comparison of dobutamine and dopamine in acute myocardial

Comparison of Dobutamine and Dopamine in

Acute Myocardial InfarctionEffects of Systemic Hemodynamics,

Plasma Catecholamines, Blood Flows and Infarct Size

KISHIO MAEKAWA, M.D., CHANG-SENG LIANG, M.D., PH.D., AND WILLIAM B. HOOD, JR., M.D.

SUMMARY To compare cardiovascular effects of dobutamine and dopamine, we administered the twoagents at a dose of 10 gpg/kg/min i.v. to two groups of chronically instrumented conscious dogs, beginning 40minutes after coronary artery occlusion and continuing for 24 hours thereafter. A control group that wasgiven an infusion of5% dextrose was also studied. During the first 30 minutes of infusion, both dobutamineand dopamine produced similar increases in cardiac output, left ventricular dP/dt and dP/dt/P, withoutsignificant changes in heart rate, mean arterial blood pressure or regional myocardial blood flow. At 24hours, cardiac output and left ventricular dP/dt and dP/dt/P continued to be greater in the dobutaminegroup than in the control group. The acute positive inotropic effects of dopamine were no longer apparent at24 hours. Epicardial blood flow in the dobutamine-treated group also was higher than that in the controlgroup. There were, however, no differences between groups in the ischemic-to-nonischemic myocardialblood flow ratio. In addition, infarct size, measured by nitroblue tetrazolium staining, was smaller in thedobutamine group (55 ± 4% of risk zone) than in the dopamine group (76 ± 6%) or the control group (76+ 5%). The dobutamine group also differed from the dopamine group in their plasma catecholamine levels.Arterial plasma concentrations of norepinephrine and epinephrine increased above the postocclusionbaseline values only during dopamine infusion by 1.50 ± 0.34 and 0.87 0.32 ng/ml, respectively.Dopamine also caused myocardial release of norepinephrine, as evidenced by a significant transmyocardialgradient (coronary sinus minus arterial difference) of 1.48 + 0.27 ng/mI. The results show that dobutamineincreases collateral flow to the ischemic myocardium, enhances left ventricular performance, and reducesinfarct size. None of these effects were produced by dopamine under these experimental conditions. Thedifference between the effects of the two drugs probably is related, at least in part, to the detrimental effectsof local myocardial release of norepinephrine by dopamine.

DOBUTAMINE is a cardioselective adrenergic agentthat augments myocardial contractility, cardiac outputand myocardial blood flow with only minimal changesin heart rate or arterial blood pressure.'-5 It may be usedclinically to improve depressed cardiac function with-out further impairment of oxygen balance or metabo-lism of the ischemic heart.6` Dobutamine not onlyimproves the global performance of the heart, but alsoreduces infarct size during acute experimental myocar-dial infarction.9 These salutary effects probably arecausally related to the increase in ischemic myocardialblood flow produced by dobutamine. However, Tut-tle'0 showed that a reduction of myocardial necrosis bydobutamine was accompanied not only by an increasein myocardial blood flow, but also by a reduction in theamount of norepinephrine released from cardiac sym-pathetic fibers that was facilitated after myocardialischemia. Local release of excessive endogenous nor-epinephrine is generally thought to be injurious to is-

From the Departments of Medicine and Pharmacology, and the Car-diovascular Institute, Boston University School of Medicine, and theDepartment of Medicine and Thorndike Memorial Laboratory, BostonCity Hospital, Boston, Massachusetts.

Supported in part by USPHS grants HL-24214, HL-14646, HL-17403 and HL-18318.

Presented in part at the 36th Annual Scientific Sessions of the Ameri-can College of Cardiology, Atlanta, Georgia, April 29, 1982.

Address for correspondence: Dr. Chang-seng Liang, University ofRochester Medical Center, Cardiology Unit, Box 679, Rochester, NewYork 14642.

Received September 16, 1982; accepted November 15, 1982.Circulation 67, No. 4, 1983.

chemic myocardium because it has both /3-receptor-mediated inotropic and metabolic effects that wouldincrease oxygen consumption, and an at-adrenergic va-soconstrictor effect that would reduce oxygen sup-ply.". 12 Tuttle'0 speculated that this reduction in nor-epinephrine release may contribute to the protectiveeffect of dobutamine on ischemic myocardium.

Like dobutamine, dopamine is a commonly usedinotropic agent. Although dobutamine and dopaminehave similar acute cardiac effects,513' '4 it probably isnot appropriate to generalize the salutary effects ofdobutamine on infarct size to dopamine, because theirmechanisms of actions as sympathomimetic aminesare different.1l 1'- ' Dobutamine acts directly on adren-ergic receptors, whereas dopamine exerts its adrener-gic action both directly on adrenergic receptors andindirectly by releasing norepinephrine from sympa-thetic nerve endings.20 Dopamine's potential action ofreleasing norepinephrine from the heart is in contrast tothe reduction in myocardial release of norepinephrineproduced by dobutamine.'0 Therefore, it appears thatdopamine may not have the same salutary effects asdobutamine in acute myocardial infarction. Indeed,dopamine has been shown to increase ischemic injury,as measured by epicardial ST-segment elevation.21 22The effects of dopamine on infarct size have neverbeen studied.

