^ BUDGETED POSITIONS $123,36^ 1.2 2,7 3.9 PATIENT DAYS PROF OTHER TOTAL FI'57 1 3 k 1,000""^. 13. BUDGET ACTIVITT; RESEARCH /Tl REVIEW & APPROVAL ^"7 BIOLOGIC STANDARDS /~~7 ADMINISTRATION PROFESSIONAL & TECHNICAL ASSIST- ANCE £7 U. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OH OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IH FT 1957. IP COOPERATING UHIT IS HTHIN NIH INDICATE SERIAL NO.(S); a) Dr„ Chozo Mitoma = MI-127 b) Dr. Wo Z. Engel„ NIMDB c) Dr„ T„ W„ Mattinglyj Walter Reed Army Hospital, Washington, D.C, (Attachment I) FmilG EEALTE SERflGE - - VATTOML INSTIfCJfES OF HEALTH INDITIDUAL PROJECT REPORT Part 0: Honors, Awards & Publications 15. NHI-133 SERIAL NUMBER 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: 1. Sjoerdsma, A„, Terry, L„L. and Udenfriend, S.t Malignant Carcinoid, A New Metabolic Disorder, Monograph, U.S.Dept. H.E.W. , NHI, Bethesda, Md. October 1955, Kevised July 1956« 2. Sjoerdsma, A„, Weissbach, H., Udenfriend, So s A Clinical, Physiologic and Biochanical Study of Patients with Malignant Carcinoid (argentaf finoma) . Am, Jo Med. 20; 520, 1956. 3. Udenfriend, S., Weissbach, H. and Sjoerdsma, A.; Studies of Tryptophan and Serotonin in Patients with Malignant Carcinoid. Science 123; 669, 1956. 4. Sjoerdsma, A., Kornetsky, C.B. and Evarts, E.s Lysergic Acid Diethylamide in Patients with Excess Serotonin. Arch. Neurol. & Psychiat. 75; 488, 1956. 5. Mattingly, T.W. and Sjoerdsma, A.; The Cardiovascular Manifestations of Functioning Carcinoid Tumors. Mod. Concept. Cardiovasc. Dis. 25; 337, 1956. 6. Sjoerdsma, A., Terry, L.L. and Udenfriend, S. ; The Malignant Carcinoid Syndrome. Modern Medicine. 24; 127, 1956. 17. LIST HONORS AND AWARDS TO PERSONNEL REUTING TO THIS PROJECT DURING CALENDAR YEAR 1956: During the past year, our scientific exhibit was shown at medical meetings in Boston, Chicago, New York, Washington, Havana and Seattle. The following honors were conferred; a) Certificate of Merit, Section of Experimental Medicine and Therapeutics American Medical Association, Chicago, June, 1956 b) First Prize, American College of Gastroenterology, New York City, October, 1956 16. PUBLICATIONS (CONTINUED) 7. Haverback, B.J. , Sjoerdana, A. and Terry, L.L.; Urinary Excretion of the Serotonin Metabolite, 5-hydroxyindoleacetic acid, in Various Clinical Conditions, N, Eng. J, Med, 255; 270, 1956, 8. Sjoerdsma, A,, Weissbach, H, , Terry. L.L. and Udenfriend, S, ; Further Observations on Patients with Malignant Carcinoid. Am. J, Med, In Press. 9. Davidson, J.D. Sjoerdsma, A. Loomis, L. and Udenfriend, S. ; Studies with the Serotonin Precursor, 5-hydroxytryptophan, in Man and Experimental Animals. In preparation. Form No. ORP-1 Calendar Year 195^ October 1956 (Attachment I) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. NHI-134 SERIAL NUMBER Clinic of General Medicine and 2. National Heart Institute 3, Experimental Therapeutics INSTITUTE 6ft DIVISlbN LABORATORY, BRANCH, OR DEPARTMEaJT k. Clinical Endocrinology 5. SECTION OR SERVICE LOCATION (IF OTHER THAN BETHESDA) Study of the Movement of Large Molecules Through Aortic and Other 6. Connective Tissues PROJECT TITLE 7. Dr. Leroy E. Duncan, Jr, PRINCIPAL INVESTIGATOR " ' 8. OTHER INVESTIGATORS 9' IF THIS PROJECT RESE34BLBS, COMPLEMENTS, OR PARALLEI^ RESEARCH DONE ELSEWHERE IN THE PUBLIC HEALTH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACILITIES OR FUNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Obiectives; A better understanding of the factors which affect the movement of large molecules from the blood stream into these tissueSo Methods Employeds The substance to be studied is injected into a series of animals. At desired times the animals are killed and the concentration of the test substance in the serim and in the tissues determined. Major Findings; The movement into and out of aorta, skin, tendon, sclera and cornea of albumin tagged with radio-iodine has been studied in the rabbit. A mathematical model which satisfactorily expresses the experimental findings has been developed. NHI-134 Significance to Heart Research: Information on factors which affect the rate of movement of various sized molecules into the aortic intima may be pertinent to the movement of lipoproteins into the aortic intima in atherosclerosis. Proposed Course of Project; Contemplated work includes (A) the study of the movement of larger molecuL 3 in experimental animals. (B) the study of the variables affecting the movement of large molecules in connective tissues, (C) the in vitro measurement of the movement of large molecules through aortic intima, and (D) an attempt to devise methods for the study of the mov«nent of large molecules in liviny man. Form No. ORP-1 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. NHI-13^ SERIAL NUMBER 12. BUDGET DATA: ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FI'57$26,000 $10,972 BUDGETED POSITIONS $36,972 1.0 2,5 3.5 PATIENT DAYS PROF OTHER TOTAL FT' 57 1 3 4 None 13. BUDGET ACTIVITY; RESEARCH /T? REVIEW & APPROVAL /~7 BIOLOGIC STANDARDS /~7 ADMINISTRATION CD PROFESSIONAL & TECHNICAL ASSIST- ANCE / / 14. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IF COOPERATING UNIT IS T7ITHIN NIH INDICATE SERIAL NO.(S): None Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15. NHI-134 SERIAL NUMBER 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: None 17. LIST HONORS AND AWARDS TO PERSONNEL RELATING TO THIS PROJECT DURING CALENDAR YEAR 1956: None October 195^ (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. NHI-135 SERIAL NUMBER 2. National Heart Institute INSTITUTE OR DIVISION Clinic of General Medicine and 3, Experimental Therapeutics LABORATORY, BRANCH, OR DEPARTMENT 4, Cxperinior.t.il Therapeutics SECTION OR SERVICE 5. LOCATION (IF OTHER THAN BETHESDA) 5. Vasoi.ioter .losponses iielated to tho Gastrointestinal Tract PROJECT TITLE Bernard J„ Haverback. :LD, PRINCIPAL INVESTTCATOR Q Henry .v'agner, iiLD, and Albert Sjoerdsia, M.D. OTHER INVESTIGATORS 9. IF THIS PROJECT RESEMBLES, COMPLEMENTS, OR PARALLELS RESEARCH DONE ELSEWHERE IN THE PUBLIC HEALTH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACILITIES OR RJNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Objectives; The objectives of this project ard i.c (1) inv'='?tigate the vasomotor mechanibr.s involved in the "dumping iiidrome" and (2) evaluate the status of the parasynipatlietic nervous system in patients with ortho- static iiypotension. Methods Employed; (1) Catechol amines are measured in the blood and urine of patients before and during the dumping syndrome. (2) The status of the parasympathetic nerves to the gastrointestinal tract is evaluated by determining (a) the gastric secretory response following insulin-induced hypoglycemia, and (b) the sigmoid colonic motility response following insulin-induced hypoglycemia. Patient Material; Admissions Adult f.lales No. Average Stay (Days) MiI-135 Major Findinc,s; (1) Preliminary studies indicate that circulating catechol amines may be increased during the dumping syndrome. (2) Some patients with orthostatic hypotension have a defect in the para- sympathetic autonomic nervous system as well as in the sympathetic autonomic nervous system. Significance to Heart research; (1) .4 study of the mechanisms of the release of catechol amines is pertinent to many phases of cardiovascular investigation. (2) The status of the parasympathetic nervous system may be evaluated by employing tests which affect gastrointestinal function. In patients with orthostatic hypotension, an evaluation of the status of the parasympathetic nervous system may be of help in determining the site of the lesion. Proposed Course of Projects Further studies are planned to extend the number of observations. Form No. ORP-1 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. MHI-135 SERIAL NUMBER 12. BUDGET DATA; ESTIMATED OBLIGATIONS MAN TEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FT' 57 $17,^00 $53,755 BUDGETED POSITIONS $71,155 1.2 ,7 lo9 PATIENT DATS PROF OTHER TOTAL FT' 57 1 1 2 5(> 13. BUDGET ACTIVITT; RESEARCH /Tl REVIEW & APPROVAL ZZ? BIOLOGIC STANDARDS /~7 ADMINISTRATION nj PROFESSIONAL & TECHNICAL ASSIST- ANCE /~7 U. IDENTIFT ANT COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FT 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO. (S): Laboratory of Kidney and Electrolyte Metabolism 5NHI Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment I) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15. NHI-135 SERIAL NUMBER 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: None 17. LIST HONORS AND AWARDS TO PERSONNEL REUTING TO THIS PROJECT DURING CALENDAR YEAR 1956: None Form No. ORP-1 Calendar Year I956 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITOTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A, Project Description Sheet 1. NHI-136 SERIAL NUMBER Clinic of General Medicine and 2. National Heart Institute 3. Experimental Therapeutics INSTITUTE 6ti DIVISI6N LABORATORY, BRANCH, OR DEPARTMENT If, Experimental Therapeutics 5, SECTION OR SERVICE LOCATION (IF OTHER THAN BETHESDA) 6, The Action and Metabolism of Drugs PROJECT TITLE "^ 7. Dr. John Do Davidson PRINCIPAL INVESTIGATOR ' ' 8 ?r^i--i-§ii22r^^ma^_B^_J_._Haverbackj^_T^_P^ Waalkes^ ^ OTHER INVESTIGATORS IF THIS PROJECT RESEMBLES, COMPLEMENTS, OR PARALLELS RESEARCH DONE ELSEWHERE IN THE PUBLIC HEALTH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACILITIES OR fUNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). 10. PROJECT DESCRIPTIO* (SEE INSTRUCTIONS): Objectives; To screen new agents for desirable pharmacologic effects in man and learn more about the action of drugs through studies of their metabolism^ Methods Employed; Intravenous and oral administration of drugs with measurements of the drug in urine and blood and measurements of other appropriate parameters, i.e., blood pressure, pulse, and respiratory rate, pupil size, EKG etc. Patient Material; Patients with persistent hypertension and other patients without hypertension and with normal renal and hepatic function. NHI-136 Ma.ior Findings; (A) Drug Action (1) Anti-hypertensive drugs (a) Ormosia panamensis - Oimosia is an alkaloid extracted from the seeds of a tree indigenous to Panama and a few other Central American countries^ It was found to exert marked hypotensive effects in dogs. Evaluation of this drug in man revealed no effect in doses which were 25% greater than the amount necessary to cause respiratory paralysis in dogs and five times greater than an amount which invariably resulted in a blood pressure fall in dogs. (b) Drug Potentiation Studies - Clinicians all agree that at least additive. benefit occurs in the treatment of arterial hypertension by the concomitant adninistration of two or Riore anti -hypertensive drugs. The pharamologic nature of this enhanced effect has been studied by tnfusing less thanminimal threshold doses of hexamethonium after priming with similar less than threshold doses of reserpine. Investigations to date suggest that this enhanced effect is in the nature of true potentiation rather than mere additive effect. (c) Effects of reserpine = Seserpine was found to increase the voluriie and free acidity of gastric secretion while chlorpromazine reduced the volume but did not affect the free acidity. (d) Methoxyphenylpiperazine - This substance was found to produce hypotension only in conjunction with the appearance of undesirable side reactions. The mechanism of action of the compound is probably related to an inhibition of the sino-auricular node and a decrease in cardiac output. In view of these findings this project has been abandoned. (2) Anti -arrhythmic drugs (a) Evaluation of MC=4112 (2-diethylaminoethylisonicotinaraide) completed and paper has been published. (b) Evaluation of BO 2-7302/4 D7-(2=p3,peridylmethyl)-3/? , 17,1^ -androstanediol lactate hemihydrate] is in progress. This compound appears useful in ventricular arrhythmias but of little use in supra- ventricular arrhythmias. (3) Miscellaneous Drugs (a) Tolazoline CPriscoline) etc., was found to evoke severe cardiac pain in a patient with a past history of angina pectoris. This phenomenon was not readily explicable in the absence of any measurable changes in cardiodynamics such as an increased pulse rate, lowered diastolic pressure, etc. An increase in myocardial contractile force of 25% was produced in a dog by the injection of therapeutic amounts of _ .NHI-136 Tplazolineo It is postulated that thds: sudjden jobiigaterincuease in work- load is sufficient to evoke myocardial ischemia in a patient with coronary atherosclerosiso _ , . . (b) Chlorpromazine SMlfoxide - This compound, the major metabolite of chlorpromazine was found to exert some of the properties of chlorpromazine in lower animals such as sedation,, Postural hypotension was not observed, however, in sedative doses, contrary to what is found with chlorpromazine. For these reasons a study of this compound's metab- olism and its pharmacologic effect in man was undertaken. Adninistration of chlorpromazine sulfoxide by a double blind technique to 12 different hypertensive and norraotensive patients revealed definite sedation with virtually no postural ^astric secretion and intestinal motility, (2) to investigate the possibility that indole compound affect gastrointestinal functions by a common mechanism and (3) to evaluate serotonin antayonistSo Methods Employeds Indole substances have been administered to dogs with ijastric fistulae and Ileidenhain pouches and to man to determine their effects on gastric secretion and intestinal raotilityo Intestinal motility was NHI-137 measured by means of open-tip tubes connected to pressure transducerso In the human, continuous gastric aspiration was accomplished by intubating the stomach under fluoroscopic guidance and constant suction was applied by a mechanical pump. Patient Material; Admissions NOo Average Stay (Days) Adult Males 6 10 Adult Females 6 10 Major Findings; Serotonin and its precursor, 5-hydroxytryptophan, inhibit gastric acid secretion. These substances inhibit gastric secretion stimulated by insulin induced hypoglycemia. The stimulus to gastric secretion by histamine and reserpihe are not inhibited by 5-hydroxytryptophan. Reserpine and lysergic-acid-diethylamide both of which contain the indole nucleus stimulate gastric acid secretion. It has also been shown in man that when reserpine is administered in a dose of 1 mg. daily, platelet serotonin becomes virtually depleted at the end of a week. Following depletion of platelet serotonin, reserpine does not stimulate gastric acid secretion. Serotonin and 5-hydroxytryptophan are potent stimuli to gastrointestinal motility, Lysergic-acid-diethylamide, which has been reported to be a serotonin antagonist in^ vitro, potentiates the stimulus of serotonin to intestinal motility. Bromlysergic=acid-diethylaraide inhibits the stimulus of serotonin to intestinal motility. The administration of 5=hydroxytryptophan produces gastric mucosal erosions in the rat. This finding takes on added significance as the incidence of peptic ulceration in autopsied cases of the malignant carcinoid syndrome is high. The benzyl analogue of serotonin which has been reported to be a serotonin antagonist did not prevent erosion formation but pretreatraent with atropine was effective in preventing gastric mucosal erosion. Significance to Heart liesearch; As serotonin has been implicated in hypertension and also in the production of valvular heart disease in the malignant carcinoid syndrome, the evaluation and clinical trial of serotonin antagonists is of interest. Proposed Course of Project; Further studies are in progress to evaluate (1) different indole compounds on gastrointestinal function and (2) serotonin antagonists. Form No. ORP-1 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. KHi^i r, SERIAL NUMBER 12. BUDGET DATA; ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FI'57 $3^.500 $107,510 BUDGETED POSITIONS $142,010 2,7 .8 3.5 PATIENT DAYS PROF OTHER TOTAL FT' 57 3 1 4 120 13. BUDGET ACTIVITY; RESEARCH /Tl REVIEW & APPROVAL Z~7 BIOLOGIC STANDARDS /~7 ADMINISTRATION PROFESSIONAL & TECHNICAL ASSIST- ANCE ZI7 lA. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S): rai-132 Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Fart C: Honors, Awards & Publications 15.. NtiI-137 SERIAL NUMBER 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: 1. Haverback, B.J„, Dutcher, T„F„, Shore, PoA., Tomich. E«G. . Terry L„L. Brodie, BoB„s Serotonin Changes in Platelets and Brain Induced by Small Daily Doses of Keserpine, New Eng„ 3. of Med. In Press. 2. Haverback, B.J., Hogben, C„A., Moran. N.Co and Terry, L.L„s Effect of Serotonin (5-hydroxytryptaraine) and Related Compounds on Gastric Secretion and Intestinal Motility in the Dog„ Gastroenterology. In Press 3. Haverback, B.J., Sjoerdsma, A., and Terry, LoL„; Urinary Excretion of the Serotonin Metabolite 5-hydroxyindolacetic Acid, in Various Clinical Conditions. New Eng. J. of Med. 255 g 270, 1956. 17. nST HONORS AND AWARDS TO PERSONNEL REUTING TO THIS PROJECT DURING CALENDAR YEAR 1956: None Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment l) PUBLIC HEALOB SERVICE - - NATIOtlAL INSTITITIES OF HEALIH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. NHI-138 SERIAL NUMBER Clinic of General Medicine and 2. National Heart Institute 3, Experimental Therapeutics INSTITUTE OR DIVISION LABORATORY, BRANCH, OR DEPARTMENT !(., Hemodynamics 5, SECTION OR SERVICE LOCATICN (IF OTHER THAN BETHESDA) Cardiac Output Determinations and Calculation of Aortic and Mitral Valve 6. Size During Surgery and Left Heart Catheterization PROJECT TITLE 7. Herbert L. Tanenbaum, M.D. PRINCIPAL INVESTIGATOR " ' " ' Q A. G. Morrow, M.D., Eugene Braunwald, M.D. OmER INVESTIGATORS 9. IF THIS PROJECT RESEMBLES, CCMPI£MENTS, OR PARALLELS RESEARCH DONE EISEMHERE IN THE PUBLIC HEALTH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACIIJTIES OR fUNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Ob.iectivess To measure cardiac output during left heart catheterization, calculate aortic valve and mitral valve size from pressure and flow data and to do similar determinations during mitral and aortic valve surgery. Methods Employed; Cardiac output obtained by dye dilution curves injecting Evan's Blue dye into the left ventricle. Pressure measured in the conventional way and valve size calculated from the above information by use of Gorlin's hydraulic formulae. Patient Material; 11 patients during left heart catheterization 3 patients at surgery Average stay - 14 days NHI-138 Ha jQT Findings; Pressure gradients vary directly with changes in the square of the flow hence the importance of measuring both simultaneously. Valwe area gives a relative estimation of degree of valvular stenosis and benefit following surgery. Significance to Heart Research; Better definition of dynamics of mitral and aortic valve disease. Proposed Course of Project; Collect more data, flelate valve areas to symptoms and other objective findings pre- and post-operatively. Establish bronchoscopic approach to left heart catheterization as valid means of defining more closely mitral and aortic valve disease. Form No. ORP-1 October 1956 (Attachment I) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. mi -138 SERIAL NUMBER 12. BUDGET DATA; ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FY' 57 $17,500 $7,253 BUDGETED POSITIONS $2^^,753 1.3 .2 1.5 PATIENT DAYS PROF OTHER TOTAL FT' 57 1 0 1 196 13. BUDGET ACTIVITY; RESEARCH /T? REVIEW & APPROVAL /~7 BIOLOGIC STANDARDS /~7 ADMINISTRATION EJ PROFESSIONAL & TECHNICAL ASSIST- ANCE n 14.. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IF COOPERATING UNIT IS IJITHIN NIH INDICATE SERIAL NO.(S): None Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment I) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15. NHI-138 SERIAL NUMBER 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: None 17. LIST HONORS AND AWARDS TO PERSONNEL HEUTING TO THIS PROJECT DURING CALENDAR YEAR 1956: None Form No. ORP-1 Calendar Year I956 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. NHI-139 SERIAL NUMBER Clinic of General Medicine and 2, National Heart Institute 3. Experimental Therapeutics INSTITUTE to DIVISION LABORATORY, BRANCH, OR DEPARTMENT !(,, Clinical Endocrinology 5, SECnCN OR SERVICE LOCATION (IF OTHER THAN BETHESDA) 5^ Studies of the Relationship of Steroid Structure to Function PROJECT TITLE Y, Frederic C, Bartter, MoD,, 8. PRINCIPAL INVESTIGATOR . Grant W. Liddle, M.D. OTHER INVESTIGATORS 9. IF THIS PROJECT RESEMBLES, COMPLEMENTS, OR PARAlIiELS RESEARCH DONE ELSEWHERE IN THE PUBLIC HEALTO SERVICE (WITHOUT INTERCHANOE OF PER- SONNEL, FACILITIES OR RJNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Objectives; The object of this project is to attempt by comparison of steroids with analogous compounds bearing a single structural alteration to determine the fundamental relationship of steroid structure to physiologic action. Methods Employed; Metabolic balance studies were conducted in normal volunteer subjects and in-patients with Addison's disease. Studies of renal function were performed at intervals throughout the studies. Assays for the acute effects of the steroids on renal sodium and potassium excretion were carried out in dogs. NHI-139 "atient Materials diiTPiJii^ni !^- Average Stay (Days) Aduit reriafes 5 100 Adult Males 4 60 Major Findings; It was found that introduction of a methyl group on the second carbon atom of steroids increased sodium retaining and potassium losing activity of the steroids which also had a hydroxyl group in the 11-beta position. The same structural alterations decreased the biologic activity of steroids possessing a ketone group or no oxygen function on the 11-carbon, It was found that steroids bearing a methyl group on the 2-carbon atom were much more slowly degraded in the body than their non- methylated analogs. Significance to Heart Research; These studies are designed to elucidate the mechanism whereby steroids exert their characteristic actions. This should contribute understanding both of the basic processes involved in inflammatory diseases (e.g., rheumatic fever) and of those involved in pathologic salt retention. It is hoped that they may also give rise to steroids effective either directly or through canpetition with endogenous mechanisms. Proposed Course of Project; Newer steroids will be tested as they are made available, largely through pharmaceutical houses. The close cooperation of the pharmaceutical houses in synthesizing steroids designed to elucidate mechanisms has been an indispensable part of this program. Syntheses have not been attempted in this department in view of this cooperation. Form No. ORP-1 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. mj;-i?}9 SERIAL NUMBER 12. BUDGET DATA; ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FI' 57 $7,500 BUDGETED POSITIONS $31,5^8 .3 .7 1.0 PATIENT DAYS PROF OTHER TOTAL FY' 57 0 1 1 160 13. BUDGET ACTIVITY; RESEARCH /X? REVIEW & APPROVAL /~7 BIOLOGIC STANDARDS /~7 ADMINISTRATION PROFESSIONAL St. TECHNICAL ASSIST- ANCE /U lU. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S): None Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment l) FDBLIC HEALTH SERVICE - - MTIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15. NHI-139 SERIAL NUI/DBER 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: 1, Liddle, G„W„ , ftichard, J„Eo and Torakins, G.MoS Studies of Structure- Function Relationships of Steroidss The 2-Methyl Corticosteroids. Metabolism Vs 384. 1956, 17. LIST HONORS AND AWARDS TO PERSONNEL RELATING TO THIS PROJECT DURING CALENDAR YEAR 1956: None Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment I) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. NHI-140 SERIAL NUMBER Clinic of General Medicine and 2. National Heart Institute 3« Experimental Therapeutics INSTITOT^ 6R DIVISlbN LABORATORY, BRANCH, OR DEPARTMENT k. Clinical Endocrinology 5» SECTION OR SERVICE LOCATION (IF OTHER THAN BETHESDA) 6. Chemical and Physiological Studies of Aldosterone Metabolism PROJECT TITLE 7. Frederic C. Bartter. M.D. PRINCIPAL INVESTIGATOR 8 .Pi^ii-iP.Chen, Ph.D., Harold P. Schedl, M.D. , Grant W^ '"i^^i^u---P: OOHER INVESTIGATORS 9< IF THIS PROJECT RESEMBLES, COMPLEMENTS, OR PARALLELS RESEARCH DONE ELSEWHERE IN THE PUBLIC HEALTH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACILITIES OR RJNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Objectives; The objectives of this study are to elucidate the mechanisms whereby sodium and water homeostasis is noimally maintained and to investigate the pathologic physiology of salt and water retention in edema formation. Because of its central role in sodium metabolism, aldosterone has commanded the large part of our attention. Methods Employed; (A) In metabolic balance studies, normal subjects have been studied under various experimental conditions during which sodium and potassium balance were altered, and aldosterone excretion studied. (B) itenal clearances were perfoimed in subjects with Addison's disease to determine the acute effects of aldosterone on renal function. (C) Chemical studies on the isolation and measurement of aldosterone in urine and in serum were instituted. NHI-140 Patient Material; Admissions No. Average Stay (Days) Adult Males 4 90 Adult Females 12 90 Ma.jor Findings; (A) Studies on role of ACTH in the control of aldosterone secretion were completed. These are described in the first paper under "Publications" and will not be referred to further. The effect on aldo"^ sterone secretion of changes in dietary potassiisn was investigated further. Studies wherein marked alterations in potassium balance were produced by potassium loading and by potassium depletion were performed on the meta- bolic ward. Determinations of inulin space were carried out in potassium depleted and potassium loaded subjects.* The previous observation that potassium loading increased aldosterone excretion was confirmed. The affect of this procedure on extracellular fluid volume is still under investigation. When extracellular fluid volume was expanded at the same time that potassium loading was done, aldosterone excretion fell. The effect of changes in extracellular fluid volume was investigated further. Changes in the intravascular volume were produced by the withdrawal and reinfusion of blood and by the infusion of albumin in the normal and hypoproteinemic subjects. It was found that the initial effect of all measures which decrease intravascular fluid volume was to increase aldo- sterone secretion and that of all the measures which increased intra- vascular volume was to decrease aldosterone secretion. (B) lienal clearances were performed on 4 Addisonian subjects before and during the administration of aldosterone intravenously. Aldosterone administration was consistently followed by retention of sodium and by increased excretion of potassium and of hydrogen ions. (C) The method of Neher and Wettstein for the physical-chemical measurement of aldosterone was set up and determinations parallel with those of our bioassay method were instituted. A number of chromatographic reactions were investigated in the attempt to produce better quantitative methods for the estimation for aldosterone. Significance to Heart i^esearch; It has been shown repeatedly that the salt retention in edematous states including cardiac failure is accompanied by high levels of urinary aldosterone. It is clearly of importance in determining the physiologic significance of edema and the fundamental mechanism by which it is produced to understand the normal mechanisms whereby aldosterone secretion is controlled, Proposed Course of Projects The physiologic studies in man will be extended to the dog where such a procedure is feasible. The chemical studies will be pursued as aggressively as pemitted by distribution of manpower. * These studies form part of another project performed in conjunction with Dr. Ernest Cotlove, Form No. ORP-1 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. MHI-^i^O SERIAL NUMBER 12. BUDGET DATA; ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FT' 57 $26,800 $83»^6l BUDGETED POSITIONS $110,261 2.0 .8 2.8 PATiMT DAIS PROF OTHER TOTAL FT' 57 2 1 3 1,000 13. BUDGET ACTIVITY; RESEARCH /O REVIEW & APPROVAL /~7 BIOLOGIC STANDARDS /~7 ADMINISTRATION nj PROFESSIONAL & TECHNICAL ASSIST- ANCE JZJ 14. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNIS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S): Dr. Ernest Cotlove - Laboratory of Kidney & Electrolyte Metabolism, MI Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment I) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15. NHI-140 SERIAL NUMBER 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: 1, Bartter, Frederic Co s The liole of Aldosterone in Normal Homeostasis and in Certain Disease States,, Metabolism, Vs 369, 1956 2. Liddle, Grant We, Duncan, Leroy E„ , Jr„ and Bartter, Frederic C.% Dual Mechanism Regulating Adrenocortical Function in Man. Amer., J. of Medicine, XXIs 380, 1956„ 3. Duncan Leroy E„ Jr., Liddle, Grant W. , and Bartter, Fredericks The Effect of Changes in Body Sodium on Extracellular Fluid Volume and Aldosterone and Sodium Excretion by Normal and Edematous Men. Jo of Clinical Investigation, 35s 1299, 1956. 4, Bartter, Frederic Co, Liddle, Grant Wo, Duncan, Leroy Eo Jr. , Barber Joan K. and Delea, Catherines The tiegulation of Aldosterone Secretion in Mans The hole of Fluid Volime, J, of Clinical Investigation, 35s 1306, 1956. 17. LIST HONORS AND AWARDS TO PERSONNEL REUTING TO THIS PROJECT DURING CALENDAR YEAR 1956: None Form No. ORP-1 October 1956 (Attachment I) Calendar Year I956 PUBUC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. NHI-141 SERIAL NUMBER 2, National Heart Institute INSTITUTE OR DIVISION Clinic of General Medicine and 3, Experimental Therapeutics LABORATORY, BRANCH, OR DEPARTMENT 1|, Clinical Endocrinology SECnCN OR SERVICE 5. LOCATI(»l (IF OTHER THAN BETHESDXJ 6. Action of Parathyroid Hormone PROJECT TITLE 7. Frederic C. Bartter, JILD. 8. PRINCIPAL INVESTIGATOR Pacita Pronove. M.D= OTHER INVESTIGATORS 9. IF THIS PROJECT RESEMBLES, COMPLEMENTS, OR PARALLELS RESEARCH DONE ELSEWHERE IN THE PUBLIC HEALTH SERVICE (WITHOUT INTERCHANOE OF PER- SONNEL, FACILITIES OR RJNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). PROJECT DESCRIPTIO* (SEE INSTRUCTIONS): Objectives; Tlie objectives of this project are to study the physiology of the paratiiyroid gland and to improve the measures available for establishing the diagnosis of hyperparathyroidism. Methods Employed; Four types of tests were carried out in a number of normal subjects and in four patients suspected of hyperparathyroidism. These were (1) 1m of phosphorus, (2) response of the urine phosphorus to intravenous calcium, (3) response of the serura and urine calcium to araphogel ingestion and (4) response of urine calcium to ammonium chloride administration„ 1 NHI-141 Patient Material; Admissions No. Average Stay (Days) Adult Males 5 40 Adalt Females 5 40 Major Findings; The tests indicated the probable presence of hyper- parathyroidism in one subject and removal of a parathyroid tumor was carried out. The normal variation of the response to the tests described was deljineated. It appeared from these studies that the response to serun calcium and phosphorus to a low phosphorus intake or to amphogel, and the Tra of phosphorus convey the most reliable iofoimation with regard to the presence or absence of parathyroid aderaona. Significance to Heart Research; These studies are designed to throw light on the fundamental mechanisms of phosphorus and calcium metabolism in biology. The information so attained may be expected to throw light on the role of abnormal phosphorus 9nd calcium metabolism in disease states. Proposed Course of Pro.iectg These studies will be pursued both in the normal and in the patients suspected of hyperparathyroidism and when at all possible in patients known to have hyperparathyroidism. Form No. ORP-1 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITDTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. NHI-i^l SERIAL NUMBER 12. BUDGET DATA; ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMPTmSEMKNT TOTAL PROF OTHER TOTAL FI'57$17o^OO $53,755 BUDGETED POSITIONS $71,155 1,2 .7 1.9 PATIENT DAYS PROF OTHER TOTAL FT' 57 1 1 2 400 13. BUDGET ACTIVITY; RESEARCH FH REVIEW & APPROVAL HI BIOLOGIC STANDARDS /~7 ADMINISTRATION EJ PROFESSIONAL & TECHNICAL ASSIST- ANCE // H. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S): None Form No. OHP-1 Calendar Year 1956 October 1956 (Attachment I) PUBLIC HEiLLTH SERVICE - - NATIONAL INSTITUTES OF BDEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Auards & Publications 15. NHI-141 SERIAL NUMBER 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS FROH THIS PROJECT DDEING CALENDAR YEAR 1956: Bartter, Frederic C. s Metabolic Bone Disease in Diseases of Metabolism, George Smart, Editor. 17. LIST HONORS AND AWARDS TO PERSONNEL REUTING TO THIS PROJECT DURING CALENDAR TEAR 1956: None October 1956 (Attacbment l) PUBLIC miOJm SERVICE - - NATIONAL INSTITUIES OF HEALTH INDIVUHJAL PROJECT REPGBT Fart A. Project Deacription Sheet 1. NHI - lh2 SERIAL NIMBER 2. National Heart Institute iNSTiTun^ ^ divisi6n Clinic of General Medicine 3« and Experimental Therapeutics LABORATORY^ BRANCH, OR DEPARTMEan? 1|.. Clinical Endocrinology SECTION OR SERVICE 5. LOCATION (IF OTHER OBAN BETHESDAT 6, Cellular Transport Systems PROJECT TITLE 7. A. Despopoulos 8. PRINCIPAL INVESTIGATOR OTHER INVESTIGATORS 9. IF THIS PROJECT RESEMBLES, COMPLEMENTS, OR PARALLELS RESEARCH DONE ELSEWHERE IN THE PUBLIC HEALTH SERVICE (WITHOin INTERCHANGE OF PER- SONNEL, FACILITIES OR RJNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WIOUIN NIH). PROJECT DESCRIPTION (SEE INSTRUCTIONS): Objectives g To describe the reactions by li^iich tissues can accuinulate the specific substances required for synthesis of biolofd-cally required materials and eliminate the unessential products of cellular metabolism. Methods Employed; The general objectives described are approached specifically by the examination of renal function in patients, in intact animals and in tissue experiments « :JBie data derived from in vitro experiments are correlated mth studies in patients and in intact animals o Major Findings: lo Seventeen derivatives of uric acid and foiirteen derivatives of barbituric acid wei*e examined for their ability to depress the accumu- lation of p-aminohippuric acid by slices of rabbit kidney cortex. The inhibitory potency of the urates depended upon the presence of a carbonyl radical at position 2 or 8 of the molecule. N-methylation of the molecule increased the inhibition. Barbituric acid, barbital and NHI-1U2 phenobarbital possessed essentially equivalent potency but were less acti^^ tJian uric acid. N=methylation of the barbiturates increased the inhibition, but N-ethylation produced no effect. The data may be interpreted as demonstrating a non=ionic interaction between urates or barbiturates and a component of the tubular excretory system for organic anions. The inhibition produced by uric acid appear to be non-coropetive and apparently is produced xri.thout influencing the respiratory function of the tissue. 2. 5-hydro3qrindolacetic acidj, the end product of tryptophane metabolism is eliminated by an active tubular excretory process in patients with malignant carcinoid and is concentrated actively by slices of rabbit kidney cortex. These findings indicate that the renal excreticn of this compound is similar to that of p~aminohippurate . Proposed course of projects The findings above represent the first demonstration of the active renal tubular excretion of an indole acid. Additional indoles will be examined in order to describe the structural requirements for renal transport and to attempt a correlation with other molecular types which are known to be excreted by tubular activity. In addition^, inhibitors of the transport system will be studied in order to establish^ if possible, their locus of action in the renal celltilar structure. Significance to Heart Research; An understanding of renal excretory mechanisms increases the probability of designing drugs which will hasten tiie excretion of undersirable metabolites or which will retard the excretion of essential metabolites or of beneficial drugs. As applied to the indoles, this information should increase the understanding of the metabolism and physiological action of this important class of coii53oundso An extension of this work to other tissues may ultimately permit a clarification of the mode of action of pharmacological agents and of the mechanisms responsible for the maintenance of tissue integrity. Form No. ORP-1 October 1956 (Attachment I) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. imi^i^2 SERIAL NUIIBER 12. BUDGET DATA; ESTIMATED OBLIGATIONS MAN TEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL Fyi57$I7,000 $8,527 BUDGETED POSITIONS $25,52? 1.0 1„0 2.0 PATIENT DATS PROP OTHER TOTAL FT' 57 1 1 2 None 13. BUDGET ACTIVITT; RESEARCH A7 REVIEW & APPROVAL /~~? BIOLOGIC STANDARDS /~7 ADMINISTRATION ZI7 PROFESSIONAL & TECHNICAL ASSIST- ANCE /__/ U. IDENTIFT ANT COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FT 1957o IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S): None Form No* ORP-1 Calendar Year 1956 October 1956 (Attachment l) PDBLIC HEALTH SERVICE - - MTIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15.MII - lii2 SERIAL NUMBER 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR lEAR 1956: None 17. LIST HONORS AND AWARDS TO PERSONNEL RELATING TO THIS PROJECT DURING CALENDAR TEAR 1956: None Form Ho. (»P-1 Calendar Year 1956 October 1956 (Attachment I) FUBUC HEAL1H SERVICE - - NATIQNM. INSTITITTES OF HEAL19 INDIVIDUAL PROJECT BEPGBT Part A. Project Description Sheet 1. MHI ° li;3 SERIAL NUMBER Clinic of General Medicine and 2. National Heart Institute 3» Experimental Therapeutics INSTITUTE ClA DIVISI6n LABQRATQRY, BRANCH, OR DEPARTMENT **■• Experimental Therapeutics 5« SECTION OR SERVICE LOCATIOM (IF OTHER THAN BEmBSDAj 6. Anaphylaxis and Hypersensitivity PROJECT TITZ^ ■ , 7. T. Phillip Waalkesg Ph.D.g M.D. PRINCIPAL INVESTIGATOR ' ' Q Herbert Weissbach^, Ph.D.; Sidney Udenfriend^ PhoD, OTHER INVESnOATORS 9. IF OBIS PROJECT RESEMBLES, COMPI£MENTS, OR PARALLBI2 RESEARCH DONE ELSEWHERE IN THE PUBUC HEALTH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACILITIES OR RJNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WIIHIN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Objectives g Anaphylaxis in animals has been studied during the past year to determine what possible physiologically active substances^, may be released within the animal from a boundj, inert form to a free active form during this process. The emphasis during this time has been on the possible release of serotonin in anaphylaxis in the rabbit and to stucfy this release along with the simultaneous liberation of histamine. Further long range objectives are to gain s better under- standing of anaphylaxis and by so doing gain knowledge into the process of hypersensitivity and allergic phenomenon » By so doings it is hoped to be able to study and to understand better those disease of hyper- sensitivity which affect the cardiovasciiLar system^ e.g., rheumatic fever o NHi-=aii3 Methods Enployed; During this year, anaphylaxis has been studied both by in vitro and in vivo techniques in the rabbit. For the in vitro workj rabbi t~Flood from a sensitized animal was used and the specific antigen mixed with it. Serotonin and histamine were measured in the plasma after anaphylaxis both in vitro or in vivo. Major Findings; The above studies have shown that serotonin is released during anaphylaxis in a similar manner to histamine both as to time and to amount* Significance i The above findings indicate that another vaso active substance (serotonin) is released during anaphylactic shock in addition to histamine. Serotonin may also be liberated d-uring less severe or during chronic allergic phenomena and may be a factor in hypersensitivity diseases. An understanding of the processes in- volved in anaphylaxis may give clues as to those processes involved in diseases of hypersensitivity in which the cardiovascular system is a fundamental part. Proposed Course of Project; The stuc^y of anaphylaxis will be ex- tended to other animal species, Whether serotonin is a major factor in the acute manifestations of anaphylaxis of animals other than rabbits should be determined. In addition, the release of other substances during anaphylaxis (e.g. adrenalin) should be investigated. By in vitro techniques, these studies in anaphylaxis will be extended to hvunan blood. Form No. ORP-1 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - HAnONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. MHI-1^3 SERIAL NUMBER 12. BUDGET DATA; ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL "prof other TOTAL FI' 57 $39,000 $19,520 BUDGETED POSITIONS $58,520 2„0 1.0 3.0 PATIENT DAYS PROF OTHER TOTAL FI«57 3 1 4 None 13. BUDGET ACTIVITY; RESEARCH /T? REVIEW & APPROVAL £Z7 BIOLOGIC STANDARDS /~7 ADMINISTRATION n? PROFESSIONAL & TECHNICAL ASSIST- ANCE // H. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S); a) John Bozicevich-NIAID b) H. Ho Weissbach-Iffll 129 Form No, OHP-1 Calendar Tear 1956 October 1956 (Attachment l) PDBLIC BEALTH SERVICE - - NATIONAL INSTIiaTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15.NHI ° lli3 SERIAL NUMBER 16. LIST PDBLIGATIONS OTHER TH&N ABSTRACTS FROM THIS PROJECT DURING CALENDAR TEAR I956t None 17. LIST HONORS AND AH&RDS TO PERSONNEL RELATING TO THIS PROJECT DURING CALENDAR t^AR 1956: None Form No. ORP-1 Calendar Year 1956 October 1956 (Attactament I) PUBLIC HEALOH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. NHI - lljii SERIAL NUMBER Clinic of General Medicine 2. National Heart Institute 3. and Experimental Therapeutics INSTITUTE (A DIVIS16n LABORATORY, BRANCH, OR DEPARTMENT SECTION OR SERVICE LOCATION (IP OTHER THAN BETHESDAJ 6. Clinical Electrocardiography PROJECT TITLE 7. Robert P. Grants M.D. PRINCIPAL INVESTIGATOR 8 S§r^§I^t-li£_T§S§S^§l?£'j_i?iP:s OTHER INVESnOATOEtS 9. IF THIS PROJECT RESEMBLES, COMPI£MENTS, OR PARAII£Ifi RESEARCH DONE ELSEWHERE IN THE PUBLIC HEALIH SERVICE (WITHOUT INTERCHAlfQE OF PER- SONNEL, FACILITIES OR iUNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WI1HIN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): We have for some years been studying the usefulness of vector methods in dinicai EGG interpretation. During the past year we coirpleted a stucfy of ventricular conduction defects ^ arrhythndaSj, and a clinical autopsy correlation stucty (see publications). The past six months has been devoted to preparing a new edition of the book "Spatial Vector ECG" which McGraw-Hill will publish this winter. Projected work for the next year includes a study of the pre -excitation syndrome and further study of hemodsmamic factors in the genesis of T wave abnormalities . Form No. ORP-1 October 1956 (Attachment l) PUBLIC HEAXTH SERVICE - - KkTIOWL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. Iffll-.l44 SERIAL NUUBER 12. BUDGET PATH! ESTIMATED OBLIGATIONS H&N YEARS DIRECT REIUBDRSiSIENT TOTAL PROP OTHER TOTAL FT' 57 $10,600 $32,536 BUDGETED POSITIONS $43,136 .7 A 1.1 PATIENT DATS PROP OTHER TOTAL FT' 57 1 0 1 60 13. BUDGET ACTIVITY; RESEARCH /T? REVIEW & APPROVAL /~7 BIOLOGIC STANDARDS ' Fl APHINISIBATION EJ FROFBSSIOIIAL & TECHNICAL ASSIST- , , AHGE n U. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IF COOPERATING UNIT IS WITHIN NIH INDICA1E SERIAL NO.(S): a) Dr. George Kelser, George Washington University Medical School b) Dr. George Manning, Royal Canadian Air Force Form No. ORP-1 Calendar Tear 1956 October 1956 (Attachment l) PDBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15.NHI - Jhh SERIAL NUUEER 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: 1. Grants R. P.^ LEFT AXIS DEVIATION5 Vol. XIVj No. 2^ August^ 19565 Circulation 2. Grant, R. P., H. T. Dodge 5 MECHMISIC OF QRS COMPLEX PROLONGATION IN MAN, June Issue, Volume XXj number 6, pages 831^-852, The American Journal of Medicine, Inc., (Left Ventricular Conduction Disturbances) 3. Dodge, Ho T., R. P. Grant, MECHANISMS OF QRS COMPLEX PROLONGATICN IN MAN, Oct. Issue, Volume XXI, nimiber h, pages 53^-550, The American Journal of Medicine, Inc., (Right Ventricular Conduction Disturbances) h. Grant, R. P., IHE MECHANISM OF A-V AREHYTHMIAS, March Issue, Volume XX, number 3» pages 33U-3Uii, "1516 American Journal of Medicines Inc. 17. LIST HONORS AND AWARDS TO PERSONNEL RELATING TO THIS PROJECT DURING CALENDAR YEAR 1956: None Fozn No. ORP-l Calendar Year 1956 October 1956 (Attachment I) PUBLIC HEALIB SERVICE - - NATIONAL INSTITUIES OF HEALOS IHDIVUXJAL PROJECT REPORT Part A. Project Description Sheet 1. NHI - IhS SERIAL NUMBER , Clinic of General Medicine 2. National Heart Institute 3, and Experimental Therapeutics iNsnTwtS 6ii div1si6n ~ laboratory, brmch, or departmeiit h. 5. SECTION or service LOCATIOM (IP OflBER THAN BEIHESDAJ 6. Hemodynamic and Metabolic Factors of Heart Disease PROJECT TITI£ Robert P. Grants M.D. 8. PRINCIPAL INVESTIGATOR OTHER INVESTIQATORS 9. IF THIS PROJECT BESQffiLES, CCNPI£MENTS, OR PARAII£I£ RESEARCH DONE ELS^IHERE IN THE PUBLIC HEALTO SBRVICE (WIIHOUT INTERCHANQE OF PER- SONNEL, FACIUTIES OR FUNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): The volumetric and pressure changes in t^e various chainbers of the heart are studied by catheter and angiocardiographic technique. We have conpleted a stucfy of the pre s sure -voliime changes in mitral valve disease and presented this material at the recent American Heart Association Meetings in Cincinnati, We are now concentrating on the cases of mitral insufficiency and giant left atrium, studying blood volume coirpartmentalizing, renal -electrolyte ^ and tissue nitrogen metabolic alterations in these subjects. We are also studying the pulmonary vascular resistance in patients with heart disease^ examining the extent and mechanisms of adaptation to increased pressure produced by the G~suit, Form No. OBP-1 October 1956 (Attacbnent I) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT _. Part B: Budget Data 11. lJIHI-1^5 SERIAL NUllBER 12. BDDGET DAT/l; ESTIMATED OBLIGAHONS MAN YEARS DIRECT REBffiUBSEMENT TOTAL PROF OTHER TOTAL FT' 57 $19,800 $62,2^4-2 BUDCffiTED POSITIONS $82,0^2 .7 A 1.1 PATIENT DATS PROP OTHER TOTAL FI'57 1 0 1 2,000 13. BUPCaiT ACTIVITT; BESEARGH /X? , HEVIEW & APPROVAL /~7 BIOLOGIC STANDARDS /~7 ADHINISTRATION £7 PROFESSIONAL & TECHNICAL ASSIST- ANCE /~7 lU* WSSTIFI ANT COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OiSER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL ^-- . : FOB THIS PROJECT IN FT 1957. IF COOPERATING_DNIT IS IflTHN;^' '^ : INDICATE SERIAL NO. (S): ■-r^:^-'ri<^'--.:.-:^^^::.... Collaborative with the Surgery Branch and the Section on Endocrinology of the General Medicine and Experimental Therapeutics Branch Form No. CSP-1 Calendar Year 1956 October 1956 (AttaehMsnt I) FDBLEC HEALTH SERVICE - - RATIONAL IffSTIITOTBS OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Avarda & Pablieations 15.NHI - IM^ SSSJAL NDUBER 16. LIST FDBLIGATIONS OIHEB IH&B ABSTRACTS FBOH THIS PROJECT DURING G&LEBDiE lEAR 1956: None 17. UST WSSOBS AND AWARDS TO PSBSOHNEL REUTING TO THIS PROJECT DURING CALEHDAS lEAR 1956: Hone Fozn No. ORP-l Calendar Year 19^ October 1956 (Attachment I) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. NHI ~ IkS SERIAL HIMBER Clinic of General Medicine 2. National Heart Institute 3» and Experimental Therapeutics INSTITtTtlS M DIVISl6^ LABORATORY, BRANCH, OR DEPARTMENT h. 5. . . SECTION OR SERVICE LOCATION (IF OTHER OHAN BEIHESDAT The Evaluation of Cardiac Reserve in Human Subjects as Reflected by 6. Alterations in Lung Elasticity s^d Resistance to Gas Flow PROJECT TITLE "~ ""^ 7. Donald L, Fry^ M.D. PRINCIPAL INVESTIQATOR a JL°JP^lJi^L^^^^. yi'Jl») Charles McCall, MoD. OTHER INVESnOATORS 9> IF THIS PROJECT RESEMBLES, COMPIZMENTS, OR PARAII£I^ RESEARCH DONE EISBfflERE IN THE PUBLIC HEALTH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACILITIES OR RJNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Project; To evaluate the cardiac reserve in human beings as reflected by the alterations in lung elasticity and resistance to gas flow. Objectives; Previous studies have shown that the elastic properties of the liing and the resistance to gas flow are markedly altered in cardiac decompensation. The purpose of this study is to determine at what level of "cardiac reserve" these changes become apparent » It is hoped that these alterations of pulmonary function may reflect enibarrassment of cardiac reserve not detectable by conventional means » Methods Employed; The intraesophageal pressure recording balloon method was used to measure the elastic properties of the lunge Other procedures as outlined by D, L^ Fry et al» The Mechanics o_ Piilmanary Ventilation in Normal and in Patients with Emphysema, Amer, J., Med« XVI; 80, 195U» NHI-llt6 I4ajor Findings g Working in conjunction with the National Instrument Laboratories an electromechanical system was devised to maintain constant gas volume in a patient spirometer system, A thermal conductivity cell senses the concentration of a tracer gas, helitun. Any change in concentration is thereby converted to an electrical impulse through a servo-mechanism which admits oxygen to the spirometer. In this way the metabolic needs of the subject are constantly met in spite of wide variations in oxygen consumption, A new type of respiratory flow meter has been developed for this project. This meter with two conventional types has been evaluated as to accxiracy and stability. Respiratoiy flow patterns under various conditions have been obtained with this meter and subjected to harmonic analyses. Although the diagnostic significance of the harmonic content of tiiese patterns is as yet \mclear, much valuable knowledge has been obtained for theoretical computations in the field of ventilating mechanics and in the field of respiratoiy instrument design. Significance to Heart Research; The possible development of a method for early detection of reduced cardiac reserve. Proposed Course of Project; Considerable difficulty has been met in perfecting the constant gas volume system.. The injecting mechanism tends to "hunt". Present efforts are toward perfection of this device for patient use. Form No. ORP-1 October 1956 (Attachment l) PUBUC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. NHI-li<'6 SERIAL NUMBER 12, BUDGET DATA; ESTIMATED OBLIGATIONS MAN TEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FT' 57 $37,000 $11^,583 BUDGETED POSITIONS $151,583 2.0 2.5 ^o5 PATIENT DATS PROF OTHER TOTAL FT' 57 2 3 5 None 13. BUDGET ACTIVITT; RESEARCH ^J REVIEW & APPROVAL /~7 BIOLOGIC STANDARDS /~7 ADMINISTRATION EJ PROFESSIONAL & TECHNICAL ASSIST- ANCE / / U. IDENTIFT ANT COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FT 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S): None Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment I) PDBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C; Honors, Awards & Publications 15. MI ^ llt6 SERIAL NUMBER 16. nST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: Fryp D„ Loj Mallos, A„ Jo^ and Gasperj A.G.T,^ A Catheter tip method for measurement of the instantaneous aortic blood velocitys Circulation Research 627§5g 1906 Fry^ D« L„j, Noble^ F, W„j and Mallos^ Ao J.^ An electrical device for the instantaneous and continuous computation of the aortic blood velocity 5 Circulation Research in press ^ Vol 6^, 19^7 17. LIST HONORS AND AWARDS TO PERSONNEL REIATING TO THIS PROJECT DURING GALENDAB YEAR 1956: None October 1956 (Attachment l) FUBOCIC BMUm SERVICE - - NATIONAL INSTITUIES OF HBAL1H IliDIVIDaAL PROJECT REPORT Part A. Project Description Sheet 1. MHI - Ikl SERIAL NUMBER Clinic of General Medicine 2. National Heart Institute 3« and Experlemental Therapeutics INSTITln^ (iR DIVISI6n LABORATORY, BRANCH > OR DEPARTMENT 4. ■ 5. ^ , SECTION OR SERVICE LOCATION (IF OIBER THAN BE'lUESDAT Evaluation of the Recording Characteristics of Modem Physiological 6. Pressure Measuring Systems raOJECT TITLE 8. 7. Bonald L. Frv„ M,D. FRINCIPAL INVESTIGATOR _Frank J4^ .^o^le ^ _M ._E ^E . _ OOBER INVESTIGATORS 9. IF THIS PROJECT RESEMBLES, CCMPI£MENT8, OR PARALLELS RESEARCH DONE EISEWHERE IN THE PUBLIC HEALTH SERVICE (WITHOin? INTERCHANGE OF PER- SONNEL, FACILITIES OR RJNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). PROJECT DESCRIPTION (SEE INSTRUCTIONS): Projects The evaluation of ttie recording characteristics of commercially available physiological pressure recording systems. Objectives g A comprehensive evaluation of the stability^ static accuracy and dynamic accuracy of the many combinations of catheters and physiological pressure gages that are commonly used. To make available to the investi- gator a fund of reference data from v*iic he may choose a pressure recording system for his specific study iidaich will reduce recording artefacts to a rainimuiao Methods Eirployedg High fidelity pressure pulse tracings cannot be recorded via conventional catheter-manometer systems j, although they are adequate for measuring mean pressures. When high frequency response if required^ a gage attached directly to a needle or a catheter tip mano- meter should be used. Gages and catheter systems varied widely in the qiialities for which they were evaluated. Care must be exercised to select the proper system for the particular study. NHI-lii7 Significance to Heart Research; Data have been compiled and presented to the investigator vdio is interested in accurate measiireinent of pressure events o Although pressure manometer systems are in common use in connection vrlth cardiac catheterization and other laboratory procedures, these limitations are little understood c A knowledge of iJie characteristics of his measuring instruments, should enable the investigator to obtain more faithful pressure contours and more confidently interpret his experimental data. Proposed Course of Project; Finished. Form No, OKP-l October 1956 (Attacbaent l) -^^kfe*^ PDBLIC HEALTH SERVICE - - MTIOML INSHTUTES OP HEALTH IflDIVUHJAL PROJECT REPORT Part B: Budget Data 11' HHI-147 SKRTAT. NDUBER 12. BDDGET DAT&t ESTIMATED OBLIOATIONS HAN YEARS DIRECT REIMBURSEMENT TOTAL PROP OTHER TOTAL FI'57 $11,^00 $5,708 BDDCffiTED POSITIONS $17,108 .5 1.0 1.5 PATIENT DATS PROP OTHER TOTAL PT'57 0 1 1 None 13. BUDGET ACTiyiTI; RESEARCH /x7 REVIEW & APPROVAL ZZ7 BIOLOGIC STANDARDS /~7 ADMINISTRATION /U PROFESSIONAL & TECHNICAL ASSIST- ANCE / / 14.. HffiNTUT ANY COOPERATING UNITS OP THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IP COOPERATING UNIT IS WITHIN NIH INDIGAIE SERIAL NO. (S) : None Pora fc. 08P-1 Calendar lear 1956 October 1956 (Attaofandnt I) PUBLIC HEALTH SER7ICE - - 1U.TI0ML IHSTITdTES OF HEALTH INDIVIIIDAL PROJECT REPORT Fart Ci Honors, Amrds & Pabllsatlons 15. Mil - il|7 SESIAL NDHBER 16. LIST FDBLIGATIOHS OTHEE IHiH ABSTRACTS FROM THIS PROJECT DURING GklSSaUiSL YEAR 1956x Fiy, Do Loj Noble, Fe W, and Mallos A,. J., An Evaluation of Modem Hydraulic Pressure Measuring Systenis, Circulation Research in press Vol. 5, 1957 ~ 17. UST BDfiaRS AND AHABDS TO FESSOSMEL REUTING TO THIS PROJECT DDBIBG CAIERDAR TEAR 1956i fioxm OcTiODer 1956 (Attachment l) FOBLIG EEALffl SERVICE - - NATIOMM. INSTITUTES OF HEALTH IHDIVIIXIAL PROJECT REPORT Part A. Project Description Sheet 1. iKI-HtS SERIAL NUMBER Clinic of General Medicine 2. National Heart Institv-te 3, and Expe ilmental Therapeutics INSTITUTE Oi^ DIVISI6N LABORATORY, BRANCH, OR DEPARTMEINT !(., Clinical Investigations 5, SECTION OR SERVICE LOCATION (IP OOHER IHAN BETHESDAJ The Evaliiation of the Mechanical ana Hydrodjmamic Characteristics 6. of tiie Cardiovascular System in Animals PROJECT TITLE 7. Donald !..« Fry^ ji. J» 8. PRIKCIPAL INVESTIGATOR OOBER INVESTIGATORS 9. IF THIS PROJECT RESEMBLES, COMPI£MBNTS, OR PARALLELS RESEARCH DONE ELSEWHERE IN THE PUBLIC HEALTH SERVICE (WllHOUr INTERCHANGE OF PER- SONNEL, FACILITIES OR RJNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Project; It vjas the original aim of this stu(^ to evaluate the power output of the heart only. The techniques devised to do this however opened up a new approach to the entire field of cardiovascular mechanics and herfiodynamics . It is proposed now to expand the original study of heart power outpu. to include the measurement of: 1) the viscous and elastic properties of the vascular bed and aorta in vivo J 2) the measurement of tne transmission time of the pvlse wave betxireen the various points of the vascular beds 3) the dynamic dimensions of the aorta in vivo k) the piean prersui'e throughout the vascular bed 5) the phase and group velocity of the pressure pulse vjsve 6) the ejection curve of the neart ■' 7) the flow curve in the distal aorta Objectives : On the basis of theoretical considerations, the above measurement! should lead to: 1) the power output of the heart NHI"lli8 2) the power losses in the aorta and peripheral vascular bed 3) elucidation of the "standing waves" mechanism h) elucidation of the role of elasticity and viscosity in the normal function of the vascular system 5) prediction of the ejection curve from the periphei^al pressure pulse*. Methods employed; Blood velocity is measured by means of a new type flow-meter developed for this study and which is inserted directly in the aortic arch, Aortic pressure is measured by means of a short flexible trocar inserted in the aorta. Instantaneous aortic diameter is measured by electronic calipers developed for this project. A Survey Gage is utilized to measure pressures in the arteries at various points in the vascular system. By mathematical consideration of the above measurements, we hope to attain the objectives stated. Major Findings; 1) Two new types of blood velocity measuring techniques have been developed and reported (see below), a) a nylon orifice meter which can be introduced low in the aorta and passed to a point just above the valves, b) a catheter tip blood velocity measuring technique consisting of a double lumen catheter attached to a differential pressxare measuring device. The catheter technique will be applicable to human beings, 2) An electrical con^juter has been developed to instantaneously and continuously compute the aortic blood velocity from the "raw data" furnished by the above noted ca't.heter and differential pressvire gage system, 3) It has been established that the mean pressiire varies only slightly between the aortic valves and the femoral arteries although marked changes in contour occur. Significance to Heart Research; The development of an accurate method for measuring instantaneous cardiac output would make possible the evaluation of pharmacologic agents and surgical procedures in the treatment of heart and vascular disease, A broader knowledge of the mechanical and hydrodynamic principles of the cardiovascular system mi^t lead to a greater insight into the etiology and treatment of cardiovascular disorders » Proposed course of project; Current research is directed along avenues leading to simultaneous measurement of all parameters outlined above. Form No. OBP-1 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. NHI-148 SERIAL NUUBER 12. BDDGET DAI/L: ESTIMATBD OBLIGATIONS HAN TEARS DIBEGT rehiburseiient TOTAL ^F OTHER TOTAL FT' 57 $12,800 $5,393 BUDGETED POSITIONS $18,193 .9 .5 1.^ PATIENT DATS PROP OTHER TOTAL FT' 57 1 1 2 None 13. BDDGET ACTIVITT; RESEARCH PTl REVIEW & APPROVAL HI BIOLOGIC STANDARDS Fl ADMINISTRATION CD PROFESSIONAL & TECHNICAL ASSIST- ANCE n U. IDENTIFI ANT COOPERATING UNITS OF THE PUfiLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FT 1957. IF COOPERATING UNIT IS WITHIN NIH INDIGA1S SERIAL NO.(S): Laboratory of Technical Development, KEI-209 Ptorm Ho. ORP-1 Calendar Year 1956 October 1956 (AttachiBent I) PUBLIC HRALTH SERVICE - - MHOHAL INSTITUTES OP HEALTH INDIVIDDIL PROJECT REPORT Part C: Honors, Awards & Publleations 15.NHI - lit8 SERIAL NOMBER 16. UST FDBUGATIOHS OTHSl THAN ABSTR&CIS FROM THIS PROJECT DDBING CALENDAR TEAR 1956t A catheter tip method of itKasvirement of the instantaneous aortic blood velocity. Circulation Be search, Septembers 1956. 17. UST assess An> AIASSS to PISSORHEL RELATING TO THIS FftOJECT SORING CUSma, YEAR 1956: Nona Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment l) FQBLrC HEALIH SERVICE > - NATIGNAL IHSTITUXE3 OF HEAL1H INDIVIIKJAL PROJECT BEPGRT Part A. Project Description Sheet 1. NHI - llt9 SERIAL NUMBER Clinic of General Medicine 2. National Heart Institute 3, and Experimental Therapeutics INSTITOT^ 4ft DIVISION LABCnATORY, BRANCH, OR DEPARTMENT ^' _ 5. __, ^ SECTION GR SERVICE LOCATION (IP OIBER THAN BETUESDA) 6, Dynamics of Aortic Stenosis PROJECT TITIE """^ 7. Dr. Harold T. Dodge - Dr^ Herbert L, Tanenbaum 8. PRINCIPAL INVESTinATOR OIHER INVESnOMORS 9> IF THIS PROJECT RESQffiLES, COMFIfMENIS, OR PARALLELS RESEARCH D(»1E ELSEWHERE IN THE PUBLIC HEALTH SERVICE (WIOHOUr INTERCHANGE OF PER- S(»(NEL, FACILITIES OR lUNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WIOSIN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Project; Development of methods to further evaluate the dynamics of aortic stenosis Objective s A better definition of the pathologic physiology in the patient with aortic stenosis Methods Enployedi In conjunction w. th the surgical group who have developed methods for measviring left intraventricular and aortic pressures^ we have been doing cardiac outputs by means of the cfye methods, at first using a multiple sampling device with analysis of individual timed dye containing blood samples. Patient Materials ' Average Stay No, Days Admissions: Adult males 3 21 MHI"lii9 Major Findings : After a period of trial and error concerning site oTdye injection, method of sanipling and analysis of curves, etc., we are finally in a position to start collecting data.. Significance to Heart Research; These studies will make it possible to calculate not only the pressure gradient across the aortic valve, but also left ventricular work, effective left ventricular xrork, aortic valve orifice size . The data can also then be conipsred to post operative data Proposed Course of Project; Work is now in progress to record outputs by means of a cuvette and densitometer with direct recording of the dye curves ^ Also further studies on methods to inject and measure dye directly into the left atrium at the time of bronchos- copy and left atrial puncture . Form No. ORP-1 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDDAL PROJECT REPORT Part B: Budget Data 11. lifil.