Effects of Glucagon on Myocardial Oxygen Consumption and Coronary Blood Flow in Man and in Dog

Transcription

1 Effects f Glucagn n Mycardial Oxygen Cnsumptin and Crnary Bld Flw in Man and in Dg By JOEL H. MANCHESTER, M.D., WILLIAM W. PARMLEY, M.D., JACK M. MATLOFF, M.D., A. JAMES LEIDTKE, M.D., PAUL J. LARAIA, M.D., MICHAEL V. HERMAN, M.D., EDMUND H. SONNENBLICK, M.D., AND RicIAiRD GORLIN, M.D. Dwnladed frm by n Nvember 15, 218 SUMMARY The effects f intravenus administratin f glucagn (5,ug/kg) n left crnary bld flw and mycardial xygen cnsumptin were studied in nine patients during diagnstic cardiac catheteriatin and in six pen-chested anesthetied dgs. Crnary bld flw was measured with the '33Xe washut technic in man, and with an electrmagnetic flwmeter placed arund the left anterir descending crnary artery in the dgs. In the patients, glucagn prduced a 31% increase in crnary bld flw and a 29% increase in mycardial xygen cnsumptin, with n change in crnary arterivenus (A-V) 2 difference acrss the heart. In the dgs glucagn prduced a 114% increase in crnary bld flw and a 131% increase in mycardial xygen cnsumptin, again with n change in crnary A-V 2 difference. Thus glucagn is a secndary crnary vasdilatr in bth man and dg. The mdest chrntrpic and intrpic effects f glucagn bserved in man were nly half as great as thse bserved in the dg. Part r all f this difference in dse-respnse relatinship between the tw species may be related t the different experimental cnditins f the study. Additinal Indexing Wrds: Crnary A-V 2 difference Crnary vascular resistance Pressure-time per minute Secndary crnary vasdilatr T HE CARDIOTONIC actins f glucagn, a 29-amin acid plypeptide hrmne, have been demnstrated in varius animal preparatinsl-5 and in humans during cardiac catheteriatin"9 and in the pstperative perid fllwing prsthetic valve replacement.1 In patients with chrnic cngestive heart failure equivcally beneficial effects have been nted Glucagn has a psitive intrpic and a This study was supprted in part by Grants , RO1-HE , and ITI frm the U. S. Public Health Service, and Grant frm the American Heart Assciatin and by the Heart Research Fundatin. Received Octber 27, 1969; accepted fr publicatin December 2, Circulatin, Vlume XLI, April Left ventricular wrk '33Xe washut mderate chrntrpic effect which are manifest as an increase in the maximum rate f ventricular pressure develpment (Ap/At) and cardiac utput, accmpanied by a small increase in heart rate, an augmentatin f atriventricular cnductin, and a reductin in systemic vascular resistance.4' 5 13, 14 The intrpic effects f glucagn are unusual in that they ccur in the absence f catechlamines r in the presence f 38- adrenergic blckade and may be superimpsed n full digitaliatin withut incurring arrhythmias.4-6, 1 Despite the recent intensive study f the cardivascular effects f glucagn, n dat.a are available cncerning its effects n mycardial xygen cnsumptin and crnary bld flw.