In the present study, we compared the effects ofdobutamine and dopamine on systemic hemodynam-ics, myocardial blood flow, and infarct size in theconscious dog with acute myocardial infarction.

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DOBUTAMINE AND DOPAMINE IN ACUTE MI/Maekawa et al.

MethodsAdult beagle dogs that weighed 6.9-17.8 kg were

studied in a conscious state. Two to 3 weeks before theexperiment, a sterile left thoracotomy was made underanesthesia with i.v. sodium pentobarbital (25 mg/kg)and mechanical ventilation with room air using a Har-vard respirator. The heart was exposed and the leftanterior descending coronary artery isolated for im-plantation of a Silastic balloon occluder (3.5 mm i.d.)immediately distal to the first diagonal branch. Normalsaline was infused transiently into the balloon, and theamount of saline that caused complete occlusion of thecoronary artery was determined. Heparin-filled Tygoncatheters (1.02 mm i.d.) were inserted into the mainpulmonary artery, left atrium and descending thoracicaorta. The catheters and the occluder tubing were thentunneled through the interscapular space and securedexternally at the back of the neck. After the wound wasclosed, the dog was returned to the animal quarters andgiven 400,000 U of procaine penicillin and 500 mg ofdihydrostreptomycin sulfate (Combiotics, i.m.; PfizerPharmaceutical Inc.) daily for 4 days.On the day of the experiment, the dog was pretreat-

ed with subcutaneous morphine sulfate (0.5 mg/kg)and placed in the right decubitus position. The ECGwas monitored. Two catheters were then inserted un-der local anesthesia with 0.5% lidocaine (Xylocaine,Astra Pharmaceutical Products, Inc.) with fluoroscop-ic guidance. A #7F catheter was inserted into thecoronary sinus through an external jugular vein and ahigh-fidelity transducer-tip catheter (Millar Instru-ments Inc.) in the left ventricular cavity through afemoral artery. In addition, a peripheral vein in a hind-leg was cannulated for drug infusion. Heparin (500 U/kg) was then administered intravenously.

Measurements and CalculationsThe intravascular catheters were connected to Sta-

tham P23Db pressure transducers and a Brush 480eight-channel recorder (Gould, Inc., Instrument Sys-tem Division). The Millar catheter was also connectedto the Brush 480 recorder for measuring left ventricularpressure, and electronically differentiated maximalrate of left ventricular pressure rise (dP/dt). In addi-tion, the ratio of left ventricular dP/dt to a developedleft ventricular pressure of 50 mm Hg occurring duringisovolumic systole was calculated using a PDP- 11/10minicomputer (Digital Equipment Corporation). Heartrate was calculated from the ECG. Cardiac output wasmeasured by the indocyanine green (Cardio-Green;Hynson, Westcott and Dunning, Inc.) dilution methodwith a Gilford model 140 cardiac output system (Gil-ford Instrument Laboratories, Inc.). Stroke volumeand total peripheral vascular resistance were calculatedusing conventional formulas.

Organ blood flows were measured by the radio-active microsphere method.23 24 Radioactive micro-spheres (New England Nuclear), 15 + 3 mg indiameter and labeled with cerium- 141, tin- 113, ruthen-ium-103, and scandium-46 at a specific activity of 10

mCi/g, were suspended in a 10% dextran solution con-taining 0.01% Tween-80 and adequately sonicatedbefore use. For flow measurements before coronaryartery occlusion, 500,000-750,000 microspheres wereinjected into the left atrium followed by a 10-ml normalsaline flush over a 30-second period; 1-1.5 millionmicrospheres were used after coronary artery occlu-sion. Arterial reference blood was collected for 90seconds at a rate of 7.75 ml/min using a Harvard pumpbeginning 10 seconds before the commencement ofmicrosphere injection. After the experiment, coronaryangiography was performed; the dog was given hep-arin and killed with a lethal dose of a sodium pentobar-bital. Organs were removed, cleaned, weighed, andprepared for radioactivity counting. Tissue and bloodsamples were counted for radioactivity using a Packardgamma spectrometer at window settings correspond-ing to the peak energies of the nuclides used. Theactivity of each isotope was corrected for backgroundand crossover activities from other isotopes. Organblood flow was calculated on the PDP- 1 1/10 minicom-puter using the reference sample method: organ bloodflow (m1l1O0g/min) = (arterial reference blood flow[ml/min] X tissue nuclide activity x 100)/ (arterialreference blood nuclide activity x tissue weight [g]).Mean aortic blood pressure was divided by organblood flow to obtain the regional organ vascularresistance.