>l'49 SERIAL NUMBER 12. BUDGET DATA: ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FY' 57 il6,i|-00 150,926 BUDGETED POSITIONS $67,3''-'6 1.3 .3 1.6 PATIENT DAYS PROF OTHER TOTAL FY' 57 2 0 2 63 13. BUDGET ACTIVITY; RESEARCH EJ REVIEW & APPROVAL HI BIOLOGIC STANDARDS /~7 ADMINISTRATION EJ PROFESSIONAL & TECHNICAL ASSIST- ANCE Z_/ 14. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IP COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S): Surgery Branch, KHI Form No. OBP-1 Calendar Year 1956 October 1956 (AttachiKnt I) PDBLIG HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15.NHI ^ llt9 SERIAL NUMBER 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: None 17. LIST HONORS AND AWARDS TO PERSONNEL REUTING TO THIS PROJECT DURING CALENDAR YEAR 1956: None Form No. ^JP-1 October I956 (Attaciment l) Calendar Year 1956 HBLIC EEALffi SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Pfojeet Inscription Sheet 1. mi -150 SERIAL NUMBER 2. k. 6. INSTITUTE dTlDIVISibN 3 , Gex' ont olo g^^' 13 ranch SECTION OR SERVICE Mstaoolisrn L Endocrlii raojEcFrafU" LABORATORY, BRANCH, OR DEPARTMENT Baltimore City Hospitals , 5. Baltimore 2lj.j, Maryland LOCATION (IF ^^ THAN BETHESDA) Ld function Wo i!iii,J.r,e, PRINCIPAL INVESTIGATOR Thy:i%)id f-uijotion ,stu.dicy: Gr e ^(xexm , B ake? ^ OTHER INVESTIGATORS Vitamin B]_2 studies; Shocks „ ^ - - „5 tSfH'_1^2l?2§ - -2JE- is - 1 - - - . 9. IP THIS PROJECT RESEMBLES, COMPLEfrffiNTS, OR PARALLELS RESEARCH DONE ELSEWHISRB IN THE PimLIC HEALTH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACILITIES OR RM»S), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). 10. PROJECT DESCHIPTICa* (SEE INSTRUCTIONS) 8 -ter-itior). ■frdth age in "normal" Objecti."^?'es; To gain ir-ifor'.-ta.tl h'orriaii "adtilt^' insias of t a 9 Thyroid ftirsctifs- 1, Ik "refuting .....:- 2a In response to thia-oid stirivalating hormone (TSH) 1-, -iaquaoy of bo<:5y stores of vitamin B-j2 as measiired hjt '' „ Seritri levels NHI-l50_ lUMBER Methods Employedg ao Thyroid gland uptake and disappearance from the plasma of iodide^Sr^ protein-'bomid iodine in the serunij, BMR (open circuit )j, body- water determinations by antipjTine and thiocyanate methods e b, 1» Microbiological estimation of Bto in serunio 2c Appearance of radio- activity in uriiie after oral administration of radioactive vitamin 3^2 followed by a large intramuscular "flushing" dose of unlabelled B^^* Patient Materials Patients of the Gerontology Branch and Infirmary Division of the Baltimore City Hospitals « Major Fjndingsg a. Thyroid functions lo In "resting state" » Preliminary evaluation of studies not yet completed indicated decrease in the uptake of radioactive iodide-^31 i-y the thyroid gland mth advancing age in "healthy" adult males o 2. Response to TSH? Studies were designed to evaluate^ in men of various ages, maximal response to administration of thyroid stimiilating hormone (TSH)o In two middle-aged (ages U^s^l) and three elderly (ages 803,861,92) males there was no significant age difference in response^ with respect to increment in BMR^, EBI^ and rate of uptake of 1I3I by the thjTToid gland, b, Vitamin B^2° ^' Serum B^^p levelsg In this stucfy of ^11 "healthy" human subjects of ages 20 to 9Us, there was significant decrease in serum Bj2 level with advancing age* Referred to an estimated B^^p level at age $0 of about 230 raicromicrograms per mlo of serumj, the 62^2 level decreased about 20 micromicro grams per ml» for each decade of ageo If diet played any significant role in this deci'ease^ the evidence suggest edj it was due to selection from an adequate diet ly the subjects themselves, 2. Absorptions Urinary excretion of orally-administered radioactive vitamin B2_2s foUowing parenteral administration of a large "flushing" dose of unlabelled Bj^2s ^^^ ^^'^ significantly different iii- elderly male subjects as compared to young adult males o *^W ' SlgnificaxLce of the Proffl:^am to the Bastituteg The program serves the needs of ttie Gerontolo^ BFanSi as a portion of fhe Institute devoted largely to the study of aging as a biological phenomenon o Proposed Goiurse of the Project^^g The above-noted studies will be completed dm=ing the next six months. Further studies of thyroid function in the "resting state" wlU utilize measurements of the protein-bound iodine and ll31-.thyToxine disappearance rate in order to estimate the rate of thyroid hormone synthesis and degradation in men of various ageso Beyond this point it is anticipated that there will be increasing need for animal studies for confirmation, under controlled laboratory conditions^ of the results obtained in man^, and also for further study to determine the mechanisms involved in the observed changes with age» Initially such NHI^IS'O SERIAL"MffiM studies -will include evaluation^ in rats of various ages^ of thyroid I^il uptaka, the rates of syr;,thesis and degradation of thyroid hoimone using the thyroxine-disappearance methodj of the maximal response of the thyroid gland to TSH administration^ and of the BMR and FBI in the rat.. Following oz' concurrent with the above studissj, there should be tissue studies in the rat to search for physiological alterations which aecoiint for the observed alterations of function^ if any, with advancing age» The studies described above would require from three to ten years to complete^ depending on personnel and other budgetary support and, to some extentj, on good fortune in choice of approaches to elucidate the key metabolic defects ^ if existent: It is anticipated that further studies with vitamin 62^9 will include measurement of plasma levels at appropriate intervals following the ad- ministration of much smaller oral doses of radioactive B]_2 than heretofore utilized; These studies i-ri-11 include measijirement of 62^2 appearing in stools T Attempt will also be made to measure radioactivity appearing in the urine in the absence of a "flushing" dose of unlabelled Bi2> l^^t it is not expected that the latter will be practical except to set upper limits on the ainount of B2_2 lost from the plasma into the urine, Form No. ORP-1 October 1956 (Attachment I) PDBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. mi~i50 SERIAL NUMBER 12. BUDGET DATA; ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FY' 57 $49,800 $2,663 BUDGE'ffiD POSITIONS 152,463 2.6 3.3 5.9 PATIENT DAYS PROF OTHER TOTAL FY' 57 3 4 7 0 13. BUDGET ACTIVITY; RESEARCH /F7 REVIEW & APPROVAL /Z7 BIOLOGIC STANDARDS /~7 ADMINISTRATION /U PROFESSIONAL & TECHNICAL ASSIST- ANCE /__./ 14-. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957= IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S): Baltimore City Hospitals lorm Bo, OiS>-l Calendar jfear 1956 October 1956 (Attachiaeiit l) PUBLIC HEALTH SHIVICE - ~ NATIORAL INSTITUTES OP HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15. NHI-^lgO SERIAL NUMBER 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS FBOII THIS PROJECT DURING CALENDAR YEAR 1956: Shockj H« We J Physiological aspects of mental disorders in later life, Cliap. 17 i£S Oscar J. Kaplan (Editor), Mental disorders ta later lif'ec Stanford Univ* Press , Stanford, 19^6, 2nd Edition, pp, Ii.7-97. Shocks Yu WoS Some physiological aspects of aging in mano Bull, NoY. Acado Medo, 32s {h) ^ 268-283, April 1956, Shook, Wo WoS The effects of some of the steroid hormones on the metabolic balances in aged maleso In; Eo T, Engle and G, Pincus, (Editors), Hoi'mones and the aging process^ Academic Press, Inc., . New York, 1956, pp. 283-298, Shockj No VJoJ Sor.'ie physiological aspects of aging in man. Amer. Practitioner^ 7s (9) s lit23-lU28, Sept, 1956, 17. LEST HONORS AND AWARDS TO PERSONNEL RELATING TO THIS PSOJECT DURING CALENDAR YEAR 1956 s Yie W, Shock v;£is appcini^ed to the Program CojTrdttee of the Foijrth International Gerontological Congress to be held jjn Mirano aiid Venice, Italy in Jiily 195 7 «. Form No. ORP-1 Calendar Year I956 October 195^ (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 2. National Heart Institute 3» Gex-'ontology Braach INSTITUTE ()A DIVISI6N ~" LABORATORY, BRANCH, OR DEPARTMENT Baltimore City Hospitals ^ k. ______,___=_:_ 5« Baltimore Zhs Maryland SECnOW OR SERVICE LOCATION (IF OTHER THAN BETHESDA) 6. Age Changes in the Chemical Composition of Various Tissues of the Rat PROJECT TITLE 7. Marvin J. Yiengst PRINCIPAL INVESTIGATOR 8. CaSER mVESTIOATQRS 9* IF 1HIS PROJECT RESSffiLES, COMPLEMENTS, OR PARALLELS RESEARCH DONE Q£EUHERE IN THE PUBLIC HEALTH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACILITIES OR RJNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Objectives; The objectives of this project are to investigate age changes in chemical composition of tissueso The principal aim of the project is the development of a suitable means for the estimation of cell ma,sSo NHI-^lgl SiiRIAL NUMBER Methods Employed; Standard methods of chemical analysis are used for the determination of tissue components such as sodium, chloride, potassium, phosphorus, nitrogen, fat and water in liver and muscle of rats of different ages.- A smaller mjiriber of components are determined in brain, kidney and heart because of the size limitation of these tissues. Major Findings; A comparison of the chemical composition of muscle was made between young rats aged 1?-15 months and older animals aged 2ij.""27 months* E:x lination of this tissxie in male rats showed an agewise in- crease in extracellular electrolj^tesj a decrease in cellular components and no change in total water. Intracellular water was calculated by difference between total water and chloride spacer The three cellular components and intracellular water a,ll shox\red a decrease of 6i' which ua.s statistically significant at the O.l's level. There xras no chanf;e with age in the ratios of the cellular co'^^onents, A sinilar ^vt Inso si^Tiif- icant trend was foijnd in muscle of old fe;nale rats. These findings indicate l) a loss in cell mass of skeletal muscle diu-ing aging and 2) suggest that this may be an actual loss of cell nvnbers because of the constancy of cell composition, There were no significant changes, due to age_, in any of the liver components exajiiined. Work, now in progress, is directed toward obtaining inform.ation on the chemical composition of brain and kidney. Significance to Heart Research i This project is directed toward an evaluation of the aging process by providing information on the degree of change of the intracellular phase of tissues: Such cellular phase changes are one of several i.piportant contributing factors to reduced tissue metabolj.s?ii, in old a:;o, the oLi^.j- Icing circulatory impairment. Thus the role of tb.e cardiovascular rr-iston Ln ar;ing i^.ay bo bettei' evaluated by estimations of cell ;;af!c Proposed Course of Project; Studies on the chemical composition of tissues x-jill be extended to include heart as old animals become available. Work currently in progress on tissues wi.ll be completed. Form No. ORP-1 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. mi-151 SERIAL NUMBER 12. BUDGET DATA; ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF ' OTHER TOTAL FI'57 118,200 1975 BUDGETED POSinONS $19,175 o7 loB 2o5 PATIENT DAYS PROF OTHER TOTAL FY' 57 1 2 3 0 13. BUDGET ACTIVITY; RESEARCH /T7 REVIEW & APPROVAL /~7 BIOLOGIC STANDARDS /~7 ADMINISTRATION ny PROFESSIONAL & TECHNICAL ASSIST- ANCE /~7 U. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILIHES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO. (S): Baltimore City Hospitals Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15. NHI-l^l SEEIIAL NUMBER 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: None 17. nST HONORS AND AWARDS TO PERSONNEL REUTING TO THIS PROJECT DURING CALENDAR YEAR 1956: None Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITOTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. ^rai^l.g; SERIAL NUMBER 2. National Heart Institute 3, Gerontologsr Branch INSTITUTE GR DIVISION " LABORATORY, BRANCH, OR DEPARTMENT Balfcliriore City Hospitals,, k, ■ 5« Baltimore 2li.<, MaiTlgM ____^ SECTION OR SERVICE LOCATION (IF OTHER THAN BETHESDA) 6. Age Changes in Renal Physiolo^ PROJECT TITLE 7. M« W, Shock and C. H„ EajTO'cJs PRINCIPAL INVESTIGATOR "^ ' 8. OTHER INVESTIGATORS 9. IF THIS PROJECT RESEMBLES, COMPLEMENTS, OR PARALLELS RESEARCH DONE EISEWHERE IN THE PUBLIC HEALTH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACILITIES OR RJNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WimiN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Objectives g The objectives of this project are to describe and eiucidaie the mechanisms of age cha.nge3 in remal fimction» Methods Employedg Foi" studies on the humaur, standard clearance methods for estimating GFR^ renal plasma flow and Tj^ are usede Studies on tissue slices and homogenates prepared from rats of different ages are analyzed by standard methods for specific enzyme activities 0 NHI-lg2 Major Findings s With rising plasma levels of vitamin B]_2 produced by- continuous intravenous infusion in male ad\ilts5 the amount of B]_2 appearing in the urine was significaatly less than the amount filtered at the glomerulus. Although the data connot offer proof of tubiilar re- absorption of 'Bi2f ^"^ ^^ apparent that under the conditions of these experiments, there was retention of B]_2 in the body. In old female rats there was a decrease (21^) in the cytochrome C oxidase activity of kidney tissue (wet weight basis) that was greater than the age reductions in DNA^ RMA on protein N of the tissue. In male, rats, no significant changes occurred in this enzyme system. Tests of oxidative phosphorylation in old (2li-27 month) and young (8-10 month) rat kidney tissue showed a decrement in the old tissue when enzyme activity was based on wet wei^t. The decrease in the rate of esterifica- tion of inorganic phosphate was greater than the reduction in oxygen up- take. Thus a reduction in P to P ratio was found in the old kidney tissue. Thus evidence of age changes in cellular metabolism is beginning to accumulate. Significance to Heart Research: The incidence of renal disease increases with age. Consequently it is important to identify changes in renal function that may occur T-rith age prior to the development of clinically identifiable renal disease. Knowledge about age changes in renal mechanisms is necessary for the development of rational methods for the prevention and treatment of kidney disease. Proposed Course of Project; Serial determinations on age changes in kidney function in the same subjects mil be continued. The experiments on rats will be extended to other enzyme systems. In addition, studies on the concentrating ability of kidney slices with respect to PAH will be initiated. Form No. ORP-1 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - MTIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. IIrX52 ■ SERIAL NUMBER 12. BUDGET DATA: ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FY' 57 $9*700 1523 BUDGETED POSinONS $10,223 o5 »6 1,1 PATIENT DAYS PROF OTHER TOTAL FY' 57 1 1 2 0 13. BUDGET ACTIVITY; RESEARCH /x7 REVIEW & APPROVAL /~7 BIOLOGIC STANDARDS /~7 ADMINISTRATION no PROFESSIONAL & TECHNICAL ASSIST- ANCE /_/ 14. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S)! Baltimore City Hospitals Johns Hopkins University School ©f Hygiene and Public Health Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment I) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Airnrds & Publications 15. ^^1-^152 SERIAL NUMBER 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: Stoloffp 1,5 D, M» Watkin and No ¥, Shock i Age and the ratio T^PAH/Tj^ diodraste J. Geronto^ ns {h) , 3QQ-390, Oct« 1956. 17. LIST HONORS AND AWARDS TO PERSONNEL RELATING TO THIS PROJECT DURING CALENDAR YEAR 1956: None Form No. ORP-1 Calendar Year 1956 October 195^ (Attactoent l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A, Project Description Sheet 1. NH] SERIAL NUMBER 2. National Heart Instltate 3- Qerontdlogy Branch INSTITUTE 5R DIVISI6N LABORATORY, BRANCH, OR DEPARTMENT BaltlTiiora Clj^' n.>splt,a2,S5 Ij. . 5* Baltjjoore 2li, Ka,ryl8.ncl SECTION OR SERVICE LOCATION (IF OTHER IHAN BETHESDA) 6. Age Changes in Cenulax and Tissue BiocheMsti^^ PROJECT TITLE 7» Charles H. Barrows PRINCIPAL INVESTIGATOR OTHER INVESTIGATORS 9. IF THIS PROJECT RESEMBLES, COMPLEMENTS, OR PARALLEIfi RESEARCH DONE ELSEWHERE IN THE PUBLIC HEALTH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACILITIES OR FUNDS), IDENTIFY SUCH RESEARCH? (BY SERIAL NO.(S) IF WITHIN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Ob^eoti^ress The cbjectlve of this projecb is to axamtee vaa'io'as tigsties of rats for age changes in the arao-tJ2;,it of protop^jism and to detetrrdne the metabolic characteriatics o.f -hhe exlstajig protoplasm. NHI-153 Methods Employeds These experiments have been carried out on slices, aad homogenates prepared from various tissues of I2-II4. month old and 2lt=27 month old ratSj, bred in our laboratory animal quarters. Established methods have been employed for the determination of specific enzyme systems and of various tissue components such as DM, RNA and protein N . Maj or_j\indin£s £ Previous studies indicated that a decreased succinoxidase of kidney and heart but not liver may represent an initiating change which occurs dai'ing aging i.- Althou^ the enz^nne system succinoxidase is an intregrated ^stem composed of two enzymes viz succinic dehydrogenase and cytochrome C oxidase^ no agevdse decrement's in the concentration of succinic dehydrogenase based on the protoplasmic mass of the tissue (concentrations of DWA^ RNA and protein W) were observed ^ Experiments now in progress indicate that the proposed agewlse decrease in the concentration of cytochrome C oxidase does exists Since "this enzyme is important in the formation of the high energr phosphate bonds of ATP, the oxidiative phosphylation of vaxious tissue of young ai:id old rats is also presently being exajnined« These data indicate that the rate of oxidiative phosphylation may be reduced in certain tissues of senescent rats when the activity is based on the wet weight of the tissue samples . Thus these results imply that the ener^'' production within the tissue of old rats is decreased,, Sjjnce all enzymes thus far isolated from tissues are proteins, the estimation of changes of these activities provides a means of measuring tissue protein synthesis f Therefore the concentration of plasma cholines--- terasOj an enzyme whose concentration is kno^m to be readily changed by conditions which effect tissue protein synthesis, was determined in men and female rats* A comparison of the concentration of this enzyme in 12 and 2ij. month old female rats dononstrated a marked decrease in the older animals (P <,001), Although no significant difference in the concentration of this enzyme in tlie liver was observed, inspection of the individual values mthin the older group showed approximately I;0^ of the old animals ■trith liver choline st erase values of only 50-75^ of all other animals. The corresponding plasma cholinesterase was extremely low* Data thus far obtained on the concentration of plasma cholinesterase of 129 men between the ages of 20-89 years demonstrate a decrease in subjects over 70 years but little if any effect before this age, , These data may indicate an impaired tissue protein synthesis by the liver of old feriiale rats and men^ The mean DNA per nucleus of washed nuclear preparations isolated from liver failed to demonstrate any agewlse differences. It has been shown that at least txTO different populations of nuclei can be isolated from liver homogenates. Separation of the nuclei has been successfully carried out using tiie density gradient technique. The txro fractions thus isolated were found to be 3$% homogeneous 0 The mean DNA per nucleus of the fraction containing -the larger nuclei was twice that of the fraction containing the smaller nuclei^ SEKtAt MtM^K Significance to Heart Researehg These studies attempt to examine the aging process at a tissue and cellular level. Since the loss of cells of various tissues is a primary factor in the reduction in reserve capacity of various organ ^stous that occurs xd-th age^ it is important to determine what functional changes occur that prevent individual cells from maintaining iiieir existence. It is also important to know whether these changes are a fundamental characteristic of the cell or whether it is secondary to circulatory impairments in aging animals. Prop;osed Course of Project; Additional enzyme systems will be surveyed for age changes^ including estimates of oxidiative phosphoiylation in isolated mitochondria. Age differences in the quantitative aspect of tissue protein synthesis of rats will be examined using the depletion- repletion method as well as adaptive enzyme systems. In addition qualitative differences in the tissue protein synthesis of rats of different ages will be investigated by examining the hydrolytic products of homogenates treated with specific proteolytic enzymes. Since the feeding of diets containing whole desiccated liver to young female rats results in a marked increase in plasma cholin esterase, it is of interest to ascertain whether this procedure is capable of increasing the concentration of this enzyme in senescent animals. Form No. ORP-1 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. Jffitl53- SERIAL NUMBER 12. BUDGET DATA; ESTIMATJiUJ OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FT' 57 131,300 $1,688 BUDGETED POSITIONS $32,988 loO 3o2 4»2 PATIENT DAYS PROF OTHER TOTAL FI'57 2 2 4 0 13. BUDGET ACTIVITY; RESEARCH /x7 REVIEW & APPROVAL /~7 BIOLOGIC STANDARDS /~/ ADMINISTRATION no PROFESSIONAL & TECHNICAL ASSIST- ANCE / / lA. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO. (S): Baltimore City Hospitals Johns Hopkins University School of Hygiene and Public Health Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment I) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15. NHi-°lg3 SERIAL NUMBER 16. UST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: Shock r, W, W. s Aging as a biological problem. Fed, Procoj Baltimore^ 15^ (3)^, 93Q~9hl:, Septo 19.56, Barrowsj, Co Hoj JroS Cellular metabolism and agingo Fed, Proc Baltimore, 15§ (3)s 9Sh"9S9, Sept. 19^.6. 17. LIST HONORS AND AWARDS TO PERSONNEL REUUNG TO THIS PROJECT DURING CALENDAR YEAR 1956: None Form No. (MlP-1 Calendar Year 1956 Octolier 1956 (Attachment l) PUBLIC HEALOH SERVICE - - NATIQNM. INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. NHI-l^h SERIAL NUMBER 2. National Heart Institute 3» Cjerontology Branch INSTITUTE 6rt DIVISI6N ~ LABORATORY, BRANCH, OR DEPARTMENT Baltimore City Hospitals j, k. 5" Baltimore 2ks Ifaiylaid SECTION OR SERVICE LOCATION (IF OTHER THAN BETHESDA) 6. Cardiovascular Hemodynamics, Illo The peripheral clreiLlatlon in maiic PROJECT TITLE 7. Milton Lat^do•i^lne PRINCIPAL INVESTIGATOR ' ~ ""^ ~" ' 8. OTHER INVESTIGATORS 9. IF THIS PROJECT RESEMBLES, COMPLEMENTS, OR PARAUiELS RESEARCH DONE ELSEWHERE IN THE PUBLIC HEALTH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACIUTIES OR RJNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). PROJECT DESCRIPTION (SEE INSTRUCTIONS): Objectives g To study the circulation in the extremities of living human subjects, with respect to changes with age^ disorders in function^ and to increase our undeis banding of factors governing the blood flow to these tissues. B'2ii lALTTCTiUiS Methods Employed; Skin tenperatiu^e is iivsed as an index of circulation to the skin^ and venous occlusion plethysmography as a measure of blood flovr to an extremity , .Studies are carried out on rate of skin cooling under controlled thermal environment, and on the resting and 'vasodilated' flovj to the foot. Rectal terr.pcraturo is recorded as an index of "core" temperature, 01 in leal i .aterial ; 'mbjects are irori) our rc;.;or!.rcii warcij other hospital wards, and m.embers of the staff * Kajor^Fi-ndinf^s iige differences in equilibrated temperature of the extremities exposed to a coo'l. (2?.5°P) environment are not explained by consistent differences in cooling rate or "core" tempera! re. The response of skin temperature to the reflex vasodilatation induced by heating the trunk has been used as an aid to evaluation in clinical and asjTiptomatic disorders of the peripheral circulation. S i^fflif icanc_e_ jbo Heart Research ; Describes the peripheral vascular responses of 'normal' adult and older men, providing standards, ShoxiTS how commonly limitation in peripheral vascular function may be encoujiterod among .■ dult m.ales without clinically demonstrable disease ^ Represents an aid to the diagnosis of peripheral vascular disease. Provides a critical evaluation of the use and limitations of secondary indices of circulatory function < Proposed Course of Progect; Venous occlusion plethysmography will be used to estimate peripheral circula.tion under various conditions of 'maximal' vasodilatation. 'Minim.al' peripheral resistance and the changes induced in resistance are to be studied in relation to altera- tions of arterial pressure. Form No. ORP-1 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. Wl-I5h SERIAL NUMBER 12. BUDGET DATA; ESTIMATiiD OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FT'-57 $14,500 $785 BUDGETED POSITIONS $15,2S5 .4 lo6 2o0 PATIENT DATS PROF OTHER TOTAL FT' 57 1 2 3 0 13. BUDGET ACTIVITI; RESEARCH /x7 REVIEW & APPROVAL f~? BIOLOGIC STANDARDS /~7 ADMINISTRATION ny PROFESSIONAL & TECHNICAL ASSIST- ANCE n U. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S): Baltimore City Hospitals Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDIIAL PROJECT REPORT Part C: Honors, Awards & Publications 15.. RI=15'li SERIAL NUMBER 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: None 17. LIST HONORS AND AWARDS TO PERSONNEL RELATING TO THIS PROJECT DURING CALENDAR YEAR 1956: Kone Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment I) PUBLIC HEALIH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. WKJ^l.^.,? SERIAL NUMBER 2. ll-aticmal Heart Inst-itute 3. gerontology- Branch INSTITUTE 6ft DIVISION LABORATORY, BRANCH, OR DEPARTMENT Baltimore Citj Hospitals, I4.. 5. raltljniore 2ljj TIarylarid SECTION C« SERVICE "^ "^ ~ LOCATION (IF OTHER THAN BETHESDA) 6. CcirdloYagcijlar Heraod;^n-iamlcs» II. Cardiac performance in rfsaru PROJECT TITLE "~~ ' "" 7. Milton Landovme PRINCIPAL INVESTIGATOR 8 . - A%. A". L^J-JJWl °il^ -1-5. Matt OTHER INVESTIOATCffiS 9 . IF THIS PROJECT RESEMBLES, COMPLEMENTS, OR PARALLELS RESEARCH DONE ELSEWHERE IN THE PUBLIC HEALTH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACILITIES OR RJNDS), IDENTIFY SUCH RESEARCH; (BY SERIAL NO.(S) IF WITHIN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Objectives^ Tc study the perforraaxice and fTonctional liiiiitations of tlienTv'jj^ human heart as affected by age anxl ctisorders of the circulatiorio Methods Epipl,Qyeds Cardi.ac outptit is measiired by dye djlution tt'chiiiqixe at "rest an.d during gi-aded exercise at two levels of exercise. Femoral art.erial pressxu'e is measured by intra~arteri.al needle and capacitance rn3,nonetere Arterial blood gases are determined manone trie ally » Ventilation^ O2 uptake arid COg pro- duction are deterndxied to provide measures of veatilation and respiratory gas exchange. Calciaations of csrdj^x outpiifc, ^#3rk NHI=l55 'power' and peripheral resistance are considered in relation to rest, exercise^ ventilation^, Oo uptake and work performed.. Clinical Material; Subjects are obtained from oui' 60 bod v;ard, the other ■wards of Baltimore City Hospitals and the Hospital Infir .ary, Major Findings; For moderate exercise the increase in cardiac output is related to the increase in oxygen uptake ^ In middle aged and old males the increase averages about 500 ml^/lOO ml* 02, a ratio within the lower limits reported as normal by other workers s Ratios below 500 reflect less adequate circulatory performance, implying diversion or altered re- distribution of circidation to other organs^ In h subjects ratios were less than 300 » After more strenuous exercise the ratios tend to be lower .- There has been no evidence of an agewise trend in these ratios in the relatively limited number of studies completed. The subjects were all of sedentary habits, about half had clinically suspected or diagnosed disorders of cardiovascular, pulmonary or central nervous systems, but the clinical diagnosis did not appear to characterize the circulatory response to exercise? Increases in cardiac left ventricular pressure work and power under exercise have been related to the resting performance and the increase in oxygen uptake, Increase in the kinetic energy component of work has been estimated^ Peripheral circulatory resistance tends to rise slightly and stroke volume falls in the subjects irith the lowest ratios of increase in output to increase in O2 uptake » Peripheral resistance falls and stroke volujne is maintained in subjects who support a more adequate perfusion of bo(^ tissues-. Significance to Heart Research; Represents a contribution to the under= standing of cardiac and total circulatory function, how these are affected by age and exercise. Helps to explain the logistical pattern of circulatory supply, by finding out how the circulation to organs is altered by diversion as well as augmentation, in response to a change in requirements for perfusion^ Suggests that decreasing circulatory performance of age and disease may be expressed in an altered distribution of circulation at rest, and re- vealed under conditions of demand, by diversion to areas of relatively lower risistance* Proposed Course^ of Project; Continuation of careful study of subjects, with and without clinically diagnosable disorders of the cardiorespiratory and neuromuscular systems| at rest and at two levels of exercise « The response of 2 body sites to an applied sinusoidal force of essentially constant amplitude and over a selected frequency range will be compared for subjects of different age and ballistocardiographic patterns » Form No. ORP-1 October 1956 (Attachment l) PDBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11- NHT-.155 SERIAL NUMBER 12. BUDGET DATA; ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FT' 57 121,500 $1,165 BUDGETED POSITIONS 122,665 1»5 .6 2.1 PATIENT DATS PROF OTHER TOTAL FI'57 2 1 3 0 13. BUDGET ACTIVITY; RESEARCH /x7 REVIEW & APPROVAL CJ BIOLOGIC STANDARDS /~7 ADMINISTRATION no PROFESSIONAL & TECHNICAL ASSIST- ANCE n 14. IDENTIFT ANT COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FT 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO. (S): Baltimore City Hospitals Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15. NHI-155' SERIAL NUMBER 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: Landowner M„% Methods and limitations in the study of human organ system fimction, Ciba Foundation Colloquim on Methodology of the study of aging. July 19$6o To appearo 17. LIST HONORS AND AWARDS TO PERSONNEL RELATING TO THIS PROJECT DURING CALENDAR YEAR 1956: None Form No. C»P-1 October 1956 (Attachment l) Calendar Year I956 PUBLIC HEALIH SERVICE - - NATIONM. INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. NHI-1?6 SERIAL NUMBER 2. Katicnal Heart Institute INSTITUTE OR DIVISION SECTION OR SERVICE 3. Gerontol o?:<- Branch LABORATORY, BRANCH, OR DEPARTMENT Baltimore City Hospitals ^ 5. Baltlinore 2Uj Maryland LOCATION (IF OTHER THAN BETHESDA) Cardiovascuiar HeLiodyna; ^liCGe I. Arteria ,1 perforiiiaiice in iiiaiic PROJECT TITLE Hilton Loiidowne PRINCIPAL INVESTIGATOR OOBER INVESTIGATORS 9. IF THIS PROJECT RESEMBLES, COMPLEMENTS, OR PARALLELS RESEARCH DONE ELSEWHERE IN THE PUBLIC HEALTH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACILITIES OR RJNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). PROJECT DESCRIPTION (SEE INSTRUCTIONS ) > Objectives; To investigate the f-.iictioning of the arterial circulation in living human subjocbs in the following manners a» To develop and to te."