2 58 MANCHESTER ET AL. Dwnladed frm by n Nvember 15, 218 In view f the ptential usefulness f this hrmne in the presence f acute cardiac insufficiency the present study was designed t analye these imprtant factrs. Methds Human Subjects Eight men and ne wman were studied during diagnstic cardiac catheteriatin. Six f the subjects had athersclertic crnary artery disease, ne had mitral stensis and nrmal crnary arterigraphy, and tw had a chest pain syndrme with nrmal crnary arterigraphy. The patients' ages ranged frm 3 t 53 years, with a mean age f 43.5 years. As judged by hemdynamic data, cardiac failure was absent. Clinical data are given in table 1. Patients were studied in the fasting state fllwing premedicatin with meperidine, 5 mg, and pentbarbital sdium, 1 mg, administered intramuscularly 45 min prir t the cardiac catheteriatin. A plyethylene catheter was placed in the left Clinical Data Table 1 brachial artery by the Seldinger technic. A Snes catheter was passed thrugh a cutdwn n the right brachial artery and advanced int the left ventricle fr the study perid. A Gdale-Lubin catheter was passed thrugh an antecubital vein and placed in the lateral crnary sinus. Bld sampled frm this site was assumed t be representative f bld frm the left ventricular mycardium. The psitin f the crnary sinus catheter was maintained cnstant thrughut the study. Selective crnary cinearterigraphy was perfrmed in multiple prjectins by the technic f Snes and Shirey,15 emplying 75% sdium and megluamine diatriate. Athersclertic crnary artery disease was defined as angigraphic evidence f any crnary arterial intraluminal narrwing r irregularity, r bth. Pressures were measured with Statham P23Db strain gauges and recrded n a Sanbm 56 plybeam phtgraphic recrder. Cardiac utput was measured by the indicatr-dilutin technic with indcyanine-green dye and a Gilfrd densitmeter. Green dye was injected int the right atrium, and arterial bld was sampled frm the brachial artery catheter. Crnary flw was measured by the methd f Rss and assciates,16 with selective left crnary injectin f '33Xe thrugh a n. 7 r 8 Snes catheter, the disappearance f the gas frm the mycardium being measured with a precrdial cunter. The time activity curve was recrded with a Picker ratemeter perating with a.3-sec time cnstant and a recrded paper speed f 3 inches/min. Flws were calculated, as described by Klein and assciates,'7 by determining the rate cnstant frm the semilg replt f the washut curves. As the washut curve is nt mnexpnential, the terminal prtin f the precrdial washut curve (slw cmpnent) was extraplated t the er time intercept anl subtracted frm the riginal curve. The resultant fast cmpnent f flw was used fr the calculatin f crnary bld flw. Bld xygen cntent and capacities were determined in duplicate by the methd f Van Slyke and Neill.18 Systlic ejectin perid and systlic and diastlic mean pressures were measured frm brachial arterial pressure pulses. Mycardial xygen cnsumptin per 1 g f left ventricle was calculated as the prduct f crnary flw and mycardial arterivenus xygen difference (ml/liter). Crnary and systemic vascular resistances were calculated.'9 Left ventricular functin was assessed in terms f Age Case Sex (yr) BSA(m2) Clinical diagnsis 1 M CAD, 3-vessel disease 2 M Atrial fibrillatin, anginal syndrme with nrmal crnary arteries 3 F Anginal syndrme with nrmal crnary arteries 4 M CAD, 3-vessel disease 5 M Mitral stensis, nrmal crnary arteries 6 M CAD, minimal arterial narrwing 7 M CAD, 1-vessel disease 8 M CAD, 1-vessel disease 9 M CAD, 2-vessel disease Abbreviatin: CAD = athersclertic crnary artery disease. Circulatin, Vlume XLI, April 197