Blood samples were taken simultaneously from theaorta and coronary sinus for measuring plasma cate-cholamine concentrations, using a radioenzymaticmethod.25The heart was removed for determination of risk

zone and infarct size. The left anterior descendingcoronary artery was cannulated at the site of the bal-loon occluder and the left main and right coronaryarteries were cannulated through their respective ostia.The heart was then perfused for 15 minutes under aconstant pressure of 100 mm Hg with a 1% MonastralRed dye solution (E.I. du Pont, de Nemours & Co.,Inc.) into the left anterior descending artery and a0.5% Monastral Blue dye solution into the other twocatheters. The area stained red was considered the"risk region."26

After staining, the left ventricle, including the inter-ventricular septum, was separated from the rest of theheart and cut transversely into six or seven slices ap-proximately 6-7 mm thick. Each slice was weighedand photographed and immersed in a nitroblue tetrazo-lium solution for 15 minutes at 37°C. (Nitroblue tetra-zolium is a marker for tissue dehydrogenase27 thatstains noninfarcted viable tissue blue and leaves in-farcted areas unstained.) Both sides of the left ventric-ular slices were then rephotographed. The risk andinfarct zones were planimetered on each photograph,and the percent risk or infarct size relative to the entireslice was determined by averaging the percent valuesfor both the apical and basal sections of that slice. Theweight for the risk or infarcted portion of the slice wasobtained by multiplying the average percent value and

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the weight of the slice. The weights for all the sliceswere than added up to determine the total risk regionand infarct size. Finally, left ventricular slices were cutinto 42-50 myocardial segments, which were dividedinto endocardial and epicardial halves. These pieceswere then weighed and counted for radioactivity andregional blood flow measurements. Left ventriculartransmural segments were grouped into four regionsaccording to their endocardial blood flows determined40 minutes after coronary artery occlusion. Trans-mural segments with endocardial blood flow less than25 ml/100 g/min were designated as severely ische-mic. Segments with endocardial blood flows of 25-50ml/100 g/min and 50-75 mi/100 g/min were designat-ed as moderately ischemic and mildly ischemic, re-spectively. Areas with flows more than 75 ml/l00 g/min were considered nonischemic.

Experimental ProtocolDogs were divided into three groups according to

drug assignments: dobutamine (10 ,ug/kg/min), dopa-mine (10 ,ug/ml/min), and 5% dextrose solution. Thedrugs were administered randomly to dogs. The rest ofthe protocols was identical in the three groups.

After a 30-minute control period, the left anteriordescending coronary artery was occluded by inflatingthe previously implanted balloon occluder with a pre-determined amount of normal saline. Systemic hemo-dynamics, including cardiac output, heart rate, aorticblood pressure, left atrial pressure, and left ventriculardP/dt and dP/dt/P, were measured at 5-10-minute in-tervals during the control period and in the first 40minutes after coronary artery occlusion. Microsphereorgan blood flows and plasma catecholamine levelswere measured immediately before and 40 minutesafter coronary artery occlusion.

Beginning 40 minutes after coronary artery occlu-sion, one of the three drug solutions was infused ineach group at a rate of 0.19 ml/min for 30 minutesusing a Harvard infusion pump. Systemic hemody-namics were again determined at 5-minute intervals;regional blood flows and plasma concentrations of ca-techolamines were measured at the end of the 30-min-ute infusion. Thereafter, the dog was continuously ad-ministered the same dose of the drugs for an additional23 hours at a rate of 0.9 ml/hour, using a battery-operated Sigmamotor mobile infusion pump (Sigma-motor, Inc.) as previously described.9On the second day, 24 hours after coronary artery

occlusion, the left ventricular and coronary sinus cath-eters were reinserted under local anesthesia, and sys-temic hemodynamics, regional blood flow, and plas-ma catecholamine levels were measured again. Theamount of the drug delivered from the infusion bagover the experimental period was verified by subtract-ing the weight of the bag after the infusion from thatbefore the infusion.

Statistical AnalysisThe experimental results are given as mean ± SEM.

The statistical significance of the difference between

the three experimental groups was determined by two-way analysis of variance for independent groups withrepeated measures.28 Dunnett's test29 was used to de-termine the significance of differences between thepreocclusion control and the serial repeated measure-ments after coronary artery occlusion in each group.The t test was used to analyze the difference betweentwo means; p < 0.05 was considered significant.

ResultsCoronary artery occlusion was successfully pro-

duced in 31 dogs, as shown by coronary angiographyand postmortem examination on the second day of theexperiment. All dogs showed evidence of acute myo-cardial ischemia in the first hour after coronary arteryocclusion, including electrocardiographic ST-segmentelevation and decreased left ventricular dP/dt. Fivedogs were excluded from the study: one dog diedshortly after coronary artery occlusion, before the druginfusion, and four dogs died during the drug infusion(two dogs received dobutamine, one dopamine andone 5% dextrose). Eight of the remaining dogs (1 1 ± 1kg) received dobutamine, eight (12 ± 1 kg) dopamineand 10 (11 ±- 1 kg) 5% dextrose.

Systemic HemodynamicsAcute coronary artery occlusion produced similar

changes in systemic hemodynamics in all three groups(figs. 1-3). There was a decrease in cardiac output andleft ventricular dP/dt and dP/dt/P, and an increase inheart rate. Mean aortic blood pressure did not changesignificantly, while total peripheral vascular resistanceincreased initially but subsequently returned to preoc-clusion control values.