-' critically methods of studying the dyna^nic behavir^i- of larga and medium sized arteries in situ, be Using tliese^ and existing methods^ to describe individual, axid ageiri-se d?.'xei'ence3 in art.erial fxmction in ostensibly no-.tiial subjects of matiire age^ Cs To characterize evidences of pathophysiological performance in arteriosclerosis^ hypertension and other circulatory disorders^ Methods Einployedg The way in x-jhich arteries function to transmit pressure and flow of blood to the small vessels is determined by viscous and elastic properties of the arterial wall,, We are using 3 methods of investigating these properties and arterial perfonnanceE, a* Small transient or sustained leaves of pressure are created in arteries by a method developed in this laboratory e c* The decline of blood pressure during diastole (between heart beats) is compared to the theoretical behavior of models ■•" increasing complexity; Pertinent intra-arterial pressures are detected at various positions with- in the arterial tree by intra-arterial needles and special catheters attached to capacitance type sensing devices ^ and recorded^ with sensitive and accurate equipment,. The speed of pressure propagation^ and its distortions^ damping, resonance and rei'lection are then com.puted at varying pressures, and for waves of different frequencies s These data provide indices of elastic and viscous behavior^ Graphic and mathematical analysis of pressure curves in diastole provide information about the validity and practicality of simplifying assuiaptions regarding the behavior of the arterial system.. Patient Material ; Subjects from our 60 bed male -jard^ the Baltirr.oi^e ity Hospitals Infirrnarj^ and other wards of Baltimore City MospitalSi. • Major Findings g The age changes in the brachio-radial arteries have been systematically examined, >)ad show descriptive and statistical significance « Findings are consistent i.Hth the hji^othesis that entropy change, noi'mally occurring during physiological stretch of the wall of medium sized human arteries^ dimnishes x-rith age. The age differences are found even in arteries which are clinically considered non-sclerotic , Because the high in idence of clinical sclerosis x.dth increasing age^ morphologically identifiable arteriosclerosis cannot be excluded as the cause of the observed changes s We have sought for an approximation of cardiac output and central arterial elasticity which m.ight be valid, Several established and some nex-; formulations which have been examined critically are based on the fall of pressure during diastole j The inJ'orm.ation obtained has been reproducible, and provided estimates of cardiac output usually accxirate to less than - 10!^ in the individual normal subject at rest,. During exercise or xmder changing cardiovascular conditionsj however, reproducibility and appropriateness of the information is not satisfactory. toBER The circulatoiy analogues upon which our formulas are based are thus in- adequate to deal with more than limited conditions. The practical value and the limitations of the underlying car'diodynamic theory have been revealed c The validity of deducing central arterial behavior from peripheral arterial records has been examined » From harmonic ajialysis of central arterial records we have obtained information about the behavior of aortic pressure waves. Significance to Heart Research; Represents advance in concepts and a knowledge of the physiologj'' of the circulation in human subjects* lUtistrates the role of more nearly basic scientific inquiry in human circulatory physiolo^o Establishes use and limitations of formulae udilch have been proposed for use in Individuals to estimate cardiovascular performance, ^'^■Epj^ -?-5}jjj|p- -Q^ ^^^ j ec t g Continuation of recording and analyces of pressure cirrves under various exjierimental conditions and at several sites in the arterial tree. Continiaed study of the influence of reflected components . Form No. ORP-1 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - MnONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. JflilrOS^- SERIAL NUMBER 12. BUDGET DATA! ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FY' 57 $13,600 $737 BUDGETED POSITIONS $14,337 o5 lo2 1,7 PATIENT DAYS PROF OTHER TOTAL FY»57 1 2 3 0 13. BUDGET ACTIVITY; RESEARCH /T7 REVIEW & APPROVAL /""? BIOLOGIC STANDARDS A~7 ADMINISTRATION EJ PROFESSIONAL & TECHNICAL ASSIST- ANCE / / lA. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO. (S): Baltimore City Hospitals Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15. NKI-156 SERIAL NUMBER 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: Landowies, M<,g PiiLse wave velocity as an index of arterial elastdc characteristics » Proceedings of the Conference on Elasticity held at Dartmouth College 195$ s National Science Foundationo Published by the American Physiological Society to appear February"- 19^ 7 » Landoi'Snej, Moj and Ro ¥<, Stacy s A list of terms used to describe the mechanical properties of tissues o Proceedings of the Conference on Elasticity held at Dartmouth College 1955 o To appear February 1957 o 17. LIST HONORS AND AWARDS TO PERSONNEL RELATING TO THIS PROJECT DURING CALENDAR YEAR 1956: None Fonn No. ORP-1 Calendar Year 1956 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 8. SERIi National Heart Institute 3. Gerontology Branch INSTITOt^ 61^ DIVISI6N """""^ LABORATORY, BRANCH, OR DEPARTMENT 5. Baltimore Ci.ty Hospital- Baltimore ak, RarylaJid SECTION OR SERVICE LOCATION (IF OTHER THAN BETHESDA) FtOjionary Fhysioloa" as Related to Age PROJECT TITLE """ A. Ho Norris PRINCIPAL INVESTIGATOR OTHER INVESTIGATORS IF THIS PROJECT RESEMBLES, COMPLEMENTS, OR PARAHEI^ BESEECH DONE ELSEWHERE IN THE PUBLIC HEALTH SERVICE (WITHOUT INTERCHANGE OF PER^- SONNEL, FACILITIES OR RJNDS), IDENTIFY SUCH RESEARCH; (BY SERIAL NO»(S) IF WITHIN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Objectives; To describe age changes In pulmonary fmctiorx, Thesfs studies involve measuremfents of the ■volumes of l;m:ig compartments. the functional capacity of the piibnonaiy system^ ijaclu-ting the mechanical aspects of bellows function atid the responsiveness of the p'olraonary system to experimental stimulation and displacement. !JH]^lg7 _ SEllIAL IWI^UER Methods Employed s In addition to the standard methods of measuring lung volumes^ a helium washout technique has been developed to give estimates of functional volumes as well. An attempt will be made to relate functional measurements to anatomical measurements made directly on the chest and roentgenographic measurements, including motion of the diaphragm. In addition^ the laboratory measurements of pulmonary function are b eing compared \rLth responses to exercise and trith clinical estimates of pulmonary and work performance limitations of older sub-- jectss Major Findings s The ventilatory and metabolic changes during and after 15 minutes of helium breathing have been compared in 135 :;; -Ejects from 20 to 89 years of age. Oxygen uptake, '''02 elimination, ventilation volume and tidal volume were increased during helium breathings Oxygen uptake and COp elimination (on the avera[e) recovered to resting levels following helium breathing^ while ventilation and tidal volumes remained at helivmi breathing levels for ten minutes or so. Younger subjects tended to over recover resting CO2 elimination levels follow- ing helium breathing^, while older subjects did not recover their resting levels > In addition^ younger subjects recovered ventilation volume while older subjects increased ventilation volume in the ten minutes following heliiun breath ing* u_ignificar:_-_ '^thg ' oj^rarn^jxL"' the Institute; P. 3vention of increased incidence of chronic pulm.onary disease in elderly people requires knowledge about age changes in pulmonaxy function ^ Previous investiga tions from this laboratory have shovm that older subjects increase tholi' pulmonary ventilation volumes much more than do younger subjects \Jhcn a standard exercise is perfonued, even when the oxygen requirements for the work are the same* Hence, studies The SCN ion in low concentration, 0.5 mM, was found to inhibit hydrogen ion secretion by 25% compared to a 90^o inhibition obtained at a concentration of 25 mM. Significance to HEART Research: The frog gastric mucosa presents a more or less isolated anion transport system which can serve as a guide and model for anion transport systems elsewhere in the body. Proposed Course of I'ro.ject: Observations on the carbonic acid bicarbonate system in relation to chloride transport will be extended. Study of the flux of nitrate and its relationship to the movement of chloride will be carried out. The electrical potential profile of the gastric tubule will be determined to indicate the locus of that portion of the active transport of chloride wiiich is responsible for the iTieti;- brane [votential and whether hydrogen and chloride are transported by the same cell. Form No. ORP-1 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH ■ INDIVIDUAL PROJECT REPORT Part B: Budget Data 11- NHI-165 SERIAL NUIIBER 12. BUDGET DATA: ESTIMATED OBLIGATIONS MAN TEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FI'57 $6,600 $3,312 BUDGETED POSITIONS $9,912 .2 o7 o9 PATIENT DATS PROF OTHER TOTAL FT' 57 0 1 1 0 13. BUDGET ACTIVITT; RESEARCH /T7 REVIEW & APPROVAL HI BIOLOGIC STANDARDS /~7 ADMINISTRATION nj PROFESSIONAL & ' TECHNICAL ASSIST- ANCE . n U. IDENTIFT ANY COOPERAnNG UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING F[JNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FT 1957o IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S)s None Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15. ^111-165 SERIAL NUMBER 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: None 17. LIST HONORS AND AWARDS TO PERSONNEL RELATING TO TEES PROJECT DURING CALENDAR YEAR 1956: Form No. ORP-1 October 195^ (Attachment l) Calendar Year I956 FUBUC HEAL^m SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description ^eet 1. NHI«i66 SERIAL NUMBER 2. Natioiual Heart Institute INSTITUTE OR DIVISION 3, Kidney & Electrolyte Metabolism LABORATORY, BRANCH, OR DEPARTMENT k. SECTION OR SERVICE 5. LOCATION (IF OTHER THAN BETHESDA) 6^ The Metabolism of Urea in Mara PROJECT TITLE Y, Mackenzie W'alse? 8. PRINCIPAL INVESTIGATOR OTHER INVESTIGATORS 9. IF THIS PROJECT RESEMBLES, COMPLEMENTS, OR PARALLELS RESEARCH DONE ELSEWHERE IN THE PUBLIC HEALTH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACILITIES OR RJNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Objective's CD To determine the rate at which urea is destroyed in normal man aad whether its destruction can be eliminated by antibiotics. (2) T© determine the significance of the apparent renal delay time f0r II re a. 14 is^^&nglo^ed; C labeled urea is administered intravenously by single injectioji ox continuous infusion^ and its concentration determined in :ine at intei^alSo NHI-166 Major Findings; Normal subjects destroy about i/3 of the urea produced. This destruction has been eliminated by intestinal bacteriostasis in one subject, but not in 4 others. Urinary urea specific activity is consistently higher than blood urea specific activity. Sig»ifXcance to HEART Research; These findings are pertinent to the study of nitrogen metabolism, the problem of hepatic coma, the determina-= tion of total body water with urea, the interpretation of urea clearance data, and the mechanism of urea excretion. osed Course of Project; Further studies of a similar nature are planned. Form No. ORP-1 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. WL^lhL. SERIAL NUMBER 12. BUDGET DATA; ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FT' 57 $5,400 116,975 BUDGETED POSITIONS 122,375 .3 o4 o7 PATIENT DATS PROF OTHER TOTAL FY' 57 0 1 1 25 13. BUDGET ACTIVITY; RESEARCH /x7 REVIEW & APPROVAL /~7 BIOLOGIC STANDARDS /~7 ADMINISTRATION n? PROFESSIONAL & TECHNICAL ASSIST- ANCE T"? 14. IDENTIFT ANT COOPERAHNG UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILIHES, OR PERSONNEL FOR THIS PROJECT IN FT 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S): Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - MTIGNAL INSTITaiES OP HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15. NHI-166 SERIAL NUMBER 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: "Reliability of Estimated Rates of Production in Simple Turnover Experiments" by M. Kalperin and M. Walser, Arch. Biochem. Biophys., in press. 17. LIST HONORS AND AWARDS TO PERSONNEL REUTING TO TEES PROJECT DURING CALENDAR YEAR 1956: rjone ""A. Form No. ORP-1 Calendar Year 1956 October I956 (Attachment I) PUBLIC HEALTH SERVICE - - NATIONAL INSTITITTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. NHI°167 SERIAL NUMBER 2. National Heart Institute 3, Kidney £ Electrolyte Metabolism INSTITUTE OR DIVISION LABORATORY, BRANCH, OR DEPARTMEINT ^. : 5. ^ SECTION OR SERVICE LOCATION (IF OTHER THAN BETRESDA) Factors Involved in the Production of Ammonia by the Kidney, and the 6. Relation of Production to Ammonia Excretion in the Dog. PROJECT TITLE ~" PRINCIPAL INVESTIGATOR o Douglas Da^ddson, Floyd Rector OTHER INVESTIGATORS 9 • IF THIS PROJECT RESEMBLES, COMPLEMENTS, OR PARALLELS RESEARCH HCm ELSEWHERE IN THE PUBLIC HEALTH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACILITIES OR RJNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Project; To investigate effects of alterations in acid-base balance and urine pll on renal artery and vein ammonia and enzyme concentration on the excretion of ammonia and other organic substance. Objectives ; To elucidate some of the mechanisms whereby ammonia excretion is modified by urine pH and acid=base balance. Methods Employed; Simultaneous femoral artery, renal vein and urinary ammonia and glutamine concentrations will be measured during in- fusions of various substances. Renal blood flow and glomerular filtration rate will also be measured. NHl-167 Major FlndltKjs: lietlsods for the mcastireneril of all three enzyme systems and the technique for renal vein catheterization have been perfected. To date no reliable method for the determination of blood ammonia has been perfected. Measurements have shown that ammonia excretion at any given urine pH is higher in dogs during acidosis and lower during alkalosis than during periods of normal acid-base balance. However, there were no significant differences in the activities of the three enzyme systems assayed to account for the differences in ammonia excretion. Sicinificance to HEART Research; The studies are of importance insofar as they may elucidate the factors involved in electrolyte transport by the kidney. Specifically they bear on the overall problem of the renal defect in edema, the mechanism of action of diuretics and their potentiation. Proposed Course of Project: The diffusion technique of Seligson has proven to be an unsatisfactory measure of blood ammonia in our hands. At- tempts are being made to develop a technique of measuring blood ammonia more directly, possibly by extraction with organic solvents. These studies are progressing and will be extended. Form No. ORP-1 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. NHI-167 SERIAL NUMBER 12. BUDGET DATA; ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FI'57 $8,500 $4,228 BUDGETED POSITIONS $12,728 o2 lol 1.3 PATIENT DATS PROF OTHER TOTAL FT' 57 0 1 1 0 13. BUDGET ACTIVITT; RESEARCH ITl REVIEW & APPROVAL /~7 BIOLOGIC STANDARDS /~7 ADMINISTRATION nj PROFESSIONAL & TECHNICAL ASSIST- ANCE n 14. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IP COOPERATING UNIT IS ITITHIN NIH INDICATE SERIAL NO. (S): None Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment I) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OP HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15.__NHI^d67 SERIAL NUniBER 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: The Mechanism of the Exeretiosi of .Ammonia in the Dog. Jack Orloff and Robert M„ Berliner. J. Clin. Invest. 35s223=235„ 1956. The Sole of the Kidney in the Regulation of Acid=Base Balance. Jack Orloff, Yale Journal of Biology and Medicine (in press). Carbonic Anhydrase Inhibitors. Robert W. Berliner and Jack Orloff. Pharm. Reviews 8; 137-174. 1956. 17. UST HONORS AND AWARDS TO PERSONNEL RELATING TO THIS PROJECT DURING CALENDAR YEAR 1956: Form No. ORP-1 Calendar Year I956 October 1956 (Attachment l) PUBLIC HEALm SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. f^'^^-l^^ SERIAL NISfBER 2. National Heart Institute 3. Kidney & Electrolyte Metabolism INSTITtM^ (A Hm^tlA LABORATORY, BRANCH, OR DEPARTMENT ^' ^ 5. ^ , SECTION OR SERVICE LOCATION (IF OTHER THAN BETHESDA) 6. Effect of Reducing Glomerular Filtration Rate on Renal Function PROJECT TITLE 7. Robert W. Berliner . D. G. Davidson 8. PRINCIPAL INVESTIGATOR OTHER INVESTIGATORS 9. IF THIS PROJECT RESEMBLES, COMPLEMENTS, OR PARALLELS RESEARCH DONE ELSEWHERE IN THE PUBUC HEALTH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACILITIES OR RJNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WIOfilN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Project; Effect of reducing glomerular filtration rate on: a) capacity to produce a solute urine b) the clearance of Creatinine and Inulin c) the action of Acetazolamide ©iamox) and Salyrgan d) the effects of lowering of the glomerular filtration rate on maximal urine concentration. Objectives; a) To determine the effect of reducing glomerular filtra- tion on the concentration of the urine produced during water diuresis. The information secured will provide evidence concerning the mechanism by which the urine is diluted and the mechanism of action of pitressln. b) If lowering the filtration rate decreases the clearance of creatine ine with respect to the clearance of inulin, and if this discrepancy occurs because of the back diffusion of creatinine at the site where NHI-168 pitressin acts, theoretically the discrepancy might be jreater during maximal pitressin activity than in the absence of pitres- sin. c) To determine' the effect of reducing the glo;:iorular fil- tration rate on the action of acetazolamide and Sairjan. It is desired to obtain information regarding the action of the drugs when the filtered load of sodium is reduced. Methods Employed; Multiple studies have been done in 18 dogs. The method for unilateral renal artery constriction, and separate uriite collections from each kidney have been reported in detail in -a;,previous report, a) The glomerular filtration rate was a= cutely lowered during water diuresis at low rates of solute ex-= cretion. Mannitol infusions, if used, were stopped when the clamp was set. Following suitable control periods with maximal water diuresis, the renal artery clamp was inflated, b) The clearance of inulin and creatinine were compared at reduced levels of glomerular filtration rates. Suitable control periods were secured during a water diuresis, then the glomerular filtra- tion rate was reduced, and periods were obtained during continued water diuresis. Pitressin was then added to the infusion and periods were obtained during maximal ADH activity, d) The effect of lowering glomerular filtration rate during Mannitol and NaCl diuresis was studied. The glomerular filtration rate was lowered when solute excretion was minimal, Pitressin » 50 mU/kilo/hr. was infused throughout. Animals were dehydrated for 24=36 hours prior to these studies. Major Findings; a) When the glomerular filtration rate was reduced during water diuresis at low rates of solute excretion, the urine concentra- tion rose to levels of 450 to 480 milleosm. These hypertonic urines were secured with 30 to 35% reductions in the glomerular filtration rates, A marked fall in the rate of sodium excretion was found. These results are interpreted to indicate; 1) that the urine is diluted by the reabsorbtion of sodium "salts", 2) that during osmostic diuresis induced by Mannitol infusion more sodium "salts" are presented to the distal tjibule with a consequent greater volume of dilute urine presented to the concentrating site, 3) that the mechanism which yields a hypertonic urine is not necessarily under the control of A.D.H, 4) that the effect of A.D.H, is on the permeability of the distal tubule to the diffusion of water and that A.D.H. assures the isotonicity of the urine delivered to the concentrating site, b) The ratio of the clearance of creatinine with respect to the clear= ance of inulin was found to be significantly less than unity when the filtration rate was reduced. The fall in the clearance of creatinine could best be correlated with the degree of reduction of the filtration rate. There was no significant fall in the clearance of creatinine unless the filtration rate (as measured by inulin) was reduced by at least 60% of the control kidney. No correlation was found with pitressin activity. NKI-166 page 3 c) During mercutial or acetazolamide diuresis; the rate of sodium excretion if reduced with lowering of the glomerular filtration rate. In one experiment equality of potassium excretion was maintained despite a 40% reduction in the glomerular filtration rate. This finding was taken as evidence that the reduction in glomerular filtration rate produced by clamping the renal artery was produced by a decreased perfusion pressure per nephron and not a "shutting off" of nephron units. With acetazolamide diuresis the urine pH was higher on the side of reduced glomerular filtration rate. Despite 30-40?o reduction in the glomerular filtration rate, an ap- preciable rate of Na excretion was maintained. d) With elevated levels of solute excretion achieved by infusions of Mannitol or hypertonic NaCl, acute rtductions of the glomerular filtration rate effect a rise in urine concentration. At minimal levels of solute excretion, increases in urine concentration occur with minimal reductions of the glomerular filtration rate. With marked reductions in the glomerular filtration rate, when the solute excretion rate is low, a fall in urine concentration occurs. However reduction of the sol !te excretion rate by reducing the glomerular fil- tration rate does not always effect the degree of rise of urine concen- tration expected by spontaneous falls in solute excretion. As with previously reported experiments the undamped kidney serves as a reference control. The problems of dead space and delay time at the very low urine flows necessary to achieve maximal urine concentrations have made the measurements of the glomerular filtration rate a diffi- cult problem. When the urine concentration did not change or fall with reduction in the glomerular filtration rate, the excretion of Na"*" was quite low. Significance to HEAIiT Research; These studies help to clarify the role of glomerular filtration rate in the excretion of salt and water. Proposed Course of Project: Llxperiment will be designed to secure more informa- tion with regard to: 1) spontaneous changes in 'Maximal°'urine concentra- tion, 2) failure of the urine concentration to rise with reduction of the glomerular filtration rate at low levels of solute excretion. 3) further experiments will be done to show equal potassium excretion when the fil- tration rate is reduced during Salrgan diuresis. Form No. ORP-1 October 1956 (Attachment I) PUBLIC HEALTH SERVICE - - NAnONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. NHI-168 SERIAL NUMBER 12. BUDGET dkTk: ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FT' 57 $9,800 $4,933 BUDGETED POSITIONS $14,733 o6 1,5 2ol PATIENT DAYS PROF OTHER TOTAL FT' 57 1 1 2 0 13. BUDGET ACTIVITY; RESEARCH /F7 REVIEW & APPROVAL £Z/ BIOLOGIC STANDARDS /~7 ADMINISTRATION £7 PROFESSIONAL & TECHNICAL ASSIST- ANCE / / 14-. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S): None Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITDTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15. NHI-168 SERIAL NUMBER 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956; None 17. LIST HONORS AND AWARDS TO PERSONNEL RELATING TO THIS PROJECT DURING CALENDAR YEAR 1956: None ironn «o. okjp-x Calendar Year I956 October I956 (Attachment I) PUBUC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. NJil=169 SERIAL NUMBER 2, National Heart Institute o^ Kidney £ Electrolyte Metabolism INSTITUTE OR DIVISION LABORATORY, BRANCH, OR DEPARTMENT ^' 5. SECTION OR SERVICE LOCATION (IP OTHER THAN BETHESDA) 6. isolation of a Cardiotonic- SMbstamce From MairaEaliasi Tissues PROJECT TITLE ' ' ~ 7. Stephen Hajdu PRINCIPAL INVESTIGATOR 8. Dto Elwood 0. Titus and Dr^ !?erbert Weiss OTHER INVESTIGATORS 9. IP THIS PROJECT RESEMBLES, COMPLEMENTS, OR PARAILEI5 RESEARCH DONE EIBEWHERE IN THE PUBLIC HEALTH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACILITIES OR JUNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Obj_e ctizg_s ; Previous studies on the frog heart suggested the presetice of a digitalis-like siibstaiice in blood serwm. The purpose of this research is to isolate this substanceo to characterize it chemically and to determine its role isi the control of the contraction of the hearts Methods Employed; An assay for digitalis-like activity has beea developed using the staircase phenomeraon of the frog heart » Methods of isolstion have involved extraction with organic solvents ^ chromatography and Gounter ciuirreBt distribiatiora. Major Findirtc}s; Previous reports have disclosed that beef heart and, to a lesser extent, liver and blood contained a substance which strongly re= sembled strophanthin, both in its effects on the staircase phenomenon in the frog heart and in the extraordinary firmness with which it is bonjnd t< the heart o Although up to about 2C9'o ©f the substance may occur free in these tissues, most of it is found in the form of an inactive precursor from which it mav be teleased bv treatment with n„001 to 0.01 N acid at NHI-169 room temperature « By far the most abundant source, however, is adrenal medulla, ira which equal amounts of free substance and inactive precursor exist, and it was from the latter tissue that sufficient material for chemical characterization was obtained. The material was isolated by acetone deproteinization of tissue, fraction- ation of the acetone extracts by partition between solvents, and chromato- graphy. Counter current distribution of the chromatographic eluates gave material which could be crystallized. Results of recent experiments are suiimiarized as follows: a). The active principle has been characterized as -palmitoyl lysoleci- thin. On a molar basis it is approximately 1/60 as active as strophanthin, 1/30 as active as digitoxin and 1/3 as active as digitoxigenin in the frog heart including the property of being very firmly bound to the heart membrane. b). Cardiotonic activity of this type appears to be a general property of ri-lysolecithins, since synthetic ?=myristyl and -o'eyl as well as a mixed lysolecithin prepared from vegetable lipids were all active, c). A toxic agent which caused very rapid contracture in a manner reminis-= cent of saponins like digitonin but which was without effect on the stair- case phenomenon, occurred in many of the tissue preparations. This has been identified as -lysolecithin. It appears to be an artefact arising by intra molecular rearrangement of the lysolecithin during chromatography and crystallization. d). The phospholipase A of Crotalus adamanteus venom has been found to hydrolyse the ester bonds of -lysolecithins rapidly and completely, but is without effect on the --isomers. This enzyme promises to become a use- ful tool in investigations of these phospholipids. Although efforts to isolate the inactive precursor in puE form have not yet succeeded, the presence of fatty aldehyde in impure preparations and the extreme ease with which the precursor is activated by very dilute acids, suggest that it is probably a hemiacetal of the structure which has recent- ly been proposed by Klenk for certain beef heart phospholipids. The name "aldolecithin" has been suggested as a means of differentiating such struc- tures from the acetal structures which have hitherto been assumed to account for the aldehyde containing phospholipids. The following structures would account for the phenomena discussed in this report. NlIl-169 page 3 li.,C-0-C-K HC-O0C(CH2)j4CH3 HC-O-P-O-CH^CHgN (0113)3 OH "Aldolecithin" Inactive precursor B^C-Uii Activation with 0.01 N HCl , HC-00C(CH2)j,jCliy HG-O-P^O-CHgCHgN C:H3)3 OH J -lysolecithin Parital rearrangement d'jring isolation H2C00C(CH2)i4CH3 I!C~0I1 , -lysolecithin "Contracture activity" The biological importance of the active substance has been further indicat- ed by two observations: (1) It exerts its characteristic cardiotonic effect on the heart of the tropical toad, an organ which is completely insensitive to all known cardiac glycosides. (2) This substance exhibits the character- istic properties of a cardiac glycoside when tested on isolated carotid strips. The active substance has been obtained in crude form as a fraction occurring in close association with unidentified choline-containing lipids. Significance to HLAltT Research; The identification and study of a substance which may play a fundamental role in regulating heart muscle ''•ontraction is obviously of the grealust importance to our understan-iriQ of l.he function oi." tlie heart. Proposed Course of Project: .,f forts arc bidnfj made to isolate or to synthesize pure aldolecithin, to sLmiy its physiological effects in intact animals and to investigate the distribution of enzynjs concerned in its bio- genesis and conversion to -lysolecithin. Form No. ORP-1 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. NHI.^16Q SERIAL NUIIBER 12. BUDGET DATA; ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FI' 57 $6,500 13,242 BUDGETED POSITIONS $9,742 o3 ok .7 PATIENT DAIS PROF OTHER TOTAL FY" 57 0 1 1 0 13. BUDGET ACTIVITY; RESEARCH /T? REVIEW & APPROVAL /~7 BIOLOGIC STANDARDS /~~/ ADMINISTRATION /U PROFESSIONAL & TECHNICAL ASSIST- ANCE / / 14. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S); None Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15._iE^ SERIAL NUMBER 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: Isolation of Cardiac=active Principle from Mammalian Tissije„ Stephen Hajdu, Herbert fe^leisSt and Elwood Titus. In press. 17. LIST HONORS AND AWARDS TO PERSONNEL REUUNG TO THIS PROJECT DURING CALENDAR YEAR 1956: None Form No. ORP-1 October 1956 (Attachment I) Calendar Year 1956 PUBLIC HEAL1H SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. SERIAL NUMBER 2. N:^t: -xt Instittste INSTITUTE OR DIVISION 3« Kidney 5 Electrolyte Metsbolisn LABQRATORy, BRANCH, OR DEPARTMENT 5. SECTION OR SERVICE 5, Stsrdies on the Mechanism of Action of Diuretics LOCATION (IF OTBER THAN BETHESDA) PROJECT TITLE Kennsdy, Jr, PRINCIPAL INVESTIGATOR R„ It/, Berliner OTHER INVESTIGATORS 9. IF THIS PROJECT RESEMBLES, COMPLEMENTS, OR PARALLELS RESEARCH DONE ELSEWHERE IN THE PUBLIC HEALTH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACILITIES OR RJNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). iJone PROJECT DESCRIPTION (SEE INSTRUCTIONS): 3^ Objectives; The objectives of this pijoject is to evaluate compounds which reduce the net transpoL.-t of sodium and chloride across the renal tubiils from two points of view. The first point of interest has to do with the mechanism if discernable whereby sodium transport is reduced „ in the hope that fundamental knowledge about the tnodus oper= andi of the tubular transport process may be advanced. The second is to evaltsate the clinical usefulness of these drugs in the management of patients with edema, especially when caused by cardiac failure, and also when due to primary renal or hepatic disease. NHI-170 b) Methods employed; Studies in animals utilize standard clearance techniques. If indicated, the effect of the drug on certain metabolic features of renal slices or horaogneates of kidney tissue may be used. Patient studies require electrolyte balance studies on normal and edematous patients wherein dietary intake of electrolyte is varied and where the ef- ficacy of this drug is studied in comparison to mercurial diuretics under relatively standard and comparable condi- tions. Mhen drugs look to be promising, more elaborate clearance studies are undertaken. c) Patient material; Patient material includes normal controls as well as edematous patients recruited from local physicians and hospitals. d) This year, a new drug, chlorothiazide has been under study. Results are too preliminary for any definite statement at this time. e) Significance to HEART Research; The understanding of the intimate details of renal tubular transport of electrolyte is central to a solution of the problem of cardiac, renal and hepatic edema and rational management of this problem will indubitably be advanced as our insight into the mechanism of its production expands. There is at present a crying need for compounds which are effective diuretics when given by mouth and the discovery of such a compound will represent a significant therapeutic advance. f) Proposed Course of Project; As diuretic agents of preliminary promise become available, they will be subjected to intensive study as outlined above. Fonn No. ORP-1 October 1956 (Attachment I) PUBLIC HEALTH SERVICE - - NATIONAL INSHTOTES OF HEALTH INDIVIDUAL PROJECT REPORT Part 6: Budget Data 11. NHI"17Q SERIAL NUMBER 12. BUDGET DATA; ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FT' 57 $11,400 $35,365 BUDGETED POSITIONS $46,765 .6 „7 1»3 PATIENT DAYS PROF OTHER TOTAL FY' 57 1 1 2 145 13. BUDGET ACTIVITY; RESEARCH /x7 REVIEW & APPROVAL /~7 BIOLOGIC STANDARDS /~7 ADMINISTRATION nj PROFESSIONAL & TECHNICAL ASSIST- ANCE / / 14. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S); None Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment l) PDBLIC HEALTH SERVICE - - NATIONAL IHSTITOTES OP HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Ai»ards & Publications 15.. ^^1-170 SERIAL NUMBER 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: None 17. LIST HONORS AND AWARDS TO PERSONNEL REUTING TO TECS PROJECT DURING CALENDAR YEAR 1956: None Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. NHI^lTl SERIAL NUMBER 2. National Heart Institute 3. Kidney & Electrolyte Metabolism INSTITUTE dft DIVISI6N ~ LABORATORY, BRANCH, OR DEPARTMENT ^' 5. ^ , SECTION OR SERVICE LOCATION (IF OTHER THAN BETHESDA) 6, Studies on the Function of Single Nephrons in Necturus Maeulosus PROJECT TITLE 7. ThoSo J. Kennedy, Jr„ 8. PRINCIPAL INVESTIGATOR _Npne___ OTHER INVESTIGATORS 9' IF THIS PROJECT RESE34BLES, COMPLEMENTS, OR PARALLELS RESEARCH DONE ELSEWHERE IN THE PUBLIC HEALTH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACILITIES OR RJNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Project^; The study of the operation performed by the nephron in the formation of urine o Objectives; The objectives of this program are to study in as intimate detail as possible the mechanisms whereby the nephron modifies glomerti- lar filtrate into the final urine. Classical clearance techniques per= mit the evaluation of the chemical compositon of both the initial material (glomerular filtrate) presented to the nephron as well as the final material, urine, elaborated by the nephron. However, there is no method evaluating what happens along the course of the nephron other than a direct approach to the various segments of this strtacture. NHI-171 ?.!Cihodj5; The general technique used is micromanipulative. The nephrons of the kidney of necturns can be visualized with proper lighting and micro- scopy. Micromanipulators have been built to which micropipettes may be attached for sampling of tubular urine at various levels of the nephron. Segments of the nephron can be isolated between blockades of oil or mercury and the intervening nephron can be perfused. Microelectrodes may be introduced into the tubular lumen for measurement of potential differences across membranes or for the measurement of pH. Ultra- raicrochemical analytical methods are used to determine the chemical composition of the urine collected from the puncture sites. ?.:a.ior Findings: Some measurements of the transluminal potential gradient have been made, A large amount of effort has been expended in an at- tempt to fabricate a microflame photometer for measurement of sodium and potassium in the microsamples, and chemical methods for the measure- ment of chloride and of inulin have been developed for the sample sizes which we expect to encounter. Significance to HEART Research: The transport of electrolytes and water across the renal tubule is altered in heart failure. Recognition of the nature and cause of this alteration requires understanding of nor- mal mechanisms of electrolyte transport. Once the normal mechanisms are understood, the possibility of characterization of the abnormali- ties seen in heart failure becomes more likely. Rational therapy based on sound physiological premises should follow. Proposed Course of Project: Over the next year the plan is to carry out a number of exploratory experiments and select lines of study that appear, on the basis of preliminary work, most promising. A systematic study of electrical potential gradients along the nephron will be undertaken and the effort thereon of various compounds known to modify electrolyte transport will be studied. In addition, it will be of interest to study simultaneously the relationship between changes in electrolyte transport and D.C. potential changes. If technically feasible, acute changes in the composition of tubular urine will be induced by perfusion of isolat- ed segments of nephron with solutions of composition different from that of glomerular filtrate. A study of the feasibility of insertion of a microglass electro.-:.i for pH determination will also be made. Form No. ORP-1 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSHTUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. 2I2I. SERIAL NUMBER 12. BUDGET DATA; ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FT' 57 $7,800 $3,876 BUDGETED POSITIONS $11,676 o5 =4 o9 PATIENT DAYS PROF OTHER TOTAL FT' 57 1 0 1 0 13. BUDGET ACTIVITY; RESEARCH JTl REVIEW & APPROVAL /~7 BIOLOGIC STANDARDS /~7 ADMINISTRATION no PROFESSIONAL & TECHNICAL ASSIST- ANCE / / 14.. IDENnFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO. (S): None Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OP HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15.. ^^^^^^'^^ SERIAL NUIIBER 16. LIST PUBLICAnONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: None 17. UST HONORS AND AWARDS TO PERSONNEL RELATING TO THIS PROJECT DURING CALENDAR YEAR 1956: None Form No. ORP-1 Calendar Year 195& October 1956 (Attachment I) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. NHI-172 SERIAL NUMBER 2. National Heart Institute 3. Kidney & Electrolyte Metabolism INSTITUTE (S^ DIVISI6N LABORATORY, BRANCH, OR DEPARTMENT SECTION OR SERVICE LOCATION (IF OTHER THAN BETHESDA) 6, The Renal Excretion of Phosphate in the Chicken PROJECT TTSIE 7. Douglas G,, Davidson PRINCIPAL INVESTTOATOR a Norman Levinsky, Robert vi, Berliner o. -------------------------------------- OTHER INVESTIGATORS 9. IF THIS PROJECT RESEMBLES, COMPLEMENTS, (B PARAXIALS RESEARCH DONE ELSEWHERE IN THE PUBLIC HEALTH SERVICE (WITHOWT INTERCHANGE OF PER- SONNEL, FACILITIES OR FUNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). None 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Objectives; To investigate a possible specific phosphaturic effect of the parathyroid hormone. If the hormoifse has a specific renal effect of increasing the renal excretion of phosphate^ it should be theoretically possible to demonstrate a unilateral rise in phosphate excretion when the hormone is administered in one leg of the chicken.. Methods Employed; Utilizing the unique circulation of the kidney in the chicken which has been discussed in previous reports, separation of glomerular and tubular effects is facilitated. Renal phosphate exGre= tion was studied by intravenous infusion of 2.5 and 25 isicroimoles per minute of sodium phosphate. The infusion contained inulin to measure GFK, Renal tubular secretion of phosphate was demonstrated by bila= teral phosphate excretion forty to sixty per cent in excess of filtered loado In other experiments parathyroid extract, 0.5 to 2.5 units per hour per kilo, was iofused continuously into one leg vein. No constant or large chanqes in plasma phosphate concentration or in the GFR of NHI-172 either kidney occurred. In several experiments unilateral phosphate secretion was demonstrated with excretion of 20 to 100 per cent more phosphate than the filtered load. Major Findings; 1. Tubular secretion of phosphate, a) The filtration rates were measured by the clearance of alkali-stable inulin. b) With systemic phosphate loading, the excretion of phosphate by the kidney has been found to substantially exceed the filtered load of phosphate. These findings have been taken as secure evidence of phosphate secretion by the chicken kidney. 2. The effect of parathyroid hormone C'Parathrone"-Lilly) on phos- phate excretion. When the hormone is administered in the leg of the chicken there is a unilateral increase in the rate of phosphate ex- cretion. The effective dosage range of the hormone is 1, 3, and 5 units per hour per chicken. The average weights of the chickens studied were two kilo. With suitable rates of hormone administration unilateral secretion of phosphate has been demonstrated. At higher levels of hormone administration there is a contralateral rise in phosphate excretion. The mechanism by which the parathyroid hormone increases the rate of phosphate excretion is not known. Significance to HEART Research: The problem is of importance insofar as it helps to define the normal mechanisms of electrolyte excretion. Proposed Course of Project; , a) Investigation of the effects of feeding and starvation on the Basal rate of phosphate excretion by the chicken kidney, b) Radioactive phosphate will be utilized in an attempt to elucidate the mechanism of phosphate excretion. Form No. ORP-1 October 1956 (Attachment I) PUBLIC HEALTH SERVICE - - NATIONAL INSTI OTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. NHI-172 S:'.IAL NUMBER 12. BUDGET DATA; ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TO^iu PROF ■ OTHER TOTAL FY' 57 $6,800 $3,383 BUDGETED POSITIONS Id 183 o2 o8 loO PATIENT DAYS PROF OTHER TOTAL FI'57 0 1 1 0 13. BUDGET ACTIVITY; RESEARCH /x7 REVIEW & APPROVAL /~7 BIOLOGIC STANDARDS /~7 ADMINISTRATION /U PROFESSIONAL & TECHNICAL ASSIST- ANCE / / 14.. IDENHFY ANY COOPERATING UNITS OF Ti.y. PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IF COOI'ERATING UNIT IS WITHIN NIH INDICATE SERIAL NO. (S): None Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment l) PDBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15- NHI°172 SERIAL NUMBER 16. LIST PUBLICAnONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: None 17. LIST HONORS AND AWARDS TO PERSONNEL RELATING TO THIS PROJECT DURING CALENDAR YEAR 1956: None Fonn No. OBP-1 October 1956 (Attachment I) Calendar Year I956 FUBLCC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. NHI-173 SERIAL NUMBER 2. National Heart Institute INSTITOtS 6ft DIVISION 3. Kidney 6 Electrolyte Metabolism LABORATORY, BRANCH, OR DEPARTMENT h. SECTION OR SERVICE 5. LOCATION (IF OTHER THAN BETHESDA) 6. 7. 8. Effect of the Chronic Administration of Pitressin in the Dog PROJECT TITLE Robert Wo Berliner PRINCIPAL INVESTIGATOR Douglas G, Davidson, Norman Levinsky OTHER INVESTIGATORS 9< IF THIS PROJECT RESEMBLES, C0MPUa4ENTS, OR PARAXIALS RESEARCH DONE ELSEWHERE IN THE PUBLIC HEALTH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACILITIES OR RJNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO»(S) IF WITHIN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Objectives; To determine the mechanism by which dogs acconmodate to the chronic administration of supra-maximal amounts of pitressin and water. The information secured should provide evidence concerning the factors which influence the action of pitressin on urine concentration. Methods Employed; 1. Conventional balance techniques have been utilized. The diet was synthetic, the daily portion containing 30 cal/kilogram, 24 meq of NaCl and 15 meq of KCl. Controlled water intake was made possible by the daily administration of known amounts of intravenous NHI-173 fluids. Following a suitable control period of 5 to 7 days, 10 units of pitressin tannate in oil were given daily. A sharp rise in urine concentration occurred, and simultaneously there was a progressive fall in plasma osmolality. After three or four days of daily administration of pitressin tannate in oil the urine concentration began to decline and leveled off at near control values. The plasma osmola- lity ceased to fall. The glomerular filtration rates during the period of accommodation were near double those of the control values. A marked rise in Na"*" excretion occurred during the first 3 to 5 days of pitressin administration. This was followed by a period of minimal NaCl excretion. This study has been completed in three dogs. Major Findings: The findings have been utilized to define more closely the accommodation of the dog to the chionic adminis- tration of pitressin. a) A marked and sustainer* rise in glomerular filtration rate, b) the excretion of r. less con- centrated urine at control levels of solute excretion, c) an initial increase of salt excretion followed by a period of salt conservation. Significance to HEART Research; Continuous excessive release of pitressin is a common occurrence in advanced cardiac failure and a number of other severe disease states. Elucidation of its consequences is therefore of considerable importance. Proposed Course of Project: 1. Attempt to correlate changes in urine concentration with changes in glomerular filtration rate by daily measurements of glomerular filtration rates during the administration of pitressin tannate in oil. 2. Continue experiments with simultaneous administration of DOCA and P.T.O. Form No. ORP-1 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. NHT°173 SERIAL NUMBER 12. BUDGET DATA: ESTBIATEa) OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FT' 57 $19,300 $9,654 BUDGETED POSinONS $28,954 lo2 lo2 2<,4 PATIENT DAYS PROF OTHER TOTAL FY' 57 1 1 2 0 13. BUDGET ACTIVITY; RESEARCH fTl REVIEW & APPROVAL CI/ BIOLOGIC STANDARDS /~7 ADMINISTRATION CJ PROFESSIONAL & TECHNICAL ASSIST- ANCE n U. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IP COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S): None Ponn No. ORP-1 Calendar Year 1956 October 1956 (Attachment l) ' PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15. NHI°173 SERIAL NmiBER 16. LIST PUBLICAHONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956! None 17. LIST HONORS AND AWARDS TO PERSONNEL RELATING TO THIS PROJECT DURING CALENDAR YEAR 1956: Nsne Form No. ORP-1 Calendar Year 19^6 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. _!5fl£Il. SERIAL NUMBER 2, National Heart Institute o^ Kidney & Electrolyte Metabolism INSTITUti (SA DIVISlbN LABORATORY, BRANCH, OR DEPARTMENT k, 5. ^ SECTION OR SERVICE LOCATION (IF OTHER THAN BETHESDA) Mathematical Formulations of the Relationship between Solute, Sodium, 5. and Water Excretion PROJECT TITLE 7. Mackenzie tiialser PRINCIPAL INVESTIGATOR ' ' Q John Stephenson, Jack Orloff OTHER INVESTIGATORS 9. IF THIS PROJECT RESEMBLES, COMPI£MBNTS, OR PARALLELS RESEARCH DONE ELSEWHERE IN THE PUBLIC HEALTH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACILITIES OR RJNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF UI1UIN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Objectives: To evaluate the consequences of various mechanisms for renal reabsorption of solute and ^vater by means of assuming the given mechanism to be operative throughout the tubule, and then obtaining the resultant relationship by integrating from one end of the tsribisle to the other, 2. To test alternative theories of solute and water reabsorption by comparing the prediction of such formulations with observed data. Methods izinployed; The relationship between sodium excretion and total solute excretion observed in patients with various disorder subjected (for other reasons) to mannitol diuresis has been compared to the relationship predicted upon the basis of a mathematical fooBuiatiori. The latter i,s obtained from^ the assumption that sodium reabsorptiosi is proportional to sodium concentration in the tubular fluid. NHI-174 Patient material: obtained from other projects. Ma.lor Findings; The correspondence between the observations and pre- dictions has been found to be close in most instances, lending support to the assumption. Significance to HEART Research: The findings shed light upon some of the factors regulating sodium excretion by providing a quantitative test of the hypothesis that sodium reabsorption is concentration- dependent. Proposed Course of the Project: Further studies of a similar nature are planned. Fonn No. ORP-1 October 1956 (Attachment I) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. MI-17fc SERIAL NUMBER 12. BUDGET DATA: ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FY' 57 |2Oj50O $10,289 BUDGETED POSITIONS $30,789 lo4 lol 2«5 PATIENT DAYS PROF OTHER TOTAL FT' 57 2 1 2 0 13. BUDGET ACTIVITY; RESEARCH /x? REVIEW & APPROVAL /"l BIOLOGIC STANDARDS A"? ADMINISTRATION EJ PROFESSIONAL & TECHNICAL ASSIST- ANCE n 14. IDENnFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILIHES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S)! None Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15. NHI°174 SERIAL NUMBER 16. LEST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: 17. LIST HONORS AND AWARDS TO PERSONNEL RELATING TO THIS PROJECT DURING CALENDAR YEAR 1956: None Form No. ORP-1 October I956 (Attachment l) Calendar Year I956 PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. NHI=l75 SERIAL NUMBER 2. NatSGkial Heart Institute INSTITUTE OR DIVISION 3. Kidney & Elect. rolyte Metabolism LABCaUTORY, BRANCH, OR DEPARTMENT k. 5. SECTION OR SERVICE LOCATICW (IF OTHER THAN BETHESDA) 6. The Ef.fe^vt. Qf ChlorQt-hia2;ide im the Chiskeri PROJECT TITLE ~~" — 7. Ori.; PRINCIPAL INVESTIGATOR Q ___rJi22'->-^£H''^^ Domglas G, Davidson OTHER INVESTIGATORS 9. IF THIS PROJECT RESEMBLES, COMPLEMENTS, OR PARALLELS RESEARCH DONE ELSEWHERE IN THE PUBLIC HEALTH SERVICE (WITHOOT INTERCHANGE OF PER- SONNEL, FACILITIES OR FUNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IP WITHIN NIH). icwrreiit studies fil the drug in Drs. Kennedy and Berliner . patients is being undertaken 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Projects The effect of chlorothiazide in the chickeiio Objectives; A new diuretic agent „ chlorothiazide „ has recently been released for ini'-sFestigati¥e purposes . It is said to prodisee effects similar to mercurial diuretics in low dosages and to inhibit carbonic anhydtase at higher dosages. The mechanism of action of the drug is being studied in the chicken. JethodsJ^m£loj^: Drugs infused into a leg vein perfuses only the peritubular capillaries of the homolateral kidney &rad is not filtered by the glomerulus until after it has entered the systemic circulation. The presence of separate ureters emptying directly to the exterior permits the collection Niil-175 of urine separately fron each kidney. Hence, it is possible in the chicken to differentiate between effects on glomerular filtration and specific tubular effects of the drug. A moderate osmotic diuresis to maintain adequate urine flows is produced by the infusion of mannitol into the systemic circulation via a wing vein. The glomerular filtration rate, urine flow, urine pH and excretion of sodium, potassium and chloride on the infused and control sides are compared during control periods and during - the infusion of graded doses of chlorothiazide. To determine whether chlorothiazide has a specific effect on potassium secretion, similar experiments will be performed in which a high level of potassium se- cretion is maintained by the infusion of potassium chloride into the wing vein. yiajor Findings: h. Chlorothiazide has been shown Lo produce a specific unilateral effect on chloride excretion on the side of the infusion. The minimum effective dose is approximately 0.1 mgm/kilo body weight/ hour. B. At all dosage levels studied (0.25 - 25.0 mgm/kilo/hr. ) the diuresis appears to be predominantly due to an increase in Na- and Cl" , Dosages of 2.5 mgm/kilo/ hour or more appear to inhibit carbonic anhydrase slightly as manifested by an increase in urine pH. (from 5.5 to 6.5). However, it does not appear to be as potent as niamox in this regard. Significance to HEART Research: The studies in a general way relate to the problem of edema formation in heart disease and nephrosis. If it is possible to elucidate the mechanism of action of this diuretic this may provide information concerning the problem of chloride excretion in qencral. Form No. ORP-1 October 1956 (Attachment I) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. MHI-175 SERIAL NUMBER 12. BUDGET DkTk: ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FY' 57 116,300 $8,160 BUDGETED POSITIONS 124,474 o8 lo4 2o2 PATIENT DATS PROF OTHER TOTAL FT' 57 1 2 3 0 13. BUDGET ACTIVITY; RESEARCH /x7 REVIEW & APPROVAL /~7 BIOLOGIC STANDARDS f~7 ADMINISTRATION /U PROFESSIONAL & TECHNICAL ASSIST- ANCE /~7 14. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO. (S): None Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment l) PDBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15. NHI-175 SERIAL NUMBER 16. LIST PUBLICAnONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: None 17. LIST HONORS AND AWARDS TO PERSONNEL RELATING TO THIS PROJECT DURING CALENDAR YEAR 1956: None Form No. (MUP-1 October 1956 (Attachment l) Calendar Year 19^6 PUBLIC HEALOH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. NHI-176 SERIAL NUMBER 2. National Heart lastityte INSTITUTE OR DIVISION 3. Kidney & Electrolyte Metabolism LABORATQRY, BRANCH, OR DEPARTMENT k. SECTION OR SERVICE 5. LOCATION (IF OOHER THAN BETHESDA) 6. 7. 8. Renal Oilisting Function in Nephrosis PROJECT TITLE Mackenzie Vialser PRINCIPAL INVESTIGATOR Jack Or OISER INVESTIGATORS 9. IF THIS PROJECT RESEMBLES, COMPLEMENTS, OR PARALLELS RESEARCH DONE ELSEWHERE IN THE PUBLIC HEALTH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACILITIES OR RJNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF VI1»IN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTKWS ) : Objectivesj To- determine the response to water=loading in nephrotics as a fisn- tioiB, of solute excretion and filtration rate CGFR) „ and the effect thereon of steroid therapy. Methods Employed; Sustained water diuresis is maintained during siaper-^ Imposed osmotic diuresis with mannitol or acetazoleamide. Filtration rate Cinjalin) and the rate of excretion of solute and electrolytes is measured o Patient material; 6 normal controls-subjects have been subjected to the above procedure as well as 8 patients with the nephrotic syndrome NHI-176 Ma.jor Find inns: As compared with normal subjects or patients with nephrogenic diabetes insipidus, the patients with the nephrotic syndrome exhibit normal or enhanced diluting function per unit of glomerular filtrate. Steroid therapy did not alter the re- lationship between urine flow an,t solute excretion per unit of glomerular filtrate although in some patients considerable change in filtration rate occnrred. Significance to HEART Research: The data are consistent with the interpretation that the diluting function of the remaining tubules in patients with nephrosis is normal, and that glomeru- lar flow per nephron unit is normal or increased. Steroid therapy apparently increases the number of functioning nephrons rather than increasing flow in the remaining nephrons. These conclusions, if substantiated by further work, are significant in understanding the pathogenesis of the nephrotic syndrome and the mechanism of steroid-induced remission. They are also relevant to the problem of the mechanism of mi lary dilution. Proposed Course of Pro.iect: After one or two more experiments this project will be completed. Form No. ORP-1 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. NHI~176 SERIAL NUMBER 12. BUDGET DATA; ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FY' 57 $7,400 $3,735 BUDGETED POSITIONS 111,335 o2 o9 lol PATIENT DAYS PROP OTHER TOTAL FT' 57 0 1 1 0 13. BUDGET ACTIVITY; RESEARCH /x7 REVIEW & APPROVAL CD BIOLOGIC STANDARDS HI ADMINISTRATION PROFESSIONAL & TECHNICAL ASSIST- ANCE no 14. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S): None Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OP HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15. NHI-176 SERIAL MUBER 16. LIST PUBLICATIONS OTHER THAN ABSTRACIS FROM THIS PROJECT DURING CALENDAR YEAR 1956: None 17. UST HONORS AND AWARDS TO PERSONNEL REUUNG TO TECS PROJECT DURING CALENDAR YEAR 1956: None Form No. OElP-l Calendar Year 1956 October 1956 (Attachment I) PUBLIC HEALTH SERVICE - - NATIOHAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. Nni-177 SERIAL NUMBER 2. National Heart Institute 3. Kidney & Electrolyte Metabolism INSTITUTE 6E^ DIVISI6n LABORATORY, BRANCH, OR DEPARTMENT »*. 5. , , SECTION OR SERVICE LOCATION (IP OTHER THAN BETHESDA) The Graded Effect of Purified Vasopressin and Urinary Solute on the 6. Excretion of Solute-Free Water 7. 8. PROJECT TITUS Jack Orloff PRINCIPAL INVESTIGATOR Henry N„ Wagner, Jro„ Douglas G, Davids ;on OTHER INVESTIGATORS 9. IF THIS PROJECT RESEMBLES, COMPLEMENTS, OR PARALLELS RESEARCH DONE ELSEWHERE IN THE PUBLIC HEALIU SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACILITIES OR RJNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). Similar studies in man are being performed by Dr. Wagner and are discussed elsewhere. LO. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Project; The graded effect of purified vasopressin and urinary solute on the excretion of soiute=free water. Objectives; To elucidate the mechanism of urinary concentrationo Major Findings; Ca) It has been found that solute=free water excretion rises in association with an increase in solute excretion. Cb) The excretion of soiute=free water is decreased progressively by the administration of purified arginine vasopressin in dosages varying from 0o5 to BoO raU/kilo/houro Cc) Dinting the administration of submaximal amounts of vasopressin, at low levels of solute excretion, the urine was hypertonic, but as solute excretion increased, the urine became hypotonic to plasma. When suffi- cient quantities of ADH were administered^ the urine remained hypertonic to plasma despite the magnitude of the increase in solute excretion. NHI-177 Significance to HEART Research: The problem is of importance insofar as it affords information concerning the normal mechanism of maintenance of water balance. Proposed Course of Project: To determine whether the transition from hypertonic to hypotonic urine during solute excretion occurs when ADH activity is initially maximal. It may not be feasible to per- form these studies other than in dogs with diabetes insipidus. Form No. QRP-1 October I956 (Attachioent I) FUBIIC HEALOB SERVICE - - NAnOHAL IMSTITaEES OF HEAI/EH IHDIVIDUAL PROJECT REPORT Part B: Budget Data ^' Wtil^l 77 SERIAL NUMBER 12. BUDGET DATA: ESTMAIED gBLIGATIQHS MAN YEARS DIBSCT FY' 57 $15,20 HEIMBURS^fEIiT BUDGETED POSITIONS TOTAL PROP OTHER TOTAL $ 2k, J, SOX OTHER TOTAL lo7 PATIEBT DAYS FY' 57 2 1 13. BUDGET ACTIVITY; RESEARCH /T/ REVIEW & APPROVAL /"T BIOLOGIC STANDARDS ^7 ADMINISTRATICW /^ PROFESSIONAL & TBCSEOilCAL ASSIST- ANCE r~7 lU. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER (BGANIZATIONS, PROVIDING FUNDS, FACILITIES, CE PERSONNEL PCR THIS PROJECT IN Ff 1957. IP COQPBRATIHG UNIT IS WITHIN NIH INDICATE SERIAL NO*(s): (use re'Terse aad. additional pages, if necessary) Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - ~ MTIOML INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C; Honors, Awards & Publications 15.. NHI=i77 SERIAL NUMBER 16. LEST PUBLICAnONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: 17. LIST HONORS AND AWARDS TO PERSONNEL REUTING TO THIS PROJECT DURING CALENDAR YEAR 1956: Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment I) PUBLIC HEALOH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. NHI--176 SERIAL NUMBER ^!atil3'n;3l Heart Imstittite o Kidsiey 6 Electrolyte ^ietabolislT! 2, MataQ'Siiai Mean imstatMte 3, INSTITUTE 6R DIVISION " LABORATORY, BRANCH, OR DEPARTMENT k, 5. SECTION OR SERVICE LOCATION (IF OTHER THAN BETHESDA) The role of the autouomiiB mser^ous system im the coHtrol of sodium g excretioiO ira man PROJECT TITLE •7 Herary N,, W5g5^er„ Jr. PRINCIPAL INVESTIGATOR ' ' 8. - — — -.