3 GLUCAGON AND RONARY BLOOD FLOW 581 Dwnladed frm by n Nvember 15, 218 the fllwing parameters: cardiac index, in liters per minute per square meter f bdy-surface area; strke index, in milliliters per beat per square meter; mean systlic ejectin rate in milliliters per secnd per square meter; left ventricular enddiastlic pressure (LVEDP), in millimeters f mercury; left ventricular external wrk in kilgram-meters per minute per square meter f bdy surface area; left ventricular pressure-time per minute in millimeters f mercury-secnds per minute; and average rate f rise f left ventricular isvlumic pressure (Ap/At) in millimeters f mercury per secnd. Observatins were made at rest, at least 2 min after cmpletin f any angigraphic prcedure,2 and a few minutes fllwing a 4 t 5-min intravenus infusin f glucagn (5,ug/kg) in nrmal saline. Animal Studies Six mngrel dgs, weighing 18 t 25 kg, were anesthetied with pentbarbital sdium, intubated, and maintained n a Harvard respiratr. A bilateral transsternal incisin in the fifth intercstal space affrded adequate cardiac expsure. One f the internal mammary r cartid arteries was cannulated with a Siln catheter fr measurement f peripheral arterial pressure. A 16 t 18-mm electrmagnetic flw prbe was placed arund the ascending arta t recrd artic flw. A 3 t 4-mm electrmagnetic flw prbe was placed arund the left anterir descending crnary artery in six dgs t recrd crnary flw. A plyethylene catheter was placed in the anterir crnary sinus thrugh an atrial-purse string suture. A shrt 8-F catheter was placed in the left ventricle thrugh an apical purse-string suture fr the measurement f left ventricular pressure. Tefln-cated pacing electrdes were placed in the right ventricular mycardium. Permanent heart blck was induced in all six dgs by transatrial infiltratin f the A-V nde with 4% frmaldehyde2l and the heart was paced at a cnstant rate abut 15 beats/min. The electrcardigram, peripheral arterial pressure, left ventricular pressure, maximum rate f left ventricular pressure develpment (Ap/At), central artic flw, and left anterir descending crnary artery flw were recrded n an 8- channel Lexingtn scillscpe-recrder. Strke vlume was btained as the electrical integral f central artic flw. Maximum LV Ap/At was electrically differentiated frm the left ventricular pressure tracing. Bld xygen cntent and capacities were determined in duplicate by the methd f Van Slyke and Neill. Measurements were made at rest at a time when pressure and flw had been stable fr at least 3 min and a few minutes after a 2 t 3-min intravenus infusin f glucagn (5,ug/kg) in nrmal saline. Circudatin, Vlume XLI, Apri 197 All statistical cmparisns were perfrmed with Student's paired t-test. Results Hemdynamic Effects The nset f actin f glucagn was evident in 3 min fllwing intravenus administratin, as nted by an increase in heart rate and arterial pulse pressure. A maximum effect was attained in 5 t 7 min, and lasted apprximately 15 min. Transient nausea ccurred in five patients. In these subjects n bservatins were made until heart rate and pressure were stable fr at least 2 min fllwing the nausea. N arrhythmias were seen in assciatin with the administratin f glucagn. The hemdynamic effects f glucagn bserved in this study are presented in table 2. The mean values fr the patient and dg studies are listed, while percentage changes fr the individual experiments are presented as the mean SEM. Statistical significance was evaluated by the paired t-test. In the patients studied, glucagn prduced a mdest increase in heart rate ( 11 4%), cardiac index (22 ± 13%), and arterial pressure (6 2%) with n change in LVEDP, and a slight fall in systemic vascular resistance (- 114%). The increase in cntractile state was manifested by an increase in left ventricular Ap/At (26 12%) and systlic ejectin rate (28 13%). As indices f an increase in ventricular wrk, there were increases in bth pressure time per minute (11 4%) and left ventricular wrk (29 6%). Infusin f glucagn int dgs (table 2) prduced directinally similar changes, but f a greater magnitude than thse seen in man. A relative cmparisn f the hemdynamic effects f the same dse f glucagn per unitweight (5 /Lg/kg) in man and dg is shwn in figure 1. Thus, in the specific circumstances under which these tw species were studied, the hemdynamic effects f glucagn were at least twice as great in the dg as in man. Effects n Crnary Flw Figure 2 shws typical precrdial scintigrams after selective injectin f 133xenn int the left crnary artery befre and after the