Figures 1-3 also show the acute effects of dobuta-mine, dopamine and 5% dextrose on hemodynamicvariables during the first 30 minutes of drug infusion.Left ventricular dP/dt and dP/dt/P increased signifi-cantly during the infusion of dobutamine and dopa-mine. Mean aortic blood pressure increased slightly inboth groups. Cardiac output also increased slightlyabove the values before drug infusion (fig. 4), but didnot differ significantly from the preocclusion controls.The changes in cardiac output and left ventricular dP/dtand dP/dt/P were of similar magnitude in the twogroups (fig. 4). In addition, total peripheral vascularresistance did not change significantly from the preoc-clusion controls in two groups. Heart rate also did notchange significantly from the preocclusion controlduring dobutamine infusion, but was higher than thecontrol value during dopamine infusion. Dextrose in-fusion did not affect any of the hemodynamic re-sponses to acute coronary occlusion. Mean left atrialpressure decreased from 4.7 ± 1.0 to 3.4 ± 0.9 mmHg (p < 0.05) during dobutamine infusion, but didnot change significantly during dopamine infusion(6.7 + 1.4 to 7.6 ± 2.2 mm Hg) or 5% dextroseinfusion (4.0 ± 1.0 to 3.7 + 0.8 mm Hg). Strokevolume increased only during dobutamine infusion(18 ± I to 20 ± 1 ml, p <0.05).At 24 hours after coronary artery occlusion, all dogs

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DOBUTAMINE Myocardial Blood Flows

0_---,2 D Myocardial blood flow decreased transmurally afterfl200 | :]scoronary occlusion; the greater decline was in the en-

\ 3 Io150.t docardial segment. There was no difference between} ;-,;1125 i the three groups. During the first 30 minutes of infu-e >_4 -100 sion, neither dobutamine nor dopamine significantly

i~ 2t'- __ 2 I ' altered myocardial blood flow (fig. 6). At 24 hours,' however, myocardial blood flow increased markedly

and was significantly higher in the dobutamine group25 in all ischemic epicardial segments and in nonischemic

myocardium than in the control group (fig. 7). There5000 * |was no difference in myocardial blood flow between

50000 T \ 0I the dopamine group and the control group.The ischemic/nonischemic myocardial blood flow

W 4000Lk 1/l \ MQ 50 t M ratio did not differ in the three roups either acutely or4000 /\ 50nogrus ateyr| {|. / I\; \ Z |Eat24 hours, except for the mildly ischemic region at 24N 40

> -Yz-?d 4\ lhours, when the ratio was greater in the dobutamine1C, 3000 40 group (0.78 + 0.03) than in the dextrose group (0.58

+0.07,p <0.05).

I ~~~~~~~~~~~~~~~~~~~DOPAMINE15 . 3 :tsa - --o~~~ 10 2000 06 0 X2

150 i I I ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~150-~~~~ ~~~ cI.c,~~~~~~~~~~. ~ ~ ~~ Lj~~~~~~.~~~~125

FIGURE1. Effects of oroar areryocluson nddobta2 600- 100

Zk ~~~~~~~~~~~~~~~7550~~~~~~~~~~~~~50

mine infusion on cardiac output, heart rate, left ventricular dPI } 4''')1 \IdtanddP/dt/P,meanaorticbloodpressureandtotalperipheral 5000vascular resistance. The abscissa denotes time after coronary K \'s tartery occlusion, and the baseline values are shown at zero 4000 'time. Bars indicate SEM. Asterisks show the values that differ

40

from the baseline control at p < 0.05, as determined by Dun-nett's test. 3000 50

exhibited ventricular tachycardia. The ventricular rates ____________________ ,were similar in the three groups. Cardiac output did notdiffer from the preocclusion or preinfusion controls inthe dextrose and dopamine groups, but it was higher in ool6000Sothe dobutamine group (figs. 1-3 and 5). Left ventricu- E Elar dP/dt and dP/dtIP fell below the levels seen during&the initial infusion of the drugs in all three groups and 100 I!0lower than the preocclusion control in the dextrose anddopamine groups. Similary, left ventricular dP/dt de- 4000creased below preocclusion values in the dobutaminegroup, but left ventricular dP/dt/P did not fall below itspreocclusion control (fig. 1). The absolute values of I Ileft ventricular dP/dt and dP/dt/P were lowest in the 0 10 20 30 40 50 60 70 24group infused with 5% dextrose (fig. 3). When these MINUTES HRSvalues at 24 hours of infusion were calculated as a FIGURE 2. Effects of coronary artery occlusion and dopaminepercentage of preinfusion controls, the values in the infusion on cardiac output, heart rate, left ventricular dPIdtdobutamine group were significantly higher than those and dPIdtIP, mean aortic blood pressure and total peripheralin the dopamine and control groups (fig. 5). vascular resistance. Format and symbols are as in figure 1.