^-- - OTHER INVESTIGATORS 9. IF THIS PROJECT RESEMBLES, COMPLEMENTS, OR PARALLELS RESEARCH DONE ELSEWHERE IN THE PUBLIC HEALTH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACILITIES OR FUNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): QbJ_ectlfes; To deterrairae the factors which inflmence the excretion of electrolytes,, chiefly sodiunic in H9n uerlals. Five patients with the syndrome of idiopathic postural hypoteRsioiio aohidrosis amd impotence. Normal persons and persons wii unrelated diseases as controlSo yjr Fi_gdi»q^; The fiye patients with diffrase hypofMnction of the awto= ra enhanced ability to excrete sodium as NHl-178 Significance to HEART Research; In contrast to patients with congestive states who have a decreased ability to excrete sodium, the patients with autonomic nervous system hypofunction have an enhanced ability to excrete sodium when the extracellular fluid volume is expanded. The studies are of significance in leading to an understanding of the mechanisms of congestion of all types, including congestive heart failure. Proposed Course of the Project: (a) To determine the role of the glomeru== lar filtration rate, venous pressure, change in serum proteins, changes in hematocrit, and other factors in determining the rate of sodium excretion, (b) To determine the effect of administration of various steroids with aldosterone-like properties on the sodium excretion of patients with autonomic hypofunction. (c) To more clearly define the role of the autonomic nervous system in controlling sodium excretion. Form No. ORP-1 October 1956 (Attachment l) FDBUC HEALTH SERVICE - - RATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. NHT-.17ft SERIAL NUMBER 12. BUDGET DATA; ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FI'57 113,600 $6,765 BUDGETED POSITIONS $20,365 1,0 o6 lo6 PATIENT DATS PROF OTHER TOTAL FT' 57 1 1 2 0 13. BUDGET ACTIVITY; RESEARCH HI REVIEW & APPROVAL dl BIOLOGIC STANDARDS /~7 ADMINISTRATION EJ PROFESSIONAL & TECHNICAL ASSIST- ANCE n 14. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S); None Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NAnONAL INSTITUTES OP HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15. NHI-178 SERIAL NUMBER 16. LIST PUBLICAnONS OTHER THAN ABSTRACTS FROM TEES PROJECT DURING CALENDAR YEAR 1956: None 17. UST HONORS AND AWARDS TO PERSONNEL RELATING TO THIS PROJECT DURING CALENDAR YEAR 1956: None Form No. OSP-1 Calendar Year 1956 October 1956 (Attachment l) PUBLIC HEAUH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Deflcription Sheet 1. NHI_179 SERIAL NUMBER 2^ National Heart Institute ^^ Kidney & Electrolyte Metabolism INSTITin^ (A DIVIS16n laboratory, branch, OR DEPARTMENT ^' «___ g» , SECTION OR SERVICE LOCATION (IF OOSER THAN BETHESDA) g Mechanisms of Fluid and Electrolyte Retention in Experimental Cardiac Failure, PROJECT TITLE James 0. Davis 7. PRINCIPAL INVESTIGATOR 8 ---il-2L9-_??i2::--5-i--J->-L-??---J?*^-'Jl't'- 'l°'^®-^^_Jl'..^^'l'lJl^V-JlC-P-3-thological OTHEr'iNV^IOATORS '/Tnat oray ," "Nfay"© *"cf i nf c „' "Roche sYer ," Mi"nne s'oTa 9. IF THIS PROJECT RESEMBLES, COMPI£MENTS, OR PARALLEI3 RESEARCH DONE ELSEWHERE IN THE PUBLIC HEALTH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACILITIES OR lUNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IFUIIHIN NIH). Research complements work done by Bartter and associates (Serial *301) 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Project: Increased secretion of aldosterone by the adrenal cortex in dogs with cardiac, failure and in dogs with thoracic inferior vena cava cons- triction and ascites. Objectives; To determine whether aldosterone is secreted at an increased rate in dogs showing chronic Na retention. Methods Employed: The concentration of aldosterone is determined in adrenal vein blood from (1) normal dogs, (2) dogs with heart failure and (3) dogs with thoracic inferior vena cava constriction and ascites. Also, the rate of flow of blood from the adrenal gland is determined so that the minute output of aldosterone can be calculated. To determine the concentration of aldosterone, in adrenal vein blood, the blood is extracted and chromato= graphed; all chromatographic fractions are assayed for aldosterone=like activity. NHI=179 page 2 Major Findings t A. .Studi^s^^is_i,ng^ nemb^^ When adrenal vein blood was obtained from dogs under nembutal anesthesiao no aldosterone was detected in 300 cc. of blood from each of three normal dogs. However o the rate of aldosterone secretion was 6 g/hour for a dog with cava! con= striction and ascites and 4 g/hour for a dog with heart failurco B. Studies using local anesthesia. In this series of dogS; adrenal vein blood was collected using local anesthesia and during transfusion of blood to replace the blood removed. Aldosterone secretion was 0,3, and 5 g/hour for three normal dogs, 7 and 16 / g/hour for two dogs with thoracic caval constriction and 5, 20 and 25 g/hour for three dogs with heart failure. Three hundred cc. of peripheral blood from one of the dogs with caval constriction and one of the dogs with heart failure showed no detectable aldosterone. The data demonstrate increased secretion of aldosterone in dogs with thoracic caval constriction and in dogs with right heart failure. ^jL2,!Li^i£.^!!££.Ji£ '' ''' ''u-il£15i§££li* ''•'his finding provides a very iiii^ ortant link in the chain of events from the heart to the kidney in elucidation of the mechanisms of Na retention in congestive heart failure. Proposed Course of_i:!XQJ.g.ct ; This project is complete. The mechanism whereby the adrenal cortex is stimulated to secrete aldosterone is the next logi= cal problem. Also, the possibility of decreased rate of degradation of aldosterone by the liver as a secondary mechanism for increased circu= lating aldosterone should be investigated. Project II. Project; Aldosterone and Na excretion in urine from hypophysectomized dogs with thoracic inferior vena cava constriction and ascites. Objectives; To determine the role of the anterior pituitary gland in the control of aldosterone production. Me t h od s Kmp 1 oy ed : The urinary excretion of aldosterone was studied by extractioi of urine with an organic solvent, methylene chloride. The solvent is evaporat- ed and the residue dissolved in absolute ethanol. The extract is injected into adrenalectomized assay dogs to characterize the effect on Na and K excretion. Potency is determined from a dose=response curve. It has been shown previous- ly that the biologically active agent is aldosterone. Dogs with thoracic caval constriction and ascites were subjected to hypo= sectomy. In the first experiment, no therapy was given during the post= hypophysectomy period, but in the second group of animals (Lixperiment ID ACTH was administered in an attempt to prevent the changes resulting from hypophysectomy. In a third group of dogs Experiment III) the pituitary gland was removed first and then the thoracic inferior vena cava was constricted. Major Fird_ings: Experimeni 1. A marked decrease in the urinary excretion of aldosterone occurred within 5=10 days after hypophysectomy. When aldo= sterone dropped to the normal level, Na excretion invariably increased. In some instances, aldosterone excretion did not return completely to normal and Na excretion remained low. Later in the course, aldosterone output returned to normal in the latter instances and Na excretion increased. NHI=I79 page 3 Experiment II. AGTH failed to prevent the fall in aldosterone excretion and rise in Na output which followed hypophysectomy of dogs with caval constric- tion and ascites. Reconstriction of the thoracic inferior vena cava with a resultant increase in inferior vena caval pressure was followed by restora= tion of aldosterone output to the high pre-hypophysectomy level, marked Na excretion and ascites formation. Experiment III. In this experiment the pituitary gland was removed first and then the thoracic inferior vena cava was constricted. Urinary aldoster= one excretion increased, marked Na retention occurred and ascites formed. The adrenal cortex of these two dogs was markedly atrophic but the atrophy was limited to the two inner layers; the zona glomerulosa appeared normal. It is concluded that the pituitary gland is not essential for increased aldosterone excretion, Na retention and ascites formation. Significance to HEART Research; The present data provide information on the relation of the anterior pituitary gland to aldosterone excretion in urine from dogs with experimental ascites. The findings also furnish valuable information on the fundamental relationship of the pituitary to the adrenal cortex. Proposed Course of Project; To determine the effect of hypophysectomy on aldo- sterone output both thyrotropin and growth hormone should be given as re= placement therapy. Also, the effect of thyroidectomy upon aldosterone ex= cretion by dogs with caval constriction should be studied. Project; Effect of hemorrhage on the urinary excretion of aldosterone and sodium in dogs. Objectives; To investigate the role of aldosterone in the retention of sodium following hemorrhage. Methods Employed; Same as in Project II. Major t^indings: An increase in tjrinary aldosterone-like activity was associated with sodj'in retention following liemorrhage. A similar amount of activity characteristic of aldoslcrono was obtained by placing normal dogs on a low Na intake which was equivalent to the net Na intake produced by bleeding. The latter finding makes it unnecessary to hypothesize that factors other than Na loss are responsible for increased aldosterone output. Significance to IKjArM llescarch: The data show the important role of aldosterone in homeostasis. Proposed Course of Project: Project completed. NHI-179 page 4. Project IV. Project; Functional changes during high output failure produced by daily hemorrhage in dogs with pulmonary artery constriction. Objectives; To determine the relationship of changes in cardiovascular and renal hemodynamic function to Na excretion during the development of high output heart failure. Major Findings; Seven dogs with constriction of the PA and 6 normal dogs were bled 15-25 cc/kg. daily until a severe anemia developed. Five of the 7 dogs with PA constriction developed signs of right heart failure, but no evidence of cardiac decompensation was observed in the normal dogs made severely anemic. Mean right atrial pressure 6iAP) inceased from 90/140 to 140/240 mm water but otherwise normal animals. Sodium retention occurred only in the dogs with PA constriction and ascites formation was associated with an RAP of 140 mm. water or above (normal RAP was 10-70 mm. water). Cardiac output increased to a similar extent (1.0-2.9 L./min.) in the two gro'ips of animals. In dogs with I'A con= striction, C^-- increased in some animals and decreased in others whereas Cp^jj increased in 4 of 5 dogs. In the normal dogs made anemic, Cqj. was decreased or unchanged while Cp^j^ was increased or unaltered. The in= crease in RPF was apparently marked since the extraction ratio done on one of the dogs with PA constriction was 65%. It is concluded that the most consistent differences between the two groups of animals in their responses to bleeding were in the effects on RAP and Na excretion; RAP increased and Na retention occurred only in dogs with PA constriction. Significance to HEART Research: The data support the "backward failure" concept of the pathogenesis of congestive heart failure. Proposed Course of Project: Project is complete. Form No. ORP-1 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. NHI°179 SERIAL NUMBER 12. BUDGET DATA: ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FT< 57 $23,800 $9,834 BUDGETED POSITIONS 133.634 1.3 lo8 3»1 PATIENT DAYS PROF OTHER TOTAL FY' 57 1 2 3 0 13. BUDGET ACTIVITY; RESEARCH Ax? REVIEW & APPROVAL /~7 BIOLOGIC STANDARDS /~/ ADMINISTRATION EJ PROFESSIONAL & TECHNICAL ASSIST- ANCE n 14.. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S): Form No. ORP-1 Calendar Year 1956 Ootober 1956 (Attachment l) PUBLIC HEALTH SERVICE NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15. NHI-i79 SERIAL NUMBER 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: 1. Davis, Jaraes 0»„ Howell, David S., Goodkind, M.Jay, and Hyatt, Robert E.; AcGuiwulatiou of ascites during maintenance of adrenaleetomized dogs witJj thoraeic inferior vena caval constriction of a high Na diet without hormone therapy. Ain, J. Physiol. 185:230,1956. 2. Da^is, James 0.„Goodkind, M.Jay, Fechet, Maurice M. and Ball, irtfilmct C.,Jr.: Increased excretion of aldosterone in urine from dogs with right=sided conges= tive heart failure and from dogs with thoracic inferior vena cava constriction, Amer. J. Physiol. 187:45, 1956, 3. Goodkind, M.Jay, Hyatt, Robert E. and Davis, James 0,: Failure of large doses of desoxycorticosterone acetate to block the natriuretic- action of mercury in adrenaleetomized dogs with thoracic inferior vena caval comstriction and ascites. Amer. J. Physiol. (Accepted for publication) 4. Goodkind, M. Jay, Davis, James 0.„ Ball, Wilmot C. Jr., and BalsK, Robert C: Alterations in cardiovascular and renal hemodynamic function following hyp(i>= physectomy In the dog. Amer, J, Physiol. (Accepted for publication) 5. Dawis, James 0.: Some aspects of the physiology of aldosterone, J, National Medical Association. '(Accepted for publication). 6. Ball, Wilmot C,,Jr., Davis, James 0, and Goodkind, M.Jay: Ascites formation without Na intake in dogs with congestive heart failure and in dogs with thoracic inferior vena cava constriction. Amer, J. Physiol, (Accepted for publication) , 17. List Honors and awards to personnel relating to this project during calendar year 1956, None Pom No. QRP-1 Calendax Year 1956 October 1956 (Attachment l) PUBLIC VEAVm SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. NHI-^180 SERIAL NUMBER 2. National Heart Institute 3, Kidney & Electrolyte Metabolism INSTITUTE 6ft DIVISION LABORATORY, BRANCH, OR DEPARTMENT k. 5. , , SECTION OR SERVICE LOCATION (IF OTHER THAN BETHESDAJ 6. Method. and Apparatus for Automatic Titration of Chloride PROJECT TI'i.il 7. tirnest Cotlove PRINCIPAL INVESTIGATOR 8. OTHER INVESTIGATORS 9 . IF THIS PROJECT RESElxIBLBS, COMPLEMENTS, OR PARALLELS RESEARCH DONE ELSEWHERE IN THE PUBLIC HEALTH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACILITIES OR FVNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Project; Development of method and apparatus for rapid, precise and automatic titration of chloride. Objectives; The -object of this project is to develop a simple, rapid, precise and sensitive method that will permit a detailed investigation of tissue chloride contents, cellular chloride content and exchangeabi= lity of chloride. *" NHI=180 Methods tiimployed- The anoiyiic method is based on titration of chloride by silver ion. The silver ion is generated at a constant rate from silver wire by electrolysis. The end-point is detected amperometricaliy by the sudden rise in diffusion current (due to free silver ion) between two stationary silver electrodes in a stirred medium. A meter=reiay , set to be actuated by the current rise just past the end=point<, stops a timer. The titration is thus entirely autoniatic. The elapsed time minus the over-titration time for relay actuation (as measured by a blank sample) is a direci. riear;;ire of chloride content. Major Findings; The ap.i.iuatus and method have been further improved and simplified so that results are obtainable from the timer reading by simple calculation. The recording and measurement of the titration curve can be eliminated. Accurate results are obtainable in biologic cal fluids (plasma, urine, tissue extracts) without prior preparation of the sample other than addition of acid reagent mixture, The pro= cedure is rapid (about a half=-minute) accurate (to within 1% or better), sensitive (to as little as one-quarter microequivalent of chloride), and can be performed by personnel without special training. Significance to HEART Research: A simple, rapid and accurate method for determination of chloride in biological materials will be of value: since chloride is the predominant anion in extracellular fluid, and Current methods are slow and depend on operator skill and judgment. The analysis of chloride in tissues in particular has presented problems. The present method should be of great usefulness not only in specialized research problems but also in clinical labora= tories involved in patient care. Proposed Course of the Project: The method is being applied to the pro= blems for which it was developed, namely a study of tissue chloride. It is also being used in a number of other projects requiring analysis of chloride in biological fluids. The plans will be released to manu= factuters who might be interested in producing it for research and clinical laboratories. Form No. ORP-1 October I956 (Attachment I) PUBLIC HEALTH SERVICE - - HATIOHAL INSTITOTES OP HEAMH IBDIVIDUAL PROJECT REPORT Part B: Budget Data 11. NHI-=.180 SERIAL NUMBER 12. BUDGET DATA: ESTIMATED OBLIGATIONS MAN YEARS DIRECT BEIMBURSEMSiT TOTAL PROF OTHER TOTAL FY' 57 $5,600 $2,604 BUDGETED POSITIONS $8,204 o2 o5 o7 PATIENT DAYS PEGS' OTHER TOTAL FY' 57 0 1 1 0 13. BUDGET ACTIVITY: RESEARCH 7x7 ADMINISTKATION REVIEW & APPROVAL BIOLOGIC STANDARDS n u PROFESSIONAL & TECHNICAL ASSIST- ANCE CJ d Ik, IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, CR PERSONNEL FOR THIS PROJECT IN FY 1957* IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL HO»(s): This project is being conducted in collaboniion with Dro Robert Lo Bownan and Mto Hillary Trantham, Laboratory of Technical Deirelopnient, NHIo (Use reverse ajod additional pages, if necessary) Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15._MI: SERIAL NUMBER 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956s 17. LIST HONORS AND AWARDS TO PERSONNEL RELATING TO THIS PROJECT DURING CALENDAR YEAR 1956: None Form No. ORP-1 October 1956 (Attachment l) Calendar Year I956 PUBUC HEALOH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Deacription Sheet 1. NHI=181 SERIAL NUMBER 2, National Heart iKstitjate INSTITUTE OR DIVISION h. 5^ Kidney S Electrolyte Metabolism LABORATORY, BRANCH, OR DEPARTMENT 5. SECTION OR SERVICE LOCATICai (IF OTHER THAN BETHESDA) £ Absorpti©n of Drugs by the Intestine 7. 8. OTHER INVESTIGATORS 9. IF THIS PROJECT RESEMBLES, COMPLEMWTS, OR PARALLELS RESEARCH DONE ELSEWHERE IN THE PUBLIC HEALTH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACILITIES OR RJNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). PROJECT TITLE Dr, Co Adrian M„ Hogben PRINCIPAL INVESTIGATOR Dr„ Le*.i?is So Schasker Ctabo of Chemical Pharmacology) 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Objectiwes; The rates of md'eaent of di^^erse compfflunds across the gastro= iretestimal tract will permit characterization ©f membrane permeability and significarat physical chemical factors o Methods b:mplo.y_eds A salimie solutioa containing the dtng is perfused thro?jgh the rat intestine _im jitj:. The decreased concentration of the cewj leading the intestine provides a ffleasmre of absorption and an apparent permeability coefficient „ The steady state distribiation of a driiig is determined by injecting the drysg intrawenoasly and them perfusing the intestine with a drtsg concentration that establishes equiiibrium. NHI=181 ^^^^___^ A survey of a large niimber of acidic and basic drugs indicates that there are limiting ionization constants determining absorption from an unbuffered solution in the intestinal lumens In the case of acids, the pKa is 2,5; for bases the pKa is 6=5. In no instance has there been evidence of competition between drugs. The rate of absorption is proportional to concentration. Among those drugs which are rapidly absorbed, there are small but significant differences in absorption rates« While these differences parallel the lipid owater partitions in some cases,, there is lack of agreement in others » Similar findings have been encountered in other biological membranes thought to have an essentially lipoid matrix. The absorption of these drugs has been examined at several pH's rang= ing from 4 to 8, Qualitatively the rates of absorption are modified in the direction expected if these drugs were absorbed in the uionized form. Quantitatively the rate of absorption dees not change as rasjich as the change in concentration of the unionized formg Ocgoo the ab= sorption ©f salicylate changes from 64% at pH4 to 11% at pH8, The dependence of absorption on intestinal lumen pH and the limiting pKa°s determining rapid absorption have been clarified by determining the steady state distribution between plasma and intestinal lumen, \tihen the intestinal lumen has a pH of 6,5 the plasma to lumen ratio of salicy= lie acid is 30:1 and of quinine is lt30. These observations and others can be interpreted on the basis of the intestinal lumen having a virtual pH of 5:5 and the steady state being determined by both the rapid move= ment of the unionized moiety and the slow movement of the ionized moiety, Significance to HEART Research; This study will provide for the first time a quantitative picture of gastrointestinal absorption of drugs o Analysis of factors governing weak electrolyte transfer will contribute inforraatior to the study of electrolyte exchange across the gut. Investigation of factors other than permeability are significant for other aspects of gastrointestinal physiology such as fat absorption. Proposed Course of Project; Extend our understanding of pH dependence of drug absorption by further steady state experiments. Analyze the absorp= tion of different regions of the intestine. Scrutinize the rates of ab= sorption of poorly absorbed drugs. Form No. (BP-1 October I956 (Attachment I) FUBUC HEALOS SERVICE - - NATICHIAL IHSOITUTES OF HEALTH HSDIVIDUAL PROJECT REPORT Part B: Budget Data 11. NHI-181 SERIAL NUMBER 12. BUDGET DATA: ESTIMATED QBLIGATICNS MAN YEARS DIRECT BEINBURS04EIIT TOTAL PROF OTHER TOTAL FY' 57 $5,700 $2,684 BUDGETED POSITIOHS 18,384 o4 o3 o7 PATIEHT DAYS mxF OTFTER TOTAL FY' 57 1 0 1 0 13. BUDGET ACTIVITY; RESEARCH /xT REVIEW & APPROVAL /~T BIOLOGIC STANDARDS f^ ADMINISTRATION /~7 PROFESSIONAL & TECHNICAL ASSIST- ANCE FT Ik, IDEHTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER CHIANIZATIONS, PROVIDING FUNDS, FACILITIES, CB. PERSONNEL FOR THIS PROJECT IN FY 1957. IP COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(s): None (Use reverse and additional pages, if necessary) Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment I) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15._NHI=181 SERIAL NUMBER 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: Shore„ P„A., Brodie, B. B, and Hogben, C.A.M. Gastric secretion of drugs = a pH partition hypothesise J. Pharra. & Exp. Therap. (In press] 17. LIST HONORS AND AWARDS TO PERSONNEL RELATING TO THIS PROJECT DURING CALENDAR YEAR 1956: None^ Pom No. ORP-1 Calendar Year 1956 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. nhi-182 SERIAL NUMBER 2, HEART 3. SURGSRY INSTITlrtfl fit^ DIVISI6N LABORATORY, BRANCH, OR DEPARTMENT h, _ 5. , , SECnCN OR SERVICE LOCATION (IF OTHER THAN BETHESDAj g THE SEQUENCE OF VENTRICULAR CONTRACTION IN HUMAN BUNDLE BRANCH BLOC::. PROJECT TITLE f , Eugene Braunwald, M, D, & Andrew G, Morrow, M. D. PRINCIPAL INVESTIGATOR ' 8. OTHER INVESTIQATORS 9. IF THIS PROJECT RESEMBLES, COMPLEMENTS, OR PARALLELS RESEARCH DONE ELSEWHERE IN THE PUBLIC HEALTH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACILITIES OR fTJNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Objective; To ascertain whether or not the ventricles contract simul- taneously or not in the presence of EKG findings of bundle branch block. Methods Employed; Simultaneous left and right ventricular pressures were determined in both normal individuals and those with bundle branch block. Major Findings; In five patients with left bundle branch block there was no delay in contraction. In some patients with right bundle branch block there was delay and in others there was not. In those with the delay there was always right ventricular hypertrophy. Niii-].8;i Significance Uo lIi^ART Research: The sij-nifi-'-ane of Llie t'.KC, patcei-n ol" bundle branch block is open to question anci Lhose slu lies ;;hou.i.u do much to clarify the clinical problem, Pro po s e d Cou r s^g of Project^: The studies vjill be coni..i.nucvi in piUicnts with and without bundle branch block. Form No. ORP-1 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NAHONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. NHI - 182 SERIAL NUMBER 12. BUDGET DATA; ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF ■ OTHER TOTAL FJ157 $5,800 $21,219 BUDGETED POSITIONS $28,019 .3 .4 .7 PATIENT DAYS PROP OTHER TOTAL FI'57 0 1 1 380 13. BUDGET ACTIVITY; RESEARCH 777 REVIEW & APPROVAL JZIl BIOLOGIC STANDARDS /~7 ADMINISTRATION EJ PROFESSIONAL & TECHNICAL ASSIST- ANCE / / 14... IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO. (S); None Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment I) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15. NHI"182 SERIAL NUMBER 16. UST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: 17. LIST HONORS AND AWARDS TO PERSONNEL RELATING TO THIS PROJECT DURING CALENDAR YEAR 1956: Form No. ORP-1 Calendar Year I956 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. NHI°183 SERIAL NUMBER 2. HEART 3. SURGERY 8. INSTITUTE OR DIVISION LABORATORY, BRANCH, OR DEPARTMEOT h. 5. , ^ SECnCN OR SERVICE LOCATION (IF OTHER THAN BETHESDA) THE USE OF DYE DILUTION CURVES FROM THE LEFT HEART AND AORTA FOR THE 5 LOCALIZATION OF LEFT TO RIGHT SHUNTS AND THE DETECTION OF VALVULAR PR6JECT TITLE — IMtJlJPFICIENC'k. J Andrew G. Morrow, M, D. , Eugene Braunwaldj, M<, D, 6e Herbert Tanenbaum, M. D. PRINCIPAL INVESTIGATOR " ' OTHER INVESTIGATORS 9. IF THIS PROJECT RESEMBLES, COMPLEMENTS, OR PARALLELS RESEARCH DONE ELSEWHERE IN THE PUBLIC HEALTH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACILITIES OR RJNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). PROJECT DESCRIPTICW (SEE INSTRUCTIONS): Objective; To assess the usefulness of left heart and aortic indicator dilution curves in the localization of left-'to~right shunts and the detection of valvular insufficiency. Methods Employed; Dye curves were made by injection into the left atrium, left ventricle and at various sites in the aorta in patients with a variety of cardiovascular lesionso Major Findings; A normal curve results when the injection is made distal to the origin of the shunt or when no insufficiency is present. An abnormal curve is obtained proximal to a shunt or in the presence of valvular insufficiency. The two types of abnormal curves are distinct. NHI-183 Significance to HEART Research; The precise localization of left-to- right shBnts is often a difficiult clinical problem. The present tech- nique promises to be of great aid in this diagnostic problem. Proposed Course of Project; Stiadies will be continued as outlined. Form No. ORP-1 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. ^^^ " ^^2 SERIAL NUMBER 12. BUDGET DATA; ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FT' 57 $15,400 $48,096 BUDGETED POSITIONS $63,496 ,7 o7 1.4 PATIENT DAYS PROF OTHER TOTAL FT' 57 ^ 1 2 573 13. BUDGET ACTIVITY; RESEARCH Zf7 REVIEW & APPROVAL /~7 BIOLOGIC STANDARDS ZZ? ADMINISTRATION /U PROFESSIONAL & TECHNICAL ASSIST- ANCE ZI7 lA. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957o IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S): None Form No. ORP-1 ' Calendar Year 1956 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15.NHI-183 SERIAL NUMBER 16. LIST PUBLICAnONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: 17. LIST HONORS AND AWARDS TO PERSONNEL REUTING TO THIS PROJECT DURING CALENDAR YEAR 1956: Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment I) PUBIIC HEALBH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Deecription Sheet 1. I^'il-IM SERIAL NUMBER 2. HEART 3. SURGERY INSTITUTE Or DIVISI6n LABORATORY, BRANCH, OR DEPARTMENT k. 5. , ^ SBCnON (» SERVICE LOCATION (IF OTHER THAN BETHESDA) EVAI.UATION OF LEFT ATRIAL PRESSURE CONTOaRS l;^' DIFFEREhNiTIATINf; MITRAL 6. STENOSIS AMD MITRAL INSUFFICIENCY. PROJECT TITLE Andrew G, Morrow, M. D. , Edward IL Sharp, M. u, , Uig^?ih^- liraaji.Tiwaldj iL I & J. Alex Haller, Jr., M, D. PRINCIPAL INVESTIGATOR "■ ' 8. OTHER INVESTIGATORS 9. IF THIS PROJECT RESEMBLES, COMPI£MENTS, OR PARALLELS RESEARCH DONB ELSEWHERE IN THE PUBLIC HEALTH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACILITIES OR RJNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Objective; To evaluate the usefulness of left atrial pressure pxilses in the assessment of the severity of mitral insufficiency. Methods Employed; Left atrial pressure was measured preoperatively in patients with mitral valve disease and the resulting curves analyzed by many methods. Major Findings; Best differentiation occurred when the slope of the y descent of the left atrial V wave was related to the mean left atrial pressure. By this technique patients with mitral stenosis and mitral insufficiency were easily distinguished. NHI-184 Significance to HEART Ilesearch; Rheumatic mitral valve disease constitutes the Jargest group of patients with acquired valvular disease. The selection of the patients for operation is greatly facilitated by the method outlined. Proposed Course of Project; Studies will be continued and the re- sults correlated with operative and autopsy findings. Form No. ORP-1 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. NHI - 184 SERIAL NUMBER 12, BUDGET DATA; ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FY!57 $25,600 $79,218 BUDGETED POSITIONS ?IQ4,818 1.6 .5 2,1 PATIENT DAYS PROF OTHER TOTAL FT' 57 2 1 3 1.140 13. BUDGET ACTIVITY; RESEARCH f^/ REVIEW & APPROVAL /~7 BIOLOGIC STANDARDS ZZ7 ADMINISTRATION no PROFESSIONAL & TECHNICAL ASSIST- ANCE ZI7 14.. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957o IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO. (S): None Form No. ORP-1 ^ Calendar Year 1956 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15. NHI~184 SERIAL NUMBER 16. UST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: 17. LIST HONORS AND AWARDS TO PERSONNEL RELATING TO THIS PROJECT DUKENG CALENDAR YEAR 1956: Pom Ho. (SlP-1 Calendar Year 1956 October 1956 (Attachment I) FUBUC HEAUIB SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. MI-18S SERIAL NUMBER 2. HEART 3. SURGERY INSTITlrtfi a^ DIVISI6N LABORATORY, BRANCH, OR DEPARTMENT h, ■ 5. . SECnOH OR SERVICE LOCATION (IP OTHER TOAN BETHESDA) 6. EXFSRniEHTAL PRODUCTION OF GRADED VALVULAR MITRAI. STENOSIS IN DC€S. PROJECT TITLE -—--—---—--_-——————----—----- Y. G, S. Weldorij M. D. & Joseph W, Gilberts IL L\ PRINCIPAL INVESTIGATOR 'rcgisal Laboratory, NHI 8. -. COSIER INVESTIGATORS 9* IF THIS PROJECT RESEMBLES, COMPI£MENTS, OR PARALLEI3 RESEARCH DONE EISEUHERE IN THE PUBLIC HEALTH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACILITIES OR FUNDS ), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIR). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS)! Objective: T© develop a dtres£ vlsi@E approach £o tte mltrcil xmlve in order £0 produce experitaental mitral stenssis aand evaluate this fceeh" aique for possible clinical applicafcioa in tb® treaCaseat of aiisral iasufficiericy. Methods Empl_Qjred; The interior ©f the left atriwa is exposed in animals by an incision on the right inferolateral border of the left atritim. The animal is supported during this time ©a the heart-lung machine during a period of elective cardiac =>.rrsst. Hypothermia has been employed in seme but with low survival. NHI~185 Major Findings; The vaLve can be safely exposed for 20-30 minutes and graded mitral stenosis produced by direct vision suture of the leaflets. Significance to HEART Research; The treatment of mitral insufficiency remains a major unsolved, problem in clinical cardiac surgery. It is believed that the technique described will provide a method for its successful repair. Proposed Course of Prelect; Animal experimentation will be continued and human autopsy material studied to determine the best operative technique. Form No. ORP-1 ' October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. NHI > 185 SERIAL NUMBER 12. BUDGET DATA: ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FT' 57 $15,800 $6,695 BUDGETED POSITIONS $22,495 J .8 lo5 PATIENT DAYS PROF OTHER TOTAL FI'57 1 1 2 None 13. BUDGET ACTIVITY; RESEARCH /77 REVIEW & APPROVAL /~7 BIOLOGIC STANDARDS /~7 ADMINISTRATION ZI7 PROFESSIONAL & TECHNICAL ASSIST- ANCE n 14.. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957o IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S)! Nons Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment I) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15. MI~185 SERIAL NUMBER 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: 17. UST HONORS AND AWARDS TO PERSONNEL REUTING TO THIS PROJECT DURING CALENDAR YEAR 1956: Porn No. QEa>-l Calendar Year I956 October 1956 (Attachment l) PUBLIC HEALBI SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. -hi- 186 SERIAL NUMBER 2. HEART 3- SURGERY INSTITUTE OR DIVISION ~~ LABORATORY, BRANCH, OR DEPARTMEaJT SECTION OR SERVICE LOCATION (IP OTHER THAN BEIHESDA) THE REACTIVITY OF CARDIAC MUSCLE TO ADRENERGIC AGENTS AFTER BILATERAL 6. THORACIC SYMPATHECTQM. PROJECT TITLE — — -— _„-..^ _—.— „ Y. Theodore Cooper, M, D PRINCIPAL INVESTIGATOR 8 OOHER INVESTIGATORS 9. IP THIS PROJECT RESEMBLES, COMPUMBNTS, OR PARALLELS RESEARCH DONE ELSEWHERE IN THE FUBUC HEALIH SERVICE (WUHOUT INTERCHANOE OF PER- SONNEL, FACILITIES OR RJNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WiraiN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): ^lt££i.Y£° To determine the effects of thoracic sympathectomy on the sensitivity of the heart to adrenergic drugs, Metlwds_ Employed ; The contractile force of the heart has been measured after varying doses of adrenalin and noradrenaiin in the normal and sympathectomized dog. Major Findings: Thus far^ no changes in the sensitivity of the heart have been found after sympathecf"™" Significance to HEART Rgsgarch: The results indicate that there would be no "supersensitivity" of the heart to adrenalin after syrapathectomy in the human. &°P2sed__,Course_of_Pjroj^ej_t: The study will be continued as outlined. Form No. ORP-1 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. NHI = 186 SERIAL NUMBER 12. BUDGET DATA; DIRECT FYt57 $9,700 PROF FI'57 ESTIMATED OBLIGATIONS REIMBURSEMENT $4,091 BUDGETED POSITIONS OTHER TOTAL $13,791 MAN YEARS PROF OTHER TOTAL TOTAL PATIENT DAIS Noise 13. BUDGET ACTIVITI; RESEARCH /T? REVIEW & APPROVAL /~7 BIOLOGIC STANDARDS /~? ADMINISTRATION nj PROFESSIONAL & TECHNICAL ASSIST- ANCE nj lA. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957» IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO. (S): None Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment I) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15. NHI-186 SERIAL NUMBER 16. LEST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: 17. LIST HONORS AND AWARDS TO PERSONNEL RELATING TO THIS PROJECT DURING CALENDAR YEAR 1956: Pom No. ORP-1 Calendar Year 1956 October 1956 (Attachment I) FUBUC HEALIH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. ^^"^^^ SERIAL NUMBER 6. 7. 8. SURGERY 2^ HLAKl O^ INSTITtW^lS fll^ DIVISI6n LABORATORY, BRANCH, OR DEPARTMENT h. 5. . , SECTION OR SERVICE LOCATION (IP OTHE!R THAN BEIHESDAT SFiJOIKS ON THE EXCITABILITY OF VENTRICULAR HE.ART MOSCLE DURING HYPO- THERMIA WITH AND WITHOUT PROCAINE BLOCKADE OF THE CAVAJ-.- ATRIAL JUNCTICM. PROJECT TITLE Leo R, Radigan, M. D, , Thomas A, Lombardo, M. D. & Tlieodore Coopet-, M. D, PRINCIPAL INVESTIGATOR OIHER INVESTIGATORS 9' IF 1HIS PROJECT RESEMBLES, COMPI£MENTS, OR PARALLELS RESEARCH DCm ELSEWHERE IN THE PUBLIC HEALTH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACILITIES OR RJNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Objective; To determine if anesthetic block of the atrial caval junction protects the heart from ventricular fibrillation due t© electrical stimuli. Methods Employed; It has been shoiJn that atrial caval infiltration in hypothermic animals protects the heart against ventricular fibrillation secondary to right ventriculotomy. In the present study the effects of the block were determined in preventing VPG's followijjg electrical stirrsulation, Maj_or__Findings_; The preliminary results indicate that the procedure does not seera to protect against electrical stiraulatlon. Hov^everj, regulation of heart rate, pH and other factors must be carefully controlled. NHI-187 Significance to HEART Rssearch; Ventricular fibrillation is a dreaded complication of operations involving hypothermia. A successful means of preventing it would be a valuable adjunct in clinical surgery. extensions outlined above. The project will be continued with the Form No. ORP-1 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. NHI - 187 SERIAL NUMBER 12. BUDGET DATA: ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FJ157 $35,600 $14,878 BUDGETED POSITIONS $50,478 2.2 ,8 3.0 PATIENT DAYS PROF OTHER TOTAL FY' 57 2 1 3 None 13. BUDGET ACTIVITY; RESEARCH /x7 REVIEW & APPROVAL HI BIOLOGIC STANDARDS Fl ADMINISTRATION EJ PROFESSIONAL & TECHNICAL ASSIST- ANCE /~7 14.. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S): None Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15. NHI-187 SERIAL NUMBER 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: 17. LIST HONORS AND AWARDS TO PERSONNEL REUTING TO THIS PROJECT DURING CALENDAR YEAR 1956: Form Ho. C»P-1 Calendar Year I956 October 1956 (Attachment l) PUBLIC HEALIH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. nhi-188 SERIAL NUMBER 2. HEART 3. SORGERY INSTITbtlS (tA DIVISl6l^ LABORATORY, BRANCH, OR DEPARTMENT k, 5. SECTION OR SERVICE LOCATION (IF OTHER IHAN BEIHESDA; IN-fRAPlJLMONARY TRANSPLANTATION OF AFTO5EN0l'S TFfROID TISSUE PER ^ COURHAJJD CATHETER, PROJECT TITLE 7. Richard Sar(,ders3 M, D, & Joseph W, Gilbert,, IL D, PRINCIPAL INVESTIGATOR 8 QIHER INVESTIGATORS 9< IF THIS PROJECT RESB4BLES, COMPUSMENTS, OR PARALLELS RESEARCH DCm EISEMHERE IN THE PUBLIC HEAI/EH SERVICE (WITOOUT INTERCHANOE OF PER- SONNEL, FACILITIES OR IVNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Cfojectiye; To determine if functioning gland tissue can be traasplanted to the lung. Methods Employed; Autogenous thyroid tissue has been injected into the pulmonary arteries in dogs and the luing studied histologically one month later. tfaj or Finding ss Thus far, no identifiable thyroid tissuie has been found in the segments of the lung. Significance to HEART Research; The l«ng did seem to be an ideal vascular bed for the auto= or homo transplantation of many tissues. Proposed Course of Project; Tlie project will be continued with tracer studies and perhaps with other acinar'' tissue. Form No. ORP-1 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11, NHI 188 SEEIIAL NUMBER 12, BUDGET DATA: ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF ■ OTHER TOTAL FYt57 $12,000 $5,021 BUDGETED POSITIONS $17,021 .7 .2 .9 PATIENT DAYS PROP OTHER TOTAL FY' 57 1 0 1 None 13. BUDGET ACTIVITY; RESEARCH H"/ REVIEW & APPROVAL /~7 BIOLOGIC STANDARDS /~7 ADMINISTRATION PROFESSIONAL & TECHNICAL ASSIST- ANCE nj 14. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S): None Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15. MI°188 SERIAL NUMBER 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: 17. LIST HONORS AND AWARDS TO PERSONNEL RELATING TO THIS PROJECT DURING CALENDAR YEAR 1956: Fozn No. ORP'l Calendar Year 19^6 October I956 (Attachment I) PUBLIC HEALOH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. NHI-1-S9 SERIAL NUMBER 2. MART 0 SIFRGERY INSTITUTE OR DIVISION LABORATORY, BRANCH, OR DEPARTMEOT ^^ _ 5. SBCnCW OR SERVICE LOCATION (IF OTHER THAN BETHESDA) REVERSAL OF THE CARDIAC EFFECTS OF SEVERAL SfMPATHOMDISTIG AMINES BY 6. DIGITALIS GLYCOSIDES DURING HYPOUffiRM.lA roOJECT TITIG " ~ 7. Jferion DeV. Gotten, Ph. D. & Theodore Cooperj M. D., Ph PRINCIPAL INVESTIGATOR ^---^-----~--— -—-----— 8. OIHER INVESTIOATORS $. IF THIS PROJECT RESEMBLES, COHPIEMENTS, OR PARALLELS RESEARCH D(»fE EISEUHERE IN THE PUBLIC HEAI/ni SERVICE (WITHOUT INTERCHANOE OF PER- SCWNEL, FACILITIES OR RJNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Objectiveg To determine the effects of digitalis and allied compounds on the response of the heart to vaso-presser agents at normal and lowered boy temperatures. Methods Employed; Contractile force of the heart was determined by a strain gauge arch and the various compounds under study were administered in both warm and hypothermic animals. Major Findings; Digitalis and allied compounds blocked or reversed the pressor effects of adrenalin or noradrenalin whan the aniraal's temparature was 30'^ but not at 37®. NHI-189 Significance to HEART Research; ifeny patients receiving digitalis must undergo operations with hypothermia. It is important to know the responsiveness of these hearts if resuscitation is necessary. Proposed Course of Project; Studies will be continued with further observations and more compounds. Form No. ORP-1 October 1956 (Attachment I) PUBLIC EKkLfS. SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. NHI - 189 SERIAL NUMBER 12. BUDGET DATA; ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT 3X3TAL PROF OTHER TOTAL FI'57 $21,500 $8,927 BUDGETED POSIHONS $30,427 1,1 .9 2.0 PATIENT DAYS PROF OTHER TOTAL FY' 57 1 1 2 None 13. BUDGET ACTIVITY; RESEARCH /l7 REVIEW & APPROVAL /~7 BIOLOGIC STANDARDS /Z7 ADMINISTRATION PROFESSIONAL & TECHNICAL ASSIST- ANCE /Z7 14.. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN WI 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S)j None Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment I) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15. NHI-I89 SERIAL NUMBER 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: 17. LIST HONORS AND AWARDS TO PERSONNEL RELATING TO THIS PROJECT DURING CALENDAR YEAR 1956: Form No. OBP-l Calendar Year 19^6 October I956 (Attachment l) FUBUC HEAUH SERVICE - - NATIQNM. INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. NHl-i90 SERIAL NUMBER 2. HEART 3, SURGERY INSTITU^ (A d1VISI6i^ LABORATORY^ BRANCH, OR DEPARTMESIT «*. 5. SECTION OR SERVICE LOCATION (IF OOSER THAN BETHESDA) CLINICAL APPLICATION OF NITROUS OXIDE IN THE DETECTION OF LEFT-TO-RIGET 5, INTRACARDIAC SHUNTS, PROJECT TITI£ ' 7. 6. Andrew G, Morrow^ M, D, , Richard Sanders, M. D. 6e Eugene Braunwald, M. D. PRINCIPAL INVESTIGATOR ' " " "' OQIER INVESTIGATORS 9< IF OHIS PROJECT RESEMBLES, CCHPIEMENTS, OR PARALLELS RESEARCH DONE ELSEWHERE IN THE PUBLIC HEAI/TH SERVICE (WIIHOUT INTERCHANOE OF PER- SONNEL, FACILITIES OR RJNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL' N0.(8) IF WITHIN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Objective; To determine the usefulness of blood nitrous oxide levels in the detection of lef t-to-right shunts. Methods Employed; Blood levels of nitrous oxide are determined in various cardiac chambers and the arterial system. Calculation of the comparative levels reveals an index which is the measure of the shunt present. Major Findings; A "nitrous oxide index" of 0,2 or greater has been found diagnostic of the presence of a shunt. The procedure is a useful screening test when performed with the catheter tip in the pulmonary artery. NHI=190 Significance to HEART Research; The precise localization of left=t©- right shunts is a contitming problem in the assessment of patients with congenital heart disease. The present method is much more sensitive than conventional cardiac catheterization techniques. Proposed Course of Project; Clinical studies will be continued and a detailed analysis of the studies performed is being made. Form No. ORP-1 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. NHI - 190 SERIAL NUMBER 12. BUDGET DATA: ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FI'57 510,800 $33,950 BUDGETED POSinONS $44,750 ,7 .2 ,9 PATIENT DATS PROF OTHER TOTAL FT' 57 i 0 I U40 13. BUDGET ACTIVITY; RESEARCH /T? REVIEW & APPROVAL £Z/ BIOLOGIC STANDARDS A"? ADMINISTRATION n? PROFESSIONAL & TECHNICAL ASSIST- ANCE /~7 lU. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILinES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S): IS 00,6 Form No. OHP-1 Calendar Year 1956 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part Cs Honors, Awards & Publications 15. Nliil-IQ'' SERIAL NUMBER 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: 17. LIST HONORS AND AWARDS TO PERSONNEL REUTING TO THIS PROJECT DURING CALENDAR YEAR 1956 j Form No. ORP-1 Calendar Year 19 56 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. mhi-i^i SERIAL NUMBER 2. HEART 3. SURGERY institute! 6r divis16n laboratory, branch, or department h. 5. ^ , section or service location (IP OTHER THAN BETHESDA) 6. TRANSBRQNGHIAL LEFT ESART CATliETERIZATION PROJECT TITLE „ Andrew G. Morrowj M. D., Edward H. Sharp, M. D. & Eugerss 'Irs-anwald, fl, D, PRINCIPAL INVESTIGATOR "^ ' 8. OIHER INVESTIGATORS 9 . IF THIS PROJECT RESEMBLES, COMPLEMENTS, OR PARALLELS RESEARCH DONE ELSEWHERE IN THE PUBLIC HEALTH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACILITIES OR RJNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Objective; To utilize the technique of transbronchial left heart catheterization in the assessment of a variety of forms of cardiovascular disease. Methods Employed; The left atrium is punctured bronchoscopically and a catheter is then passed into the left atrium and left ventricle where pressures are recorded and indicator solutions injected, tfe|or_Finding s ; The technique has been proved safe its nearly 500 studies. As a tool the method has been useful in studies concerning bundle branch blocks press'ure-volume relationships in the left heart,, the assessment of NHI-191 Significance to HEART Research; This technique and its applications represent one of the significant steps in recent years in the clinical management and investigation of patients with heart disease. Proposed Course 0f Project; The project will be continued and expanded along the lines indicated. Fora No. ORP-1 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NAHONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. ■HI SERIAL NUMBER 12. BUDGET DATA: ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL pyi57 $14,500 $45,267 BUDGETED POSITIONS $59,767 .3 ]., . 3 1.6 PATIENT DAYS PROF OTHER TOTAL FT' 57 0 2 2 X577 13, BUDGET ACTIVITY; RESEARCH /x~7 REVIEW & APPROVAL /~7 BIOLOGIC STANDARDS r~/ ADMINISTRATION EJ PROFESSIONAL & TECHNICAL ASSIST- ANCE / / 14.. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S): None Form No. ORP-1 Calendar lear 1956 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15. NHI-191 SERIAL NUMBER 16. LEST PUBLICAHONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: 17. LIST HONORS AND AWARDS TO PERSONNEL HEUTING TO THIS PROJECT DURING CALENDAR YEAR 1956: Form No. ORP-1 Calendar Year I956 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. KKi"i92 SERIAL NUMBER 2. "^f'^Vr 3. ST'"^-ERY INSTITUTE OR DIVISION LABORATORY, BRANCH, OR DEPARTMENT h, 5. SECTION OR SERVICE LOCATION (IF OTHER THAN BETHESDA) 6^ ST']D'' '?-D APPLICATION OF THE ^'ELSOSE VWT OXYGEHATOR PROJECT TITLE •J ^ f"dw:;ri "^, S- rr:" M« I'.., Clarence Weldon. M. D., .:i:epb V, ^iiibert, M. D, PRINCIPAL INVESTIGATOR 6 i;-^-. G- ft.vrcw M, u. ' 8 OTHER INVESTIGATORS 9> IF THIS PROJECT RESEMBLED, CCMPLEMENTS, OR PARALLELS RESEARCH DONE ELSEWHERE IN THE PUBLIC HEALTH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACILITIES OR FUNDS ), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS)! Ob.iectiie; To perfect the MeLrose feesrt and lung machine and adapt ic fc'i' safe and practical cl]i.nical use, 'Hetbods Employed; The Melrose machine was purcbased and ysed is 5b anitnais siubjected to total cardiac bypass. Many changes were foirrad necessary In the tsiachine and in the manner in which it was used. ^^iSL-ZiSiiSSJ." Perfusion rates of more than 3000 cc,/roin, are practical and the animal's oxygen and other metabolic requirements can be kept normal, 807o survival in animals can now be obtained with the open left or right heart. NHI=192 Siggjifigance^^to HEART Research; The development of a practical and safe heart-lung machine is necessary for the treatment of many forms of congenital and acquired heart disease. Proposed Course of Project; Continued animal experimentation will be carried out with particular emphasis upon exposure of the mitral and aortic valves. Clinical application will be increased with emphasis upon ventricular septal defects and mitral insufficiency. Form No. ORP-1 October 1956 (Attachment I) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. NHI ° 192 SERIAL NUMBER 12. BUDGET DATA; ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL 57157 $32,600 $13,576 BUDGETEa) POSITIONS $46,176 1.2 2.0 3.2 PATIENT DAYS PROF OTHER TOTAL FY' 57 2 2 4 60 13. BUDGET ACTIVITY; RESEARCH /x7 REVIEW & APPROVAL HI/ BIOLOGIC STANDARDS /~7 ADMINISTRATION EJ PROFESSIONAL & TECHNICAL ASSIST- ANCE n 14. IDENTIFY ANY COOPERATING UNITS OP THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957, IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S): None Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Fart C: Honors, Awards & Publications 15. NHI°J-92 SERIAL NUMBER 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: 17. LIST HONORS AND AWARDS TO PERSONNEL RELATING TO THIS PROJECT DURING CALENDAR YEAR 1956: Form No. ORP-1 Ceilendar Year I956 October 1956 (Attachment l) PUBLIC HEALffl SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. MI-^93 SERIAL NUMBER 2. HEART 3. SURGERY INSTITUTil (B DIVISlbN " LABORATORY, BRANCH, OR DEPARTMENT ^. 5. ^ , SECTION OR SERVICE LOCATION (IF OTHER THAN BETHESDA) 6. EXFERIME.NTAL CLOSURE OF RUPTURED SINPS OF VALSALVA ANBURYSMS PROJECT TITLE Ro Robinson Baker^ M. D,, Hans Erik HansoHi, M, D. & Andrew G. McTrow, M. D. PRINCIPAL INVESTIGATOR 8. - - OTHER INVESTIGATORS 9. IF THIS PROJECT RESEMBLES, COMPLEMENTS, OR PARALLELS RESEARCH DONE ELSEWHERE IN THE PUBLIC HEALTH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACILITIES OR CTJNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Objective; To develop a method for the closure of fistuilae between the aorta and right heart. ^'jg ,^IL'^ j.g- -^PP,'^''^?'-^'^ • Fistolae were created in dogs between the right atrium, right ventricle and aorta. They were then closed by means of a plastic sponge prosthesis introduced via the aorta. ^ig.^_ZJ:PJj-g&? ° '^® operation was technically successfiul in animals and has recently been used sBccessfully in the treatment of two patients with this form of heart disease. NHI-193 Significance to HEART Rasfeareh; Althotagln cardio^aortic fistalae are rare they usually lead to rapid and progressive heart failure. Proposed Course of PrjLlgc^t; Continued clinical lase ®f the technique is planned and the method has been extended to sach that it is useful in other forms of congenital heart disease. Form No. ORP-1 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 12. BUDGET DATA; 11. NHI - 193 SERIAL NUMBER ESTIMATED OBLIGATIONS MAN TEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FI'57 $28,500 $51,218 BUDGETED POSITIONS $79,718 1.7 =8 2,5 PATIENT DATS PROP OTHER TOTAL FY»57 2 1 3 118 13. BUDGET ACTIVITT? RESEARCH /IT? REVIEW & APPROVAL d/ BIOLOQIG STANDARDS /~7 ADMINISTRATION EJ PROFESSIONAL & TECHNICAL ASSIST- ,__ ANCE rj 14-. IDENTIFI ANT COOPERAHNG UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FT 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S); None Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, A?rards & Publications 15. NHI-I93 SERIAL NUMBER 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: 17. LIST HONORS AND AWARDS TO PERSONNEL REUTING TO THIS PROJECT DURING GiX^NDAE TEAR 1956: Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - < NATIONAL INSOSTUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. NHI-194 8. SERIAL NUMBER 2. HEART 3. SURGERY INSTITUTEl 6R DIVISlbN LABORATORY, BRANCH, OR DEPARTMENT SECTION OR SERVICE LOCATION (IF OTHER THAN BEIHESDAJ CARDIAC OUTPUT DETEBJttNATIONS AND CALCULATION OF AORTIC AND MITRAL 6, VAIVE SIZE DURING SURGERY AND LEFT HEART CATHETERIZATION. PROJECT TITI£ Herbert L, , Tanenba^iMj M. D. PRINCIPAL INVESTIGATOR Andrew G. {■forrowj M. D. 6e Eugene Braunwald, M. D. OTHER INVESTIGATORS 9. IF THIS PROJECT RESEMBLES, CCMPUBMENTS, OR PARAXIALS RESEARCH DONE ELSEWHERE IN THE PUBLIC HEAI/IH SERVICE (WITHOUT INTERCHANOE OF PER- SONNEL, FACILITIES OR lUNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO. (S) IF WITHIN NIH). < 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Objective; To measure cardiac output during left heart catheterization, calculate aortic valve and mitral valve size from pressure and flow data and to do similar determinations during mitral and aortic valve surgery. Methods Employed; Cardiac output obtained by dye dilution curves injecting Evans bluie dye into left ventricle. Pressure measured in the conventional way and valve size calculated from the above information by use of Gorlin's hydraulic formulae. Patient Material; 11 patients during left heart catheterization. 3 patients at surgery. NHI-194 Major Findings; Jressjirfi gradients vary directly with flow hence the iioportanGe of measuring both similtaiaeously gives a relative estimation of degree of valvular stenosis and bep.efit following surgery. Significance to HEART Rageareh; and aortic valve ^Isease^ Better definition of dynamics of mitral Proposed Course of Project; Collect more data, symptoms and other objective findings pre- and p®s bronchoscopic approach to left heart catheter IzaEiosii defining more closely mitral and aortic valve di valve areas toperatively. Es as valid means Forrft No. ORP-1 October 1956 (Attachment I) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part Bj Budget Data 12, BUDGET DATA; 11. NHI - 194 SERIAL NUMBER ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FI'57 $15,000 $49,511 BUDGETED POSITIONS $65,511 J .8 1,5 PATIENT DAIS PROF OTHER TOTAL FI'57 1 1 2 196 13. BUDGET ACTiyiTT; RESEARCH /T] REVIEW & APPROVAL CJ BIOLOGIC STANDARDS HI ADMINISTRATION £7 PROFESSIONAL & TECHNICAL ASSIST- , ^ ANCE EJ 14-. n)lNTXFI ANY COOPERAnNG UNITS OF THE PUBLIC HEALTH SERVICE, OR ^TSm ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FT 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE S^IAL NO.(S)i None Form No. ORP-1 Calendar lear 1956 October 1956 (Attachment I) PDBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15. NHI-194 SERIAL NUMBER 16. LIST PDBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: 17. LIST HONORS AND AWARDS TO PERSONNEL REUTING TO THIS PROJECT DURING CALENDAR YEAR 1956: Form No. (S(P-1 Calendar Year I956 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. NHI 195 SERIAL NUMBER 2. National Heart Institute 3« Laboratory of Technical Development institute! (SR DIVISION LABORATORY, BRANCH, OR DEPARTMENT *^. 5. ^ , SECTION m SERVICE LOCATION (IF OTHER THAN BETHESDA) 6. Developraent of Methods for Measurement of BloodFlow PROJECT TITLE y^ Robert L. Bowman PRINCIPAL INVESTIGATOR 8. Fran5i_ w\_ ]'Ipt)le OTHER INVESTIGATORS 9. IF THIS PROJECT RESEMBLES, COMPLEMENTS, OR PARALLELS RESEARCH DCm ELSEWHERE IN THE PUBLIC HEALTH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACILITIES OR RJNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). NONE 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Objectives; To develop an efficient method of blood flow measurement that^p reduces a minimura disturbance in the system being measured. Metho^d3_Empl^;eds Physical techniques that offer the possibility of application to the problem are applied as they come to attention. At present the application of a magnetic and radio frequency field is used to induce the nuclei of the hydrogen atoms to precess and the energy absoi'bed by the interaction is utilized to indicate the effect. This effect is slow and time dependent so that in flovjing system.s the amplitude of the effect is changed by the flow. No mechanical or electrical contacts are necessary for the system to operate. Major Findings g It has been relatively easy to obtain flow signals by this method and they have been relatively free of temperatiire, viscosity and salinity effects. It would appear that non-contacting flow systems can be made utilizing the principle noted. Significance to HEART Researchs Measurement of blood and bocfy fluid flows without introduction of interfering probes or tubes offers a method of study that will minimize the influence of the method on the measurand. Proposed Course of Projects To develop the method into a practical device and to examine its possibilities in relation to measurement of concentration and content of other elements. Form No, ORP-1 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NAHONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. >jh? - -95 SERIAL NUMBER 12. BUDGET DATA; ESTIMATED OBLIGATIONS MAN TEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FT' 57 $11,400 $5,708 BUDGETED POSITIONS $17 9 108 J .9 Io6 PATIENT DATS PROF OTHER TOTAL FT' 57 1 1 2 None 13. BUDGET ACTIVITT; RESEARCH HH REVIEW & APPROVAL /~7 BIOLOGIC STANDARDS /~7 ADMINISTRATION £7 PROFESSIONAL & TECHNICAL ASSIST- ANCE n 14.0 IDENTIFT ANT COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FT 1957 » IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S)j None Form No, ORP-1 Calendar Year 1956 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15- NHI'-19g SERIAL NUMBER 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: None 17. LIST HONORS AND AWARDS TO PERSONNEL REUTING TO THIS PROJECT DURING CALENDAR YEAR 1956: None Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. ^^ " ^^'^ SERIAL NUMBER 2. National Heart Institute 3. Laboratory of Technical Development INSTITUTE 6R DIVISION LABORATORY, BRANCH, OR DEPARTMENT h. 5. , SECTldN OR SERVICE LOCATION (IF OTHER THAN BETHESDA) 6 Microanalytic Methods for Alkali Metals in Micropiincture Samples PROJECT TITLE Y. Dr. Robert L. Bownan _^ 8. PRINCIPAL INVESTIGATOR Dr. T, J. Kennedys Jr. OTHER INVESTIGATORS 9. IF THIS PROJECT RESEMBLES, COMPIiMENTS, OR PARALLELS RESEARCH DONE ELSEWHERE IN THE PUBLIC HEALTH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACILITIES OR RJNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). None 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Objectives; To develop an accurate dependable method of analysis of samples of 0.0001 and .01 ml containing 50x10-12 to 150x10"^'^ moles of Na and SOxlO'^^ to 5x10-1° moles of K, Methods Bmployedi Micropuncture samples are sealed into quartz ■ "capillary sample tubes and the tubes evacuated. These tubes are then lit by inducing an electrodeless discharge to occur due to a powerful microwave field. The field is produced by a specially developed timable cavity of high efficiency. Analysis of the sainple is made by spectrophctometric scanning of the emitted light and recording the intensity of the spectral lines. A specially constructed photometer extends the spectral sensitivity to the near infra-red. NHI-196 Major Findings g The sensitivity of the method appears to exceed our requirements and this sensitivity extends to Lithium^ Cesium and Rubidium^ as well as Na and K. Halide bands due to Clo may provide for the detennination of CI. at the same time.. Significance to HEART Research; This problem is designed to provide methods for analysis of the material obtainable from secretory and excretory systems involved in the regulation of electrolyte balance© Proposed Course of Projects To work out the method to provide a practical accurate method for analysis of minute samples of body fluids. Form No, ORP-1 October 1956 (Attachment I) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. NHI - 196 SERIAL NUMBER 12. BUDGET DATA; ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL Fy!57 $18,300 $9,161 BUDGETED POSITIONS $27,461 ,5 2.5 3,0 PATIENT DAYS PROF OTHER TOTAL FY' 57 1 3 4 None 13. BUDGET ACTIVITY; RESEARCH /x? REVIEW & APPROVAL /~7 BIOLOGIC STANDARDS /~7 ADMINISTRATION nj PROFESSIONAL & TECHNICAL ASSIST- ANCE n 14. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S); None Form No„ ORP-1 Calendar Year 1956 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15. MHI - 196 SERIAL NUMBER 16. LIST PUBLICAnONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: None 17. LIST HONORS AND AWARDS TO PERSONNEL REUTING TO THIS PROJECT DURING CALENDAR YEAR 1956: i^uiviiMu None Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. NHI - 197 SERIAL NUMBER 2. National Heart Instit'dt-e 3' Laboratory of Technical DeveloPinent institute! (5R division laboratory, BRANCH, OR DEPARTMENT h. 5. , .^ __ SECTION OR SERVICE LOCATICM« (IF OTHER THAN BETHESDA) 6. Dfti^elopinent of a Mechanical Pump PROJECT TITLE 7. Dr, Selwyn McCabe PRINCIPAL INVESTIGATOR 8. OIHER INVESTIGATORS 9. IP THIS PROJECT RESEMBLES, COMPLEMENTS, OR PARALLELS RESEARCH DONE ELSEWHERE IN THE PUBLIC HEALTH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACILITIES OR JUNDS), IDENTIFY SUCH RESEARCH? (BY SERIAL NO«(S) IF WITHIN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Objectives? To construct a small and relatively simple pump for use in open heart surgery. The pump must be capable of working two pressure systems smultaneously. Methods Employed; A prototype machine has been made. There are two parts - an activating mechanism at a distance from the actual pump. The pump is four chambered and uses four semilunar type valves. Its action is similar to the heart - the myocardial action being mimicked by fluid tmder compression "contracting" two "ventricular" (sacs). The pumping is dependent upon "venous return" i. e.j a cam comes in contact when the ventricles are NHI-197 appropriately filled to the desired output and the activating mechanism thus comes into play ejecting the ventricular contents. The two pressure systems are dependent on the peripheral resistance and the stroke volume. The total output can be controlled by either increasing the stroke volimie or by increasing venous return and thereby speeding the action of the pump, "Diastole" can be shortened or lengthened by this same action. Some control of the length of "systole" can be obtained by increasing the revolutions of the power motor » Thus the pressure curves can be simply controlled* If the "venous" pressure on one side of the system becomes elevated then the receiving "ventricle" will be filled rapidly and displacing the fluid outside the sac will therefore fire off the power mechanism with a resultant increase in pump rate^ Thus no overloading occurs r Significance to HEART Research; A simple easily controlable and relatively small by-pass heart pump has been made<^ The pump tests the use of the artificially made semilunar valves and points to their advantages for use in artificial pump systems. The machine can be used for demonstrating the hearts action and the problems that arise when valves are damaged, etCf "Heart Sounds" 1, 2 and 3'^d can be heard at the same time as the valves can be observed. It seems the machine is therefore useful for teaching purposes .