4 582 MANCHESTER ET AL. 6 6 V V V V V CC 1 L 1 LO b * 1 1 cc 1 LO 1 cl CS T,-q I O L. I t., 1i c I-r, Ce~ eq r - Dwnladed frm by n Nvember 15, 218 Pt- V E.- - P t I2e QD m 4) s.,. b Z@3 b. U V 1O 6 V CC cc 6V v r-h C. 6 V - l V -H ) 1 ) r-q 6 V L D ' 1r _ C c ~~~~~~~~~c - Ca :)4 a) cc4 Ce (12c 3,4- -- Ca '; P-4~~~~~~C ~ Crult,Vu exl,a -rl17

5 GLUCAGON AND RONARY BLOOD FLOW 583 Dwnladed frm by n Nvember 15, I. LU L HEMODYNAMIC EFFECTS OF GLUCAGON (5pO/kg) HEART RATE CARDIAC OUTPUT SYSTEMIC VASCULAR RESISTANCE MAN n= 9 DOG n=6 I) I- LV SYSTOLIC dp/dt EJECTION RATE Figure 1 The cmparative hemdynamic effects f glucagn (5 ug/kg) in man and dg are pltted as the percentage change frm cntrl values. Results are expressed as the mean SEM. infusin f glucagn. Calculatin f the mycardial clearance rate is illustrated. The increase in mycardial clearance is bvius frm the precrdial curves and the semilg replt f the fast cmpnent f the washut curves. The subject, a 38-year-ld man with athersclertic disease in tw crnary arteries, had an increase in crnary flw frm 73 t 118 ml/min/ 1 g f left ventricle. The cmbined results f such studies in bth species are presented in table 3. In man glucagn prduced a mdest increase in crnary bld flw (31 1%) and mycardial xygen cnsumptin (29 13%) with n change in crnary A-V 2 difference, r 2 extractin rati. A mderate decrease in crnary vascular resistance (-2 8%) ac- Circulatin, Vlume XLI, April 197 cmpanied this increase in crnary bld flw. Again directinally similar but larger changes were seen in the dgs studied (table 3) as further illustrated in figure 3 by a direct cmparisn f the percentage changes bserved. The marked difference between the tw species in the magnitude f the increased crnary flw and mycardial xygen cnsumptin is evident, under smewhat different experimental cnditins. Metablic alteratins secndary t glucagn in man are shwn in table 4. Bld glucse increased by an average f mg % (P <.5) whereas serum ptassium cncentratin fell frm an average f 4.1 t 3.9 meq/l (-1 ± 2%; P <.5). Transmycardial lactate extractin ccurred at rest in eight f the nine subjects. With glucagn infusin, transmycardial lactate prductin was reversed t extractin in ne subject with anaerbisis at rest, and persistent lactate extractin was nted in the eight subjects with extractin at rest. Discussin Recent studies have shwn glucagn t have a direct psitive intrpic actin'-1 n the heart despite cardiac catechlamine depletin, blckade f f3-adrenergic receptrs,4-5 r the presence f full digitaliatin.4 6, 1 Furthermre, glucagn has a mderate chrntrpic effect,4' 5 and increases atriventricular cnductin with little r n arrhythmagenic activity.13' 14 Accrdingly, it has been suggested that glucagn may be beneficial in the presence f depressed cardiac functin as in pstperative lw utput states, cardigenic shck, acute cngestive heart failure, r in the presence f 8-adrenergic blcking agents. Since the xygen cnsumptin f the heart is largely determined by heart rate, arterial pressure, and cntractility,22 all f which were increased t sme degree by glucagn, an increase in mycardial xygen cnsumptin wuld be anticipated and has been bserved. Since the extractin f xygen frm arterial crnary bld is nearly cmplete, any increase in xygen cnsumptin is generally