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FIGURE 3. Effects of coronary artery occlusion and 5% dex-trose infusion on cardiac oultput, left ventricular dP/dt and dPIdt/P, mean aortic blood pressure, and total peripheral vascularresistance. Format and symbols are as in figure 1.

Arterial and Coronary Sinus PlasmaCatecholamine Concentrations

Plasma norepinephrine and epinephrine levels in-creased after coronary artery occlusion in both arterialand coronary sinus blood (table 1). Subsequent infu-sions of dobutamine and dextrose did not alter thecatecholamine concentrations. In contrast, dopaminesignificantly increased arterial and coronary sinus con-centrations of catecholamines (table 1, fig. 8). Theincrements at 24 hours after coronary artery occlusion,however, were smaller than those found 30 minutesafter occlusion. Figure 8 also shows that the differencebetween coronary sinus and arterial concentrations ofnorepinephrine was acutely increased only by dopa-mine, suggesting a net release of norepinephrine fromthe heart. In contrast, the difference between coronarysinus and arterial concentrations of epinephrine sug-gests a net uptake in the heart. There were no differ-ences between the three groups.

M 5% Dextrose

0 Dobutomine

a DopomineT

*r

FIGURE 4. Effects of5% dextrose, dobutamine and dopamineon cardiac output, left ventricular dPIdt, and dP/dt!P during thefirst 30 minutes of infusion. The effects are expressed as apercentage ofpreinfusion control values (averages of the fourvalues obtained 25-40 minutes after coronary artery occlu-sion). Bars show SEM. Asterisks indicate values that differ sig-nificantly from the dextrose group at p < 0.05.

Myocardial Infarct SizeThere were no differences in the weight of either the

left ventricle or the risk zone between the dextrose,dobutamine and dopamine groups (table 2). Infarctsize was smaller in the dobutamine group, regardlessof whether infarct size was expressed in terms of theactual weight of the infarcted region or as a percentageof the whole left ventricle or of the risk zone.

Regional Blood FlowsCoronary artery occlusion resulted in a decrease in

blood flow to kidney, lung, and the splanchnic circula-tion (table 3). Dobutamine infusion increased bloodflow and decreased vascular resistance in skeletal mus-

,e 150

100

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5 % Dextrose

M Dobutomine

U Dopomine

Cardioc Output Left Ventriculor dP/dt Left Ventricular dPIdt/P

FIGURE 5. Effects of5% dextrose, dobutamine and dopamineon cardiac output, left ventricular dPIdt, and dPldt/P 24 hoursafter coronary artery occlusion. The effects are expressed as apercentage ofpreinfusion control values obtained 25-40 min-utes after coronary artery occlusion. Bars show SEM. Asterisksindicate values that differ significantly from the dextrose groupat p < 0.05. Dagger signs denote values that differ significantlyfrom the dobutamine group.

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DOBUTAMINE AND DOPAMINE IN ACUTE MllMaekawa et al.

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ISCHEMIC REG/ONFIGURE 6. Epicardial and endocardial blood flows obtained30 minutes into the infusion of 5% dextrose, dobutamine, ordopamine. The left ventricle was divided into four regions,according to the endocardial blood flow immediately beforedrug infusions. Bars show SEM. There are no significant differ-ences in flow values between the three groups.

cle. In contrast, dopamine infusion did not changeskeletal muscle blood flow (fig. 9). Instead, dopamineincreased blood flow to kidney and adrenal gland, anddecreased renal and adrenal vascular resistance. Noneof these changes occurred in the group receiving 5%dextrose. No significant vascular changes occurred inthe splanchnic circulation.

DiscussionThe present study confirms our earlier report9 that

dobutamine improves global mechanical function ofthe heart during acute myocardial infarction, and fur-ther shows that the beneficial effects on cardiac func-tion persist during dobutamine infusion for 24 hoursafter the coronary occlusion. These salutary effects ofdobutamine are accompanied by increases in bloodflow to ischemic epicardium and a reduction in infarctsize. Our earlier study0 showed that blood flow in-creased to ischemic myocardium shortly after dobuta-mine infusion was started. In the present study, dobu-tamine did not produce an immediate increase inischemic myocardial blood flow. It was accompaniedby an increase in blood flow to the ischemic epicardi-um 24 hours after coronary artery occlusion, but whenmyocardial blood flow began to increase cannot bedetermined. However, since infarcts are usually com-pleted within 6 hours after coronary artery occlusion,30it appears likely that the collateral flow must haveincreased by dobutamine within the first several hoursof dobutamine infusion in our study. Later changes inflow are not likely to have significant effects on reduc-ing infarct size. The discrepancy in the timing of onsetof myocardial blood flow rise between the two studies

probably was related to the different doses. The dose ofdobutamine in the present study was only half that inthe earlier study. The increase in blood flow to ische-mic epicardium in preference to endocardium is con-sistent with the observation that native collateral ves-sels are more abundant in the epicardium than in theendocardium.31 Furthermore, dobutamine increasedblood flow to both ischemic and nonischemic myocar-dium, without effects on the ratio of ischemic tononischemic blood flow. This finding suggests thatdobutamine did not cause a "coronary steal" as itincreased blood flow to normal myocardium. Thus,the reduction in infarct size by dobutamine appears tobe causally related, at least in part, to the increase incollateral flow to ischemic myocardium. The mecha-nisms by which dobutamine increases collateral floware not known. Dobutamine has /3-receptor-mediatedvasodilator effects.4 In addition, the well-maintainedaortic blood pressure in the dobutamine group mayhave contributed to the relatively higher coronary per-fusion pressure for the coronary circulation comparedwith that of the dextrose group.

