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. J<HI-92
SERIAL NUMBER
2. National Heart Institute 3« Chemical Pharmacology
INSHTOt^ CiA DIVISKbN LABORATORY, BRANCH, OR DEPARTMEIIT
h, Fharmacodynamics 5»
SECTION OR SERVICE LOCATION (IF OTHER THAN BETUESDAJ
6. Reflex Control of Cardiac Contractile Force
PROJECT TITE£ '■ ""^
1 • Marion deV. Cotten
PRINCIPAL INVE3T1BAT0R
8 l"^ii-5j-l?sr§i?------.
OTHER INVESnOATORS
9. IF OHIS PROJECT RESEMBLES, C0MPI£MENT8, 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; The objecti've of this project vjas to study the extent to vhich reflex sympathetic nervous activity could influence the force of cardiac contraction and to compare the latter changes with con- cc: ' tant changes in the blood pressure.
Methods Employed; Anesthetized dogs with intact circulatory systems were used in which direct measurements of the force of ventricular contraction were made vjith a strain gauge arch. Blood pressure was measured in the usual manner vjith an electronic pressure transducer. Changes in the size of the left ventricle were determined with a mercury-filled rubber-tube resistance attached to the left epicardial surface of the left ventricle. Increases in reflex sympathetic activity
NHI-92
SERIAL NO.
were produced by temporary occlusion of the common carotid arteries and tjr electrical stimulation of the cut central ends of the vagus and sciatic nerves, "electrical stimulation of the postganglionic carcisc sympathetic fibers v/as also employed to compare these effects with ■'.hose produced by reflex sympathetic stimulation »
Ka.ior Findings; Increased reflex sympathetic activity resulted in marked increases in the blood pressure but only moderate direct increases in the ventricular contractile force. Thus, the heart did not receive sufficient direct sympathetic stimulation during such maneuvers to sllow it to operate against the increased blood pressure without moderate dilation. Admirj. strati on of methoxamine; a vasoconstrictor amine lack- ing direct cardiac stimulant properties, produced a marked rise in blood pressure, no direct change in the contractile force and a marked increase in the size of the left ventricle. In contrast, the injection of 1-norepinephrine, in doses which produced increases in contractile force comparable to those produced by reflex sympathetic stimulation, resulted in much smaller pressor responses and a small decrease in the size of the left ventricle. The latter changes indicated that suffi- cient direct cardiac stimulation had been supplied to allow the heart to operate against the increased blood pressure without increasing its fiber length. Larger doses of norepinephrine, which produced marked increases in cardiac contractile force and blood pressure, also produced a slight decrease in the size of the left ventricle. Electrical stimu- lation of the cardiac postganglionic sy-pathetic :erve fibers resulted in marked increases in contractile force, a small pressor response and a slight decrease in the size of the left ventricle, suggesting that the cardiac sympathetic nerve fibers are potentially capable of producing far greater increases in cardiac contractile force than are obtained following reflex sympathetic stimulation. The surgical removal of the cardiac sym- pathetic nerve fibers resulted in a -moderate reduction in the contractile force response to reflex sympathetic stimulation while bilateral removal of the adrenal gDands resulted in a more marked reduction. The concom- itant removal of both the cardiac sympathetic fibers and the adrenal glands virtually abolished the moderate increase in contractile force produced by reflex sympathetic stimulation.
Significance to HEART Research; Little is known of the central and reflex sympathetic control of the cardiac contractile force. It is anticipated that experiments such as those described above will provide useful informa- tion regarding this important area of physiology.
Proposed Course of Project; These experiments will be extended to deter- mine the mechanisms responsible for the striking disparity between the effects of increased reflex sympathetic activity on the blood pressure and cardiac contractile force. These experiments will be done in cats in which reflex sympathetic stimulation produces similar effects on the blood pressure and cardiac contractile force (see accompanying Individual Project Report for 1956 entitled "Contrast Between the Effects of Increased Cerebrospinal Fluid Pressure and iiugmented Reflex Sympathetic Activity on the Contractile Force of the Heart"). The studies v.dth cats will include; (l) Observations on the effects of direct stimulation of various areas in the ht-ain stem to determine vihether se^'&^a^o "centers" in the brain stem
NHI-92
CI RIAL EC.
are concerned with Ihe control of the cardiac contractile force and blood pressure and (2) observations involving measurement of electrical activity in peripheral sympathetic nerves to compare the impulse frequency in cardiac sympathetic postganglionic nerve fibers with the impulse frequency in splanchnic postganglionic fibers before and during reflex sympathetic stimulation.
Form No. QRP-1 October 1956 (Attachment I)
PDBUC HEALTH SERVICE - - NATIOMAL INSTITUTES OF HEALTH
INDIVIDUAL PROJECT REPORT
Part B: Budget Data 11. i^fHI-92
SERIAL NUMBER
12. BUDGET DATA;
|
ESTIMATED OBLIGATIONS |
MAN YEARS |
||
|
DIRECT |
REIMBURSEMENT |
TOTAL |
PROP OTHER TOTAL |
|
FT' 57 $5,200 |
$2,270 BUDGETED POSITIONS |
$7,470 |
o3 .2 .5 PATIENT DAYS |
|
PROP |
OTHER |
TOBLL |
|
|
FT' 57 0 |
0 |
0 |
0 |
13. BUDGET ACTIVITY;
RESEARCH /T?
REVIEW & APPROVAL £0
BIOLOGIC STANDARDS Fl
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. IF COOPERATING UNIT IS WITHIN NIH INDICATE SERIAL NO.(S):
None
Form No. ORP-1 Calendar Tear 1956
October 1956 (Attachment l)
PUBLIC HEALTH SERVICE - - NATIONAL INSTITUTES OF HEALTH INDIVIDUAL PROJECT REPORT
Part C: Honors, Anards & Publications 15. NHI-92
SMIAL 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. C»P-1 CEdendar Year 19^6
October I956 (Attachment I)
FUBUC HEALIH SERVICE - - NATIONAL INSTITUTES OF HEALTH
IMDIVHJUAL PROJECT REPORT
Part A. Project Description Sheet 1. NHI-93
SERIAL NlAffiER
2. National Heart Institute 3, Chemical Pharmacology
INSHTUTE OR DIVISICHI LABCEATCftY, BRANCH, OR DEPARTMEMT
1|., Pharmacodynamics 5,
SBCnOB OR SERVICE LOCATION (IF OTHER OBAN BEIHESDAT
6, hypersensitivity of the Heart to Epinephrine and Norepinephrine Following
PROJECT TITLE ~~ '
Experimental Coronary Artery Occlusion in the Dog
7. Harriet M. Maling and Neil Ce Moran
8.
PRINCIPAL INVESTIGATOR
OTHER INVESTIGATORS
9« IF TBIS PROJECT RESEMBLES, COMPLEMENTS, OR PARALLELS RESEARCH T>CXSE 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,