6 584 EFFECT OF GLUCAGON ON RONARY BLOOD FLOW MANCHESTER ET AL. NTROL A.G. # I=u - ti u39 se left cr. flw u 73cc/min/1g CPM(13) 11 I --I~* 3 2 Minutes li GLUCAGON(Spjsg/kg) Minutes iinn wu 1 t - ti 24sec left cr. flw 5 llscc/min/loo CPM(3) 1 I - Dwnladed frm by n Nvember 15, Minutes I b.5 Figure Minut-s The left panels shw the washut f 133Xe frm the mycardium befre and a few minutes after the intravenus injectin f glucagn (5 pg/kg). 133Xe was selectively injected int the left crnary artery f this patient, and the curves were btained frm a precrdial cunter placed ver the apex f the left ventricle. The data have been repltted n a lg scale in the right panels and separated int a fast and slw cmpnent by the curve-peeling methd. The t3 was measured frm the fast cmpnent fr the calculatin f crnary flw. I assciated with a decrease in crnary vascular resistance and an apprpriate increase in flw, as was nted fllwing glucagn administratin. T be cnsidered a vasdilatr, an agent must prduce an increase in crnary flw ut f prprtin t a rise in perfusing pressure.23 Such was the case here, since crnary flw rse substantially mre than did diastlic perfusin pressure, and calculated crnary vascular resistance significantly decreased. Hwever, vasdilatin may be primary r secndary t the increased xygen requirements f the heart. Vasdilatin is cnsidered t be primary if the arterivenus xygen difference acrss a vascular bed narrws, indicating that the flw rse mre than energy demand, and secndary if arterivenus xygen difference remains cnstant.24 In the present study, crnary arterivenus xygen difference, crnary venus xygen saturatin, and per cent extractin f xygen by the mycardium did nt change significantly, despite significant increases in crnary bld flw and mycardial xygen cnsumptin. Thus, glucagn may be cnsidered t be a secndary vasdilatr in bth intact man and pen-chested anesthetied dgs. This is similar t the effect f epinephrine25 and different frm the primary vasdilating actin f isprterenl26 n the crnary circulatin. Nrmally the mycardium functins n an aerbic basis with virtually n anaerbic glyclysis ccurring in the heart at rest r under stress.27 This can be measured by the Circulatin, Vlume XLI, April 197

7 GLUCAGON AND RONARY BLOOD FLOW 585 EFFECTS OF GLUCAGON (5Opg) IO a.. v RONARY BLOOD FLOW MYOCARDIAL 2NSUMPTION 18 16C 14 uq " Dl: as el c *~~~~ * c I -H CI 4 4- v p: 2 - C, 4 12/ 1CI. 8-6 / a n * O DC *._- C9 R 1 RONARY VASCULAR RESISTANCE -2 -i. -4- u 2 PRESSURE TIME 2r MAN n=6 DOG * n= 6 PER MINUTE Dwnladed frm by n Nvember 15, ;4 i P-Q ~ ~~~ Ciclain,VlueXL,Api17 V ZV O.) C O C- 6 ) ) O Ca C H * - ) C._._,*_. Figure 3 The cmparative efects f glucagn (5 Ag/kg) n crnary bld flw and mycardial xygen cnsumptin in man and dg are pltted as the percentage change frm cntrl values. Results are expressed as the mean SEM. persistent extractin f lactate by the prtin f mycardium sampled. In the present study the persistent transmycardial lactate extractin befre and after glucagn infusin revealed n apparent anaerbic metablism. This finding cnfirms the xygen data and suggests that the augmentatin f crnary flw was sufficient t meet the increased energy requirements f the heart fllwing glucagn. The bserved hemdynamic actins f glucagn were similar t thse already nted.6-9 In man, glucagn prduced a slight increase in heart rate, a slight decrease in peripheral vascular resistance, and a mderate increase in cardiac cntractility. In the animals glucagn effected a marked increase in cntractile state and a mderate decrease in peripheral vascular resistance. The increased cntractile state was manifested by increases in mean systlic ejectin rate, average Ap/At,