Neither coronary sinus norepinephrine concentra-tion nor the transmyocardial (coronary sinus minusaortic) norepinephrine concentration gradient de-creased during dobutamine infusion. Our results, how-

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FIGURE 7. Epicardial and endocardial blood flows obtained24 hours after coronary artery occlusion in the three groups thatreceived 5% dextrose, dobutamine, or dopamine. The left ven-tricle was divided intofour regions, according to their endocar-dial blood flow values obtained immediately before drug infu-sion. Bars show SEM. Asterisks indicate values that differsignificantly from the dextrose group; dagger signs indicatevalues that differ significantly from the dobutamine group.

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TABLE 1. Effects ofDobutamine, Dopamine and 5% Dextrose on Plasma Catecholamine Levels in Dogs After Coro-nary Artery Occlusion

Norepinephrine (ng/ml) Epinephrine (ng/ml)

Time Arterial Coronary sinus Arterial Coronary sinus

Group 1 - dobutamine0 0.42±0.09 0.44±0.05 0.93±0.18 0.26±0.05

40 min 0.54±0.08* 0.55±0.07* 1.53±0.34* 0.53±0.10*70 min 0.66 ± 0.13* 0.63 ± 0.07* 1.49 ± 0.30* 0.71 0.09*

24 hr 0.74±0.12* 0.89±0.07* 0.70±0.15 0.37 ±0.05

Group 2 - dopamine0 0.51 ±0.09 0.67±0.13 0.98±0.15 0.35±0.0740 min 0.79±0.13* 0.73±0.14 1.93±0.40* 0.71 ±0.30

70 min 2.27±0.39* 3.75±0.46* 2.82±0.43* 1.58±0.33*

24 hr 1.48±0.25* 1.64±0.29* 1.77±0.39 1.05±0.23*Group 3 - 5% dextrose

0 0.53±0.09 0.61 ±0.15 0.91 0.15 0.32±0.0540 min 0.68±0.11* 0.78±0.22 1.58±0.39* 0.48±0.1270 min 0.70±0.13* 0.69±0.19 1.76±0.49* 0.50±0.10

24 hr 0.71 ±0.06* 1.11 0.10* 0.73±0.08 0.30±0.04

Values are mean ± SEM. Asterisks indicate values that differ significantly from the control values (zero time) obtainedbefore coronary artery occlusion. The 40-minute values represent the effects of coronary artery occlusion, whereas theeffects of drug infusion are shown by the values obtained at 70 minutes and 24 hours after coronary artery occlusion.

Epinephrine

t01.5 t 35% Dextrose

'a,c : 5 llDobutamine~~~~Dopamine

0.5

0

-0. 5

X-1 . 5-

FIGURE 8. Acute effects of5% dextrose, dobutamine and dopa-mine infusion upon plasma catecholamines. (top) Changes inarterial plasma concentrations of norepinephrine and epineph-rine, obtained after 30 minutes of infusion, compared withpreinfusion values. (bottom) Coronary sinus minus arterialplasma concentration difference of norepinephrine and epi-nephrine. Bars show SEM. Asterisks indicate values that differsignificantly from the dextrose group; dagger signs indicatevalues that differ significantly from the dobutamine group.

ever, do not disprove Tuttle's hypothesis'0 that themyocardial salvage by dobutamine may result partlyfrom diminished release of norepinephrine from theischemic myocardium, because most of the coronarysinus blood came from nonischemic myocardium andonly a small fraction from the ischemic region. Signifi-cant changes in the amount of norepinephrine releasedfrom the ischemic myocardium might have beenmasked by norepinephrine-containing blood returningfrom nonischemic regions.Our results further indicate that unlike dobutamine,

dopamine affected neither cardiac function nor isch-emic myocardial blood flow 24 hours after coronaryarterial occlusion, although the acute cardiovasculareffects of dobutamine and dopamine during the initialinfusion were similar. Infarct size also was unaffected

TABLE 2. Effects ofDobutamine, Dopamine and5% Dextrose onInfarct Size

Dobuta- Dopa- 5% dex-mine mine trose

(n = 7) (n = 7) (n = 8) F

Left ventricleWeight (g) 46±4 55±4 55±4 1.63

Risk zone

Weight (g) 13 ± 1 18 ± 1 17± 1 3.13% left ventricle 30±3 34±3 31±2 0.57

Infarct sizeWeight (g) 7±1* 14±2 13± 1 6.69% left ventricle 16±2* 26 ± 3 23 ± 2 4.67% risk zone 55±4* 76±6 76±5 5.49

Values are mean ± SEM. The F values show that only infarct sizediffered in the three groups. Asterisks indicate values that differsignificantly from the dextrose group.