- Form No, ORP-1 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - MnONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. Will " 197 SERIAL NUMBER 12. BUDGET DATA: ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FY' 57 £6,000 $3,030 BUDGETED POSITIONS $9^030 ,5 .5 PATIENT DAYS PROF OTHER TOTAL FT' 57 I = 1 None 13. BUDGET ACTIVITY; RESEARCH /Z7 REVIEW & APPROVAL /~7 BIOLOGIC STANDARDS /~7 ADMINISTRATION /U PROFESSIONAL & TECHNICAL ASSIST- ANCE /~7 lA. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S): None Form No. ORP-1 Calendar-Iear 1956 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15 . NHI-197 SERIAL NUMBER 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: None 17. LIST HONORS AND AWARDS TO PERSONNEL RELATING TO THIS PROJECT DURING CALENDAR YEAR 1956: None Form No . ORP-1 a Calendar Year I956 October I956 (Attachment l) PUBLIC HEALOH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. NHI'-193 SERIAL NUMBER 2. National Heart Institute 3. Laboratory of Technical EevelopTjent institute! 6R DIVISION LABORATORY, BRANCH, OR DEPARTMENT h, 5. , SECTION OR SERVICE LOCATION (IF OTHER THAN BETHESDA) g Development of Prosthetic Heart Valves PROJECT TITLE 7. Dr. Selwyn McCabe 8. PRINCIPAL INVESTIGATOR OTHER INVESTIGATORS 9. IF THIS PROJECT RESEMBLES, COMPLEMENTS, OR PARALLELS RESEARCH DONE ELSEWHERE IN THE PUBLIC HEALTH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACILITIES OR FVNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Objectivesg To continue to develop prosthetics to be used in the replacement of diseased heart valves. Since the semilunar tricuspid valve has prooved its efficiency both in nature and during our mechanical tests in the laboratory it seems only necessary to find a satisfactory material and design that will withstand the dangers of clottii and the rigors of time. Such a valve can be inserted at the WHI-198 site of the original diseased valve - in the aortic site below the coronaries = and even the mitral valve can be replaced with this type valve as dynamically shown by the work of Dr^ Murray of Toronto «. Methods Employeds Semilunar type valves have been assembled in plasticso Concurrently an investigation into all types of speculatively sviitable materials has been in progress. The valves constructed have undergone tests in two pumps. They pass all the mechanically necessary criteria naraelys they are sufficient^ have no practical impedance to flow or stenotic effect^ withstand pressures well beyond the range demanded in nature o Major Findings; The semilunar type valve has by its performance warranted consideration as the kind to replace diseased or congenitally aberrant heart valves. Success seems hinged on details of valve structure and problems of clotting with fibrin formation. The latter involves the consideration of the materials, «. Significance to HEART Research success in the repair of congenital defects With the advent of open heart surgery, the the modified approach and success of the third coronary artery as outlined by Dr, Sidney Smithy the field of heart surgery will inevitably be pointed toward the replace- ment of the valves* Intensive research by this department is directed in this direction^ Valvesp theoretically and mechanically suitable for replacement of all hopelessly diseased heart valves^ have been constructed. Their fabrication is reasonably straight forwards '^yoE-Q^^A .9:9,M^j_.°^" Projects Continued search and testing for suitable materials. The use of human tissues is also under investigation. The long term trials in dogs to determine whether the designed valves will be tolerated. Speculated approaches to the insertion of the valve will be tested. Form No. ORP-1 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NAHONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. NHI - 198 SERIAL NUMBER 12. BUDGET DATA: ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FT' 57 $6^000 $3^030 BUDGETED POSITIONS $9,030 .5 .5 PATIENT DAYS PROF OTHER TOTAL FT' 57 1 = 1 None 13. BUDGET ACTIVITY; RESEARCH ZE7 REVIEW & APPROVAL ^"7 BIOLOGIC STANDARDS /~7 ADMINISTRATION PROFESSIONAL & TECHNICAL ASSIST- ANCE EJ 14.. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S): Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15. NHI ° 198 SERIAL NUMBER 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: None 17. LIST HONORS AND AWARDS TO PERSONNEL RELATING TO THIS PROJECT DURING CALENDAR YEAR 1956: None Form No. ORP-1 Calender Year I956 October 195^ (Attachment l) PUBLIC HEALIS SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. NHI-199 8, SERIAL NUMBER 2. National Heart Institute 3, Laboratory of Technical Development INSTITUTE 6R DIVISION ""~" LABORATORY, BRANCH, OR DEPARTMENT 1*. SECTION OR SERVICE ^» P^i^^g and Hydration Studies of Proteins and Tissues PROJECT TITLE John L. Stephenson PRINCIPAL INVESTIGATOR Murray Eden OIHER INVESTIGATORS 9. IF THIS PROJECT RESEMBLES, COMPLEMENTS, OR PARALLELS RESEARCH DONE EISEWHERE IN THE PUBLIC HEALTH SERVICE (WITHOOT INTERCHANGE OF PER- SONNEL, FACILITIES OR RJNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). None PROJECT DESCRIPTION (SEE INSTRUCTIONS): Objectivess To obtain information on the nature of the solid-liqiaid °~ interface in protoplasitij particularly its area and hydration structure. Methods^Qnplo^Bds By stmultajaeous recording of the weight and tatiperature of a sample being dried after rapid f reezingj the probability of a water molecules originating from the interface between the exterior dried shell and the still solidly frozen interior, escaping through the dried shell without returning to the interface, can be measured. Utilizing the transport theory which we have developed,, this probability can be used to compute the envelope of the surface area per unit voliame of the dry shell which is available for collisions NHI=199 Major Findings g The previously described apparatus has been calibrated on waterj giving results within the estimated magnitude of experimental error J and measurements have been begun on gelatin^ The preliminary data on gelatin give an estimate of the order of 100 square meters per gram of dry gelatine Gas adsorption techniques have given an estimated area of about 300 square meters per gram of dry weight of collagen. This difference is not unexpected and is in the anticipated direction, since the kinetic flow method should exclude certain kinds of area-- for example, that interior to raacromolecules or to crystalline micells^ Significance to HEART Researchs This study shows promise of providing a method for characterizing the coarseness of molecular aggregates in gel structures - and so of measuring one very important aspect of protoplasmic structure » In addition, the drying data are of use in the design of drying apparatus for drying biological material such as blood and plasma from the frozen states Proposed Course of Projects Drying data on a variety of proteins and tissues are being compiled r The theory by which surface areas are computed from the raw drying data is being extended^ In connection with this theoretical development, experimental studies of gas flow through mazes of known geometry are planned. Attempts are also being made to refine the technique so that drying rates of samples of dry weight less than one microgram can be determined. Here, there are two possibilities? One is the use of a specially designed torsion balance mounted in the drying chamberi the other is by measuring the rate at which heat is supplied to the sample. The iiaportance of this refinement is so that the drying rates of samples sufficiently small that no ice crystal formation occurs (as judged by electron :iicroscopic studies) can be measured.. Form No. ORP-1 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 12. BUDGET DATA: 11. 199 SERIAL NUMBER ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FY' 57 5'^;, 000 $4,017 BUDGETED POSIHONS $12,017 PATIENT DAYS PROF OTHER TOTAL FI'57 I 1 None 13. BUDGET ACTIVITY; RESEARCH /T? REVIEW & APPROVAL /~7 BIOLOGIC STANDARDS /~7 ADMINISTRATION EJ PROFESSIONAL & TECHNICAL ASSIST- ANCE J__/ 14. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S): NOTSS Form No. 0RP~1 Calendar Year 1956 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15. NHI-199 SERIAL NUMBER 16. LIST PUBLICAHONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: None 17. LIST HONORS AND AWARDS TO PERSONNEL REIATING TO THIS PROJECT DURING CALENDAR YEAR 1956: None Form No . QRP-1 Cfi^endar Year 19^6 October 1956 (Attachment I) PUBLIC HEALTH SERVICE - - NATIOIiAL IIIS!£iTUEES OF HBALIH IliDIVIBUAL FROJBCT REPQR!tl Part A. Project Description Sheet 1. NHI j- 200 SERIAL NUMBER 2. National Heart Institute 3, Laboratory of Technical revelopment iUBXITUTE €R DIVISION ' LABORATORY, BRANCH, OR DEPARTMBNT u. 5. SBCJnai Ofi SEBVIC^ LOCATICN (IF OOBER THAN BETHESDA) 6, Development of a Self -Balancing Potentiometer raOJBCT ITSLE 7. John Lo Stephenson PRINCIPAL INVESTIGATOR 8. F raiA W.^ Np]5le. . , , _ OIHER INVESSI0A9QRS 9. IF THIS FROJZCT BS8EMBLBS, CONPIAISKIS, OR PARALLELS RESEARCH DONE EISEWEERS ZN fSE FUBUC HEALIH fflRVZCS (WITHOUT INTERCHANQE OF PER- SCIDCBL, FACILITIES OR FUNDS), IQEaiTIFY SUCH RESEARCH: (BY SERIAL No.(d) irniTBiu vm). Ndhe 10. mojBCT w&mm.w isEB imrnxK^ Objectlvesl" To develop a potentiometer type circuit of high sensitivity and rapid response^ for the meastiPemeiit of rapid cooling curves^ occuring in one second or less and having rapid transient^ in various parts of the curve* j; ' The signal to be measured ia applied to a galvanometer. The motion of the light spot of the galvanometer is amplified with a photoelectric following system consisting of a single photomultiplier and one power tube, A fraction of this signal is used to counteract the motion of the galvanometer » The entire signal is us^d to drive an appropriate recording systems recording milliammeters speedomaXj, oscilloscor^, ,.,,.. NHI°200 Major Findings g The previously described instruments have been used in daily laboratory work for over a year now and have performed satisfactorily^ The general theory of such instruments has been developed somewhat more extensively than has so far appeared in the literature and correlates satisfactorily with the performance of our specific instruments and should in the future greatly facilitate the design of instruments for particular problems. Significance to HMRT Researchg The instrument will be of use in recording a variety of bioelectric phenomena and is more sensitive and stable in the frequency range doC. to 500 cps than conventional electronic amplifiers « Except for publication the project is completede Form Wo,, OBP-1 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH IHDIVIDUAL PROJECT REPORT Part Bs Budget Data 11. NHI - 200 SERIAL NDMBER 12 » BUDGET DATA; ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIffiURSEMENT TOmL PROF • OTHER , TOTAL FI'57 $7,500 $3,735 BUDGE'Sa) POSinONS $11,235 .4 .6 loO PATIENT DAIS PROP OTHER TOTAL FI«57 0 1 1 None 13. BUDGET AGTIVITI; RESE.4RGH RETIEW & APPROVAL /~7 BIOLOGIC STANDARDS /~7 ADMINISmATION EJ PROFESSIONAL & TECHNICAL ASSIST- ANCE ZI7 1^, IDENTIFI ANI COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN F7 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S): None Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment I) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15. ^^"^'^^ SERIAL NUMBER 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: None 17. LIST HONORS AND AWARDS TO PERSONNEL RELATING TO THIS PROJECT DURING CALENDAR YEAR 1956: None Form No. ORP-1 October 1956 (Attachment l) Calendar Year 1956 PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. NHI-201 SERIAL NUMBER 2. National Heart Institute INSTITUTE (m DIVISION 3, Laboratory of Techriical Development LABORATORY, BRANCH, OR DEPARTMENT k. SECnCN OR SERVICE 5. LOCATION (IF OTHER THAN BETHESDA) 5, Electron Microscopy PROJECT TITLE John L. Stephenson 8. PRINCIPAL INVESTIGATOR Murray Eden OOJIER INVESTIGATORS 9. IF THIS PROJECT RESEMBLES, COMPLEMENTS, OR PARALLEI^ RESEARCH DONE ELSEWHERE IN THE PUBLIC HEALTH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACILITIES OR RJNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). None 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS); Ob;iectivesj To further theapplication of electron microscopy to cytological problems. Methods Employedg Thin sections of biological matei-ial fixed by freezing^ then dried,, are examined in the electron microscopeo Various staining procedures to heighten contrast have been tried. Major Findings; The original project has been essentially completed! that is, procedures have been developed for the freezing and drying of biological tissues for electron microscopy which apparently avoid NHI=201 ice-crystal foimationo During this year several trips were made to North American Philips Company to investigate the possibility of applying emission microscopy to biological material* Without doubt the method has possibilities both in regard to theimal emission from incinerated specimens and photon induced emission from tissue sections o Significance to HEART Researchg These techniques should open up new approaches in the submicroscopic pathology of cardiovascular disease. Proposed Course of Project? If some sort of suitable collaborative arrangement can be made with an electron microscopist further correlj.tions of freezing and electronmicroscopic data are planned. At the present time^ because of limitations of personnel^ no further investigation of emission microscopy is planned. Form No. ORP-1 October 1956 (Attachment I) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. NHI =• 2C SERIAL NUMBER 12. BUDGET DATA; ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FY' 57 55,600 $2,819 BUDGETED POSITIONS $8,419 .4 .2 ,6 PATIENT DAYS PROF OTHER TOTAL FI'57 1 = 1 None 13. BUDGET ACTIVITY; RESEARCH /T? REVIEW & APPROVAL HI BIOLOGIC STANDARDS A~7 ADMINISTRATION nj PROFESSIONAL & TECHNICAL ASSIST- ANCE / / 14.. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S): This has been a cooperative study with Dr. Isadora Gersh,, Departmenc of Anatomy, University of Chicago. Form No. ORP-1 Calendar Year 1956 October 1956 (Attaehtaent I) POBLIG HEALTH SER7IGE - - NATIONAL INSTITUTES OF HEALTH INDIVIDnAL EaOJECT REPORT Part Cs Honors, Awards & Publications 15. NHI=201 SERIAL NUMBER. 16 » LIST PUBLICATIONS OTIffiR THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956-. Ti-?o papers from Dr. Isadore Gersh's laboratory have been accepted for publications I. Gersh^ I. Isenberg^ J, L, Stephenson. ¥<, Eondareff^ "Submicroscopic Stracture of Frczen-Lried Liver Specifically stained for Electron- Microscopy, Part I. Technical", Anatomical Recorde I, Gershj I. Isenbergj W, Bondareff, J, L„ StepJiensoUj ''Submicroscopic Structtire of Frozen-Lried Liver Specifically Stained for Electron Microscopy, Part II. Biological". Anatomical Recordo 17 » LIST HONORS AND AWARDS TO PERSONNEL RELATING TO THIS PROJECT DURING GALEMJAR YEAR 19565 None Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. NHI-202 8. SERIAL NUMBER 2. National Heart Instit-ute 3» Laboratory of Technical L-'^-v>'^ '.--rrTMnt INSTITUTE 6R DIVISION LABORATORY, BRANCH, OR DEPARTMENT h. 5. ^ ^ SECTION OR SERVICE LOCATION (IF OTHER THAN BETHESDA) ^ I hysics of Ultra-rapid Freezing of Water, Colloidal Solutions and Protoplasm, PROJECT TITLE Y JoViriL. Stephenson PRINCIPAL INVESTIGATOR —— — > OTHER INVESTIGATORS 9 . IF THIS PROJECT RESEMBLES, CCMPL£!MBNTS, OR PARALLEI3 RESEARCH DONE ELSEWHERE IN THE PUBLIC HEALTH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACILITIES OR FUNDS ), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). None 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Objective's (1) To investigate the basic physics of the rapid freezing process in water, colloidal solutions and protoplasm. (2) To apply t.bls infomation to the analysis of hydration phenomena in protoplasm,. (3) To extend the range of application of freezing and drying as a method of fixation and preservation of biological material. Methods Employed? The rate of cooling of various systems is measured with "" small anbedded theimocouples . The output of these theDnocouples is anplified and recorded from a cathode r'ay oscilloscope o From the theoretical analysis of these curves the properties of various coolants and various constants relating to ice crystal formation during cooling can be determined. NHI-202 Major Findings g The recording techniques have been improved|5 partictjlarly a variety of methods of constructing microtheimocouples and microcalorimeters have been devised including vacuum evaporation of metals* Additional cooling studies on water in small capillary tubes (0,2 ram diameter) have confinned the earlier results that if water is cooled beliow about -100 to -130°C in less than 2/100 of a secondj heat release indiciitive of tha phase transformation of ice to water is not observed. We have interpreted this as meaning that water solidifies in a metastable vitreous state ^ The theory of rapid cooling and of ice crystal formation during rapid cooling has bean further developed. An experimental study was also made of the effects of freezing under pressure. Red blood cells were frozen under pressures of 3^^000 lbs. per square inch^, high enough so that on freezing water goes into ice II instead of the usual ice le In this transformation there is a volime contraction instead of a volume expansion. The purpose of the experiment was to test the hypothesis that the cause of protoplasmic damage on freezing at ordinary pressures is the voliane increased It was found that on freezing and thawing iinder pressure complete hemolysis occurred* Significance to HEART Research? These studies on freezing provide basic informa-= tion which can be used to improve and extend freezing and drjring as a method for preserving and storing biological materials such as arterial grafts^ plasma, biologicals and whole blood* Secondlyj they give information on the type of changes which may occur in protoplasm during freezing and drying and so provide a basis for extrapolating from data (such as microspectrometric and electron microscopic) obtained on frozen dried material to the living state. Finally, as discTossed below, they may in themselves provide fundamental information on the organization of aqueous gels including protoplasm, ?osed Course of the Projectg The principal immediate problem is to demonstrate conclusively by calorimetric and volumetric studies during warming that samples whose cooling curves do not appear to show release of the latent heat of crystallization are actually vitrified during the cooling. Experiments which it is hoped will show this have been planned, A second problem to be explored is whether in aqueous gels it is possible to correlate ice-crystal fonaation during freezing with the hydration of the macromolecules. It has been observed that in certain parts of cells such as nuclei, ice crystals are particularly likely to form during rapid freezing - - whereas in certain other structtires sudi as mitochaEidTia,io8 crystals are rarely observed^ These differences probably have some relation both to the degree of aggregation of the colloidal particles and the therniod3mamic activity of the water in the different regions <, If this relation could be detenaiE«d it would be possible to gft information on both the colloidal morphology and the activity of the water ^ Form No, ORP-1 , October 1956 (Attachment I) WBIZG HEALTH SERVICE - - NATIONAL INSTITOTfiS OF HEALTH INDIVIDUAL PROJECT REPORT Part Bs Budget Data 11. ^HI - 202 SERIAL NUMBER 12. BUDGET DATA: ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FI<57 ?4,S0CJ $2,396 BUDGETED POSITIONS $7,156 .2 .5 .7 PATIENT DAYS PROF OTHER TOTAL FT' 57 - 1 1 Horii«j 13. BUDGET ACTIVITY; RESEARCH /i? REVIEW & APPROVAL /~7 BIOLOGIC STANDARDS /~7 ADMINISTRATION PROFESSIONAL & TECHNICAL ASSIST- ANCE Z_/ 14.. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE , OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S): Kome Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15. MI°2Q2 SERIAL NUMBER 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: John L. Stephenson, "Ice-GrystaJ. Growth Diiring the Rapid Freezing of Tissues", Journal of Biophysical and Biochemical Cytology; July 25^ 1956, Vol. 2s'To7T7^p7"k5-52. ~~ 17. LIST HONORS AND AWARDS TO PERSONNEL RELATING TO THIS PROJECT DURING CALENDAR YEAR 1956: Nons Form No. ORP-1 October 1956 (Attachment I) Calendar Year I956 PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. NHI-203 SERIAL NUMBER 2. National Heart Institute INSTITUTE OR DIVISION 3, Laboratory of Technical Development LABORATORY, BRANCH, OR DEPARTMENT k. SECTION OR SERVICE 5. LOCATION (IF OTHER THAN BETHESDA) g Infra-Red Hicrospectrometry PROJECT TITLE JohnL. Stephenson 8. PRINCIPAL INVESTIGATOR OTHER INVESTIGATORS 9. IF THIS PROJECT RESEMBLES, COMPLEMENTS, OR PARALLELS RESEARCH DONE ELSEWHERE IN THE PUBLIC HEALTH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACILITIES OR fUNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). None 10. PROJECT DESCRIPTI<»» (SEE INSTRUCTICWS ) : Objectivess To develop an infra-red spectrometer suitable for obtaining absorption spectra of tissues and cells. Methods Ein.ployed5 Infra-red radiation from a monochromator is passed "through a reflecting microscope into a suitable detector, thus permitting absorption spectra of microscopic samples to be obtained. Major Findings? k Ferkin-Elmer infra-red spectrometer has been acquired and set up. NHI-203 >igriiricance to I-J/-_,T iiesearch; If techniques can be developed, should be useful in the study of intracellular metabolism and organization. 'rooossd Course of .'reject; It is planned to use the Perkin-Elmer instrument to investigate the effects of dehydration on the absorption spectra of proteins. Beccuse of the very large absorption of water in the 3 micron region, of the spectra, k greater than 700 cm"^, infra-red absorption i.lu/old be a very sensitive measure of the aviount of x^rater boiind to tissue. In addition, vj:i.th changes in the degree to xfhich water is bound to protein there are shifts in the wsvelenfth of the absorption maximum. If the methods can be developed in proteins, there is some possibility of utilizing them en individual cells because spectra can be taken on areas of about 100 square micra. Form No. ORP-1 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. NHI - 203 SERIAL NUMBER 12. BUDGET DATA; ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FY' 57 $7,200 $3,594 BUDGETED POSITIONS $10,794 .2 1,0 1.2 PATIENT DAYS PROF OTHER TOTAL FT' 57 1 1 2 None 13. BUDGET ACTIVITY; RESEARCH A"? REVIEW & APPROVAL HI BIOLOGIC STANDARDS /~7 ADMINISTRATION PROFESSIONAL & TECHNICAL ASSIST- ANCE CJ U. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S); None Form No. ORP-1 Calendar Tear 1956 October 1956 (Attachment I) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15. NHI-203 SERIAL NUIIBER 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: None 17. LIST HONORS AND AWARDS TO PERSONNEL REUUNG TO THIS PROJECT DURING CALENDAR lEAR 1956: None Form No. QE?P-1 Calendar Year I956 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Description Sheet 1. MHI-20U SERIAL NUMBER 2. National Heart Institute 3' Laboratory of Technical Development INSTITUTEi OR DIVISION LABORATORY, BRANCH, OR DEPARTMENT k, 5. , , SECTION OR SERVICE LOCATION (IF OTHER THAN BETHESDA) 6. Developrient of a Method of Separating Erythroc^rbes by Their Density PROJECT TITLE 7. Murray Eden PRINCIPAL INVESTKATOR 8. David Chaifin OOTER INVESTIGATORS 9. IF THIS PROJECT RESEMBLES, CCMPI£MENTS, OR PARALLELS RESEARCH DONE EISEWHERE IN THE PUBLIC HEALTH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACILITIES OR RJNDS), IDENTIFY SUCH RESEARCH; (BY SERIAL NO.(S) IF WITHIN NIH). None 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): Objectivess To determine what properties of red blood cells affect their density. In particular^ to ascertain whether there is a change in the density of erythrocytes with age. Methods Employed; A gradient density tube has been devised consisting of layers of varying concentrations of serum albumin^ made isotonic and adapted to pH ?.!;<. The whole blood is layered on top of the tube and the tube centrifuged to equilibrium. Radioactive iron is emclovgd as a tracer to determine the function of age vs. density. NHI-201+ Major Findingss Normal hviraan blood shows a wide distribution of density. In a given individual there are only minor day to day fluctuations. There is a statistically significant increase in density with age for the hviman erythrocyte. Significance to HEART Research; It is hoped this will contribute to an understanding of the aging of red blood cells. Further^ if the separation of young from old cells can be done readily, it may increase the lifetime of stored blood. Proposed Course of Project; Efforts will be made to ascertain whether the separation of cells by age is sufficiently sharp as to permit correlations of various properties of blood cells, e. g., ion fluxes with the age of cells. Form No. ORP-1 October 1956 (Attachment l) PDBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. NHI - 204 SERIAL NUMBER 12. BUDGET DATA; ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL Fit 57 $16,600 $8,315 BUDGETED POSIHONS $24,915 1.2 .5 1.7 PATIENT DAIS PROF OTHER TOTAL FY' 57 1 1 2 None 13. BUDGET ACTIVITY; RESEARCH /x7 REVIEW & APPROVAL iZJ BIOLOGIC STANDARDS /~7 ADMINISTRATION PROFESSIONAL & TECHNICAL ASSIST- ANCE CJ H. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S): N >ne Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15. NHI-20l|. SERIAL NUMBER 16. UST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR TEAR 1956: Hone 17. LIST HONORS AND AWARDS TO PERSONNEL REUTING TO THIS PROJECT DURING CALENDAR YEAR 1956: Wone Form No. ORP-1 Calendar Year I956 October 1956 (Attachment l) PUBLIC HEALm SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part A. Project Deacription Sheet 1. WHI-20$ SERIAL NUMBER 2. National Heart Institute 3. Laboratory of Technical Development INSTITUTEl 6R DIVISION " LABORATORY, BRANCH, OR DEPARTMENT U. ^ 5. , - SECTION OR SERVICE LOCATION (IF OTHER THAN BETHESDA) 5 Development of a Probabilistic Model for Groxdih PROJECT TITLE 7. Hurray 5 den PRINCIPAL INVESTIGATOR 8. OTHER INVESTIGATORS 9. IF THIS PROJECT RESE21BLES, COMPI£MENTS, OR PARALLELS RESEARCH ^Cm ELSEWHERE IN THE PUBLIC HEALTH SERVICE (WITHOUT INTERCHANGE OF PER- SONNEL, FACILITIES OR PUNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). Hone 10. PROJECT DESCRIPTI<» (SEE INSTRUCTIONS): Objectivess To construct a minimal information, stochastic, two- ~ dimensional model of a growing organism and to study the properties^ of the model. Methods Employ«ds Combinatorial analysis and probability theory are the basis for most of the analysis. A high speed digital computer is necessary for certain of the computations. Major Findings; A measure of the effect of environmental factors on the growth pattern of an orgaiiism has been devised using the techniques of infomation theory. The growth properties of a very simple .system, analogous to tissue culture growth, has been studied. irai-205 Significance to HEART Research; Theoretical studies of this sort are intended to throw some light on the nattire of the process that specifies and limits the patterns of growth and repair. Proposed Course of Projects An attempt will be made to formulate more ccmplicated models as analog to embryonic processes, e. g., development to the blastular stage. The results of the simpler model will be extended to larger numbers of cells. Form No. ORP-1 October 1956 (Attachment l) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. NHI " 2 . V^ cv PRIKGIPAL INVESTIGATOR :„t:ri ■'.. Dociie, Karold T, Dodge 8. ---: OraER INVESTIGATORS 9. IF TdlS PROJECT RESEMBLES, COMPI£MENTS, OR PARALLELS RESEARCH HCm ELSIMIERE IN THE PUBLIC HEALTH SERVICE (WITHOUT INTERCHANOE OF PER- SOMEL, FACILITIES OR RJNDS), IDENTIFY SUCH RESEARCH: (BY SERIAL NO.(S) IF WITHIN NIH). 10. PROJECT DESCRIPTION (SEE INSTRUCTIONS): _;.: To provide an electrokymograph having response do-vm to true : frequency^ This is a desirable featiore because it prevents ; :.,,:tortiori of the record due to action of coupling capacitors. it also makes it possible to obtain accurate calibration of : oi.'jnni:- Of densities* NHI-210 Methods Employed; The instrument has been improved and rebuilt in final form. Two copies of the final design have been built by the NIH Instrument Shop. After testing here, these models will be loaned for clinical testing to? Dr. M.J. Oppenheimer, Temple University Medical School, Philadelphiaj Pennsylvania Dr. Gordon rJing, University of Miami Medical School^ Miami, Florida Major Findings; This instrunaent is superior to the commercial instrument in regard to speed, accviracy, and ease of calibration. Significance to HEART Research; The /lectrokymograph is already established as a useful instriETient for studying the characteristic motions of the heart border in health and disease. It is hoped that the D. C, response feature of this new instrument will enhance the usefulness of the Electrokymograph by decreasing errors and allowing for easy calibration. Proposed Course of Project: The instrument will be evaluated by Drs. Oppenheimer and Ring. Alterations snd improvements will be made during the clinical tests. Finally, details of the instrument \rill be published. Form No. ORP-1 October 1956 (Attachment I) PUBLIC HEALTH SERVICE - - NAHONAL INSTITDTES OF HEALTH INDIVIDUAL PROJECT REPORT Part B: Budget Data 11. NEI - 210 SERIAL NUMBER 12. BUDGET DATA: ESTIMATED OBLIGATIONS MAN YEARS DIRECT REIMBURSEMENT TOTAL PROF OTHER TOTAL FI'57 $9,700 $4,862 BUDGETED POSITIONS $14,562 .7 .4 1.1 PATIENT DAYS PROF OTHER TOTAL FI'57 1 - 1 None 13. BUDGET ACTIVITY; RESEARCH /^T? REVIEW & APPROVAL HI BIOLOGIC STANDARDS /~7 ADMINISTRATION PROFESSIONAL & TECHNICAL ASSIST- ANCE EJ U. IDENTIFY ANY COOPERATING UNITS OF THE PUBLIC HEALTH SERVICE, OR OTHER ORGANIZATIONS, PROVIDING FUNDS, FACILITIES, OR PERSONNEL FOR THIS PROJECT IN FY 1957. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S): None Form No. ORP-1 Calendar Year 1956 October 1956 (Attachment I) PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OP HEALTH INDIVIDUAL PROJECT REPORT Part C: Honors, Awards & Publications 15. NHI-210 SERIAL NUIUBER 16. LIST PUBLICATIONS OTHER THAN ABSTRACTS FROM THIS PROJECT DURING CALENDAR YEAR 1956: None 17. LIST HONORS AND AWARDS TO PERSONNEL RELATING TO THIS PROJECT DURING CALENDAR YEAR 1956: None t 1S^- DATE DUE J K http: " Beth) SAYLORD P»,NTED.»U.. 'ijSi'