8 586 MANCHESTER ET AL. Metablic Data Table 4 Dwnladed frm by n Nvember 15, 218 Lactate extractin Bld glucse K Case (A-V/A) (%) (mg%7) (meq/l) 1 Rest Glucagn Rest Glucagn Rest Glucagn Rest 16.6 Glucagn Rest Glucagn Rest Glucagn Rest Glucagn Rest Glucagn Rest Glucagn 17.4 Mean rest Glucagn % change Paired t-test - P <.5 P <.5 maximum LV Ap/At, and cardiac index (in the presence f an unchanged r decreased left ventricular vlume). That the change in cntractility in man was independent f the small change in heart rate is supprted by the canine experiments in which heart rate was kept cnstant by pacing. The majr determinants f mycardial xygen cnsumptin are intramycardial tensin, heart rate, and the cntractile state f the heart.22 Tensin in the wall f the ventricle is a direct functin f the intraventricular radius and pressure and an inverse functin f the ventricular wall thickness. Heart rate determines the number f times per minute the heart is activated and, thus, the cumulative tensin that is develped. Since LVEDP, which reflects left ventricular end-diastlic vlume, was nt changed by glucagn in man, ne may assume that there was a mdest increase in tensin-time per minute. In the animals with cnstant heart rate, a smaller increase in tensin-time per minute ccurred since a 5% reductin in enddiastlic pressure ccurred. Thus, in the dg the rise in mycardial xygen cnsumptin appears t be in excess f the increase in tensin-time per minute. This suggests that anther factr, increased cntractility, must be respnsible fr the large increases in mycardial xygen cnsumptin, as reflected in the increased mean systlic ejectin rate, and LV Ap/At. Thus, ne may cnclude that the increase in cntractile state induced by glucagn may lead t a substantial increase in xygen cnsumptin. In bth species the increased xygen cnsumptin f the heart (table 3) was similar in magnitude t the calculated increase Circulatin, Vlume XLI, April 197

9 Dwnladed frm by n Nvember 15, 218 GLUCAGON AND RONARY BLOOD FLOW in left ventricular wrk (table 2). Thus, it wuld appear that glucagn had n measurable uncupling r xygen-wasting effect. The greater hemdynamic respnse t glucagn in dgs bserved in this study might be due either t a species difference in dserespnse relatinships r t the different experimental cnditins f the study. Supprt fr the latter view is gained frm the recent bservatins f Lucchesi and assciates14 that the awake, unanesthetied dg has little r n chrntrpic respnse t glucagn as cmpared t the anesthetied dg. Certainly the degree f cardiac depressin present in the anesthetied dg wuld allw fr a greater intrpic respnse because the heart is far belw its ceiling f cntractility. These studies lend supprt t the view that glucagn is a ptentially useful intrpic agent which may supplement glycsides r catechlamines under the prper circumstances since its mde f actin is independent f these agents r their receptrs. Like all agents which increase cntractility, it t augments xygen cnsumptin f the heart. While the usefulness f glucagn has been suggested in cardigenic shck,28 the assciated increase in xygen cnsumptin must still be cnsidered. References 1. FARAH A, TUTTLE R: Studies n pharmaclgy f glucagn. J Pharmacl Exp Ther 129: 49, REGAN TJ, LEHAN PH, HENNEMAN DH, ET AL: Mycardial metablic and cntractile respnse t glucagn and epinephrine. J Lab Clin Med 63: 638, WHITEHOUSE FW, JAMES TN: Chrntrpic actin f glucagn n sinus nde. Prc Sc Exp Bil Med 122: 823, GLICK G, PARMLEY WW, WECHSLER AS, ET AL: Glucagn: Its enhancement f cardiac perfrmance in cat and dg and persistence f its intrpic actin despite beta receptr blckade with prpranll. Circulatin Research 22: 789, LUCCHEsi BR: Cardiac actins f glucagn. Circulatin Research 22: 777, PARMLEY WW, GLICK G, SONNENBLICK EH: Cardivascular effects f glucagn in man. New Eng J Med 279: 12, KLEIN, SW, MORCH JE, MAHON WA: Cardivas- Circulatin, Vlume XLI, April cular effects f glucagn in man. Canad Med Ass J 98: 161, LINHART JW, BAROLD SS, HEN LS, ET AL: Cardivascular effects f glucagn in man. Amer J Cardil 22: 76, WILLIAMS JF JR, CHILDRESS RH, CHIP JN, ET AL: Hemdynamic effects f glucagn in patients with heart disease. Circulatin 39: 38, PARMLEY WWAT, MATLOFF JM, SONNENBLICK EH: Hemdynamic effects f glucagn in patients fllwing prsthetic valve replacement. Circulatin 39 (suppl I): 1-163, BROGAN E, KZONIS MC, OVERY DC: Glucagn therapy in heart failure. Lancet 1: 