Norepinephrine

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TABLE 3. Effects ofAcute Coronary Artery Occlusion on OrganBlood Flows

Organ blood flow(mll 100g/min)

Organ Control OcclusionBrain 58±3 55±3Lungs (bronchial artery) 52 ± 7 34 ± 5*Right ventricle 88 ± 7 85 ± 7

Adrenal glands 295 ± 18 272 ± 20Kidneys 506± 22 396 ± 24*

Liver (hepatic artery) 37 ± 4 30 + 3*Stomach 41±4 31±5*Small intestine 46±4 38±3*Large intestine 64+6 53±4*Spleen 266 ± 21 260 ± 19Bladder 10±1 6±1*Pancreas 35 ± 4 32 ± 3Splanchnics 63 ±4 54 ± 3*Femoral muscle 5.1± 0.5 4.1± 0.5*Skin 3.0±0.3 3.4±0.4Bone 15±3 10±2*

Values are mean + SEM. N = 26.*p < 0.05 vs control (paired t test).

by dopamine infusion. The changes in plasma catechol-amine demonstrate that as expected, dopamine causeda release of endogenous catecholamines from bothsympathetic nerves endings and adrenal medulla. Incontrast, dobutamine, which, like isoproterenol, has alarge N-substituent group,32 is not taken up into thesympathetic nerve endings and does not cause releaseof endogenous norepinephrine. Dopamine produced anet release of norepinephrine from the heart. Norepi-nephrine probably was released from both the ischemic

150

100

50

Adrenal Glands

r* t

_

Splanchnics

150.

100

50-

FIGURE 9. Changes (percentage of preinfusion values) inblood flow and vascular resistance in skeletal muscle, adrenalglands, kidneys, and splanchnics after 30 minutes ofinfusion of5% dextrose, dobutamine, and dopamine. Bars show SEM. As-terisks indicate values that differ significantlyfrom the dextrosegroup; dagger signs indicate values that differ significantlyfromthe dobutamine group.

and nonischemic myocardium, because tissue norepi-nephrine was depleted in both of these regions afteracute myocardial infarction.33 This endogenously re-leased norepinephrine may produce a greater vasocon-strictor effect than circulating catecholamines .' Al-pha-receptor-mediated vasoconstriction could havelimited the increase in myocardial blood flow.36

In addition, endogenously released norepinephrinemay exert deleterious effect on the ischemic myocardi-um by its oxygen-wasting effects in the'mitochondria,and its actions causing calcium accumulation in thecardiac cell.'1 12 Myocardial cellular damage may beproduced in isolated rat heart by even small doses ofnorepinephrine released by hypoxia or myocardial in-farction.37 Furthermore, dopamine increases arterialconcentrations of free fatty acids22 'whereas dobuta-mine does not.4 Since myocardial lipolysis increasesmyocardial oxygen requirements, these effects of do-pamine are detrimental in the setting of acute myocar-dial ischemia.'2

Earlier studies in anesthetized, open-chest dogsshowed that dopamine exaggerated the ischemic in-jury, as evidenced by epicardial ST-segment eleva-tions.21' 22 On the other hand, our results in consciousdogs indicate that infarct size was not significantlyincreased by dopamine. This apparent discrepancymay be related in part to the use of anesthesia andopen-chest preparations by previous investigators. Inaddition, epicardial ST-segment elevation was used todetect acute effects of dobutamine in the earlier stud-ies, whereas infarct size was measured 24 hours laterin our experiments. Aggravation of ischemic insultduring the acute phase of myocardial ischemia mightnot necessarily produce a greater infarct size in ourpreparation because the infarct size, as expressed bypercent risk zone, was already nearly maximal in' thecontrol dextrose group (76%).38

Dobutamine improves myocardial mitochondrial ul-trastructure in patients with congestive cardiomyo-pathy.39 This may lead to better mitochondrial use ofoxygen and better recovery of depressed cardiac func-tion. The mechanism responsible for these biochemi-cal effects, however, is poorly understood.The diminished inotropic effects of dopamine 24

hours after coronary artery occlusion probably are re-lated to both the loss of viable myocardium and thedecrease in tissue catecholamine storage.33 Dopaminemight have enhanced the rate of norepinephrine deple-tion in the heart. Although depletion of norepinephrineby itself does not necessarily change intrinsic myocar-dial contractility,33 40 it would attenuate the inotropicresponse of the heart to indirectly acting adrenergicagents like dopamine.

Dobutamine and dopamine exert different effects onperipheral vasculature. Dobutamine increased skeletalmuscle blood flow. In contrast, dopamine increasedblood' flow to the kidneys and adrenal glands. Theincrease in renal blood flow probably is caused by thedopaminergic action of the drug.'6 The increase inadrenal blood flow was accompanied'by increases inplasma catecholamines, suggesting the blood flow re-

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sponse was closely coupled to the adrenal release ofcatecholamines. The mechanism for this change is notknown.