482, WILLIAMS JF JR: Glucagn and the cardivascular system. Ann Intern Med 71: 419, STEINER C, WIT AL, DAMATO AN: Effects f glucagn n atriventricular cnductin and ventricular autmaticity in dgs. Circulatin Research 24: 167, LUCCHESI BR, STUTFZ DR, WINFIELD RA: Glucagn: Its enhancement f atriventricular ndal pacemaker activity in dgs. Circulatin Research 25: 183, SONES FM, SHIREY EK: Cine crnary arterigraphy. Md Cnc Cardivasc Dis 31: 735, Rss RS, UEDA K, LICHIrTrEN PR, ET AL: Measurement f mycardial bld flw in animals and man by selective injectin f radiactive inert gas int the crnary arteries. Circulatin Research 15: 28, KLEIN MD, HEN LS, GORLIN R: Kryptn 85 mycardial bld flw: Precrdial scintillatin versus crnary sinus sampling. Amer J Physil 29: 75, VAN SLYKE DD, NEILL JM: Determinatin f gases in bld and ther slutins by vacuum extractin and manmetric measurements. j Bil Chem 61: 523, GORLIN R: Measurement f crnary flw in health and disease. In Mdern Trends in Cardilgy, edited by Jnes AM. New Yrk, Paul B. Heber, Inc., 196, p BROWN R, RAHIMATOOLA SH, DAVIS GD, ET AL: The effect f angicardigraphic cntrast medium n circulatry dynamics in man. Circulatin 31: 234, STEINER C, KOVALIK ATW: A simple technique fr prductin f chrnic cmplete heart blck in dgs. J Appl Physil 25: 631, SONNENBLICK EH, Rss J JR, BRAUNWALD E: Oxygen cnsumptin f the heart: Newer cncepts f its multifactral determinatin. Amer J Cardil 22: 328, ScTT JC, BALOURDAS TA: Analysis f crnary flw and related factrs fllwing vagtmiiy,

10 588 atrpine, and sympathectmy. Circulatin Research 7: 162, HEN LS, ELLIOT WC, GORLIN R: Measurement f mycardial bld flw using kryptn- 85. Amer J Physil 26: 997, SULLIVAN JM, GORLIN R: Effect f I-epinephrine n the crnary circulatin in human subjects with and withut crnary artery disease. Circulatin Research 21: 919, KRASNw N, ROLETT EL, YURCHAK PM, ET AL: MANCHESTER ET AL. Isprterenl and cardivascular perfrnmance. Amer J Med 37: 514, KRASNw N, NEILL WA, MESSER JV, ET AL: Mycardial lactate and pyruvate metablism. Clin Invest 41: 275, MATLOFF JM, MANCHESTER JH, PARMLEY WW, ET AL: Hemdynamic effects f glucagn and intra-artic balln cunterpulsatin in canine mycardial infarctin. Amer J Cardil. In press. Dwnladed frm by n Nvember 15, 218 Pertinent t the Dialgue Regarding Labratry and Clinical Research Lrd Mynihan 1923 Clinical research and the tilsme discveries f new technical methds are as fully entitled t the term "scientific" as any f the gd wrk dne in ur labratries. The cmplexities f clinical research are s intricate, and because f the human material upn which they are cnducted are s bewildering as perhaps t surpass all frms f labratry research in difficulty. They call fr qualities f insight, imaginatin, patience, and intellectual integrity t a n less cnsiderable degree. The practice f clinical medicine r surgery makes a further heavy demand upn qualities f temperament and f character which are little exercised in the clistered tranquillity f the labratry. Yet the rewards pen t the clinical investigatr by the nly scientific bdy cmpetent t give them, the Ryal Sciety, are cnsistently withheld. The present President f the Ryal Sciety is a medical man whse life has been spent in the labratry, with the result that physilgy and general medicine have been permanently and very greatly enriched by his laburs. But there are physicians and surgens whse lives have been spent in the wards and in the peratin theatres f ur hspitals whse cntributins t "scientific" medicine are entitled t rank even with his. The jint and separate laburs f the labratry wrker and f the clinician are bth, perhaps equally, necessary fr the future prgress f medicine in all its branches. Bth are deserving f recgnitin at the hands f thse empwered t cnfer it; in "scientific" value ne des nt surpass the ther.-frm MOYNIHAN, BERKELEY: Letter t the Editr. The Times, Lndn, July 27, Circulatin, Vlume XLI, April 197