Both dobutamine and dopamine are useful inotropicagents in patients with heart failure. Dobutamine is apreferred agent to improve depressed myocardial per-formance in patients with low output cardiac failure34&and patients with acute myocardial infarction.42 Dobu-tamine produces favorable effects on hemodynamics inmost patients with acute myocardial infarction6 and inheart failure complicating coronary artery disease'without serious deleterious side effects. Nevertheless,dopamine may increase renal perfusion by its uniquedopaminergic action, not present with dobutamine.Our present study suggests that dobutamine is moreeffective than dopamine in producing sustained cardiacimprovement after acute myocardial infarction, andthat the norepinephrine-releasing property of dopa-mine may be detrimental to the ischemic myocardium.

AcknowledgmentThe authors thank Samuel Rivers, Stephanie Arnold, Debra Gins-

burg, Catherine H. Mesner, and Chhanda Panda for their excellenttechnical assistance. The following chemicals were generously suppliedby pharmaceutical companies: Indocyanine green (Cardio-Green) byHynson, Westcott and Dunning, Division of Becton, Dickinson andCompany, Baltimore, MD; dobutamine HCl (Dobutrex) by Lilly Re-search Laboratories, Indianapolis, IN.

References1. Tuttle RR, Mills J: Dobutamine. Development of a new catechol-

amine to selectively increase cardiac contractility. Circ Res 36:185, 1975

2. Hinds JE, Hawthorne EW: Comparative cardiac dynamic effects ofdobutamine and isoproterenol in conscious instrumented dogs. AmJ Cardiol 36: 894, 1975

3. Leier CV, Heban PT, Huss P, Bush CA, Lewis RP: Comparativesystemic and regional hemodynamic effects of dopamine and dobu-tamine in patients with cardiomyopathic heart failure. Circulation58: 466, 1978

4. Liang C, Hood WB Jr: Dobutamine infusion in conscious dogswith and without autonomic nervous system inhibition: effects onsystemic hemodynamics, regional blood flows and cardiac metab-olism. J Pharmacol Exp Ther 211: 698, 1979

5. Vatner SF, Baig H: Importance of heart rate in determining theeffects of sympathomimetic amines on regional myocardial func-tion and blood flow in conscious dogs with acute myocardial isch-emia. Circ Res 45: 793, 1979

6. Gillespie TA, Ambos HD, Sobel BE, Roberts R: Effects of dobuta-mine in patients with acute myocardial infarction. Am J Cardiol39: 588, 1977

7. Tubau JF, Bourassa MG, Cote P: Hemodynamic and metabolicchanges induced by dobutamine in patients with coronary disease.(abstr) Circulation 60 (suppl II): 11-41, 1979

8. Pozen RG, DiBianco R, Katz RJ, Bortz R, Myerburg RJ, FletcherRD: Myocardial metabolic and hemodynamic effects of dobuta-mine in heart failure complicating coronary artery disease. Circula-tion 63: 1279, 1981

9. Liang C, Yi JM, Sherman LG. Black J, Gavras H, Hood WB Jr:Dobutamine infusion in conscious dogs with and without acutemyocardial infarction. Effects on systemic hemodynamics, myo-cardial blood flow, and infarct size. Circ Res 49: 170, 1981

10. Tuttle RR: The experimental basis for using dobutamine in acutemyocardial infarction. In Proceedings: European DobutamineSymposium, edited by A Glynne, RA Lucas. London, Guy's Hos-pital, 1978, pp 58-67

11. Ceremuzyfiski L: Hormonal and metabolic reactions evoked byacute myocardial infarction. Circ Res 48: 767, 1981

12. Opie LH: Myocardial infarct size. Part I. Basic considerations. AmHeart J 100: 355, 1980

13. Crexells C, Bourassa MG, Biron P: Effects of dopamine on myo-cardial metabolism in patients with ischemic heart disease. Cardio-vasc Res 7: 438, 1973

14. Goldberg LI, Hsieh Y, Resnekov L: Newer catecholamines fortreatment of heart failure and shock: an update on dopamine and afirst look at dobutamine. Prog Cardiovasc Dis 19: 327, 1977

15. Tsai TH, Langer SZ, Trendelenburg U: Effects of dopamine and ,B-methyl-dopamine on smooth muscle and on the cardiac pacemaker.J Pharmacol Exp Ther 156: 310, 1967

16. Goldberg LI: Cardiovascular and renal actions of dopamine: poten-tial clinical applications. Pharmacol Rev 24: 1, 1972

17. Kho TL, Henquet JW, Punt R, Birkenhager WH, Rahn KH: Influ-ence of dobutamine and dopamine on hemodynamics and plasmaconcentrations of noradrenaline and renin in patients with lowcardiac output following acute myocardial infarction. Eur J ClinPharmacol 18: 213, 1980

18. Robie NW, Nutter DO, Moody C, McNay JL: In vivo analysis ofadrenergic receptor activity of dobutamine. Circ Res 34: 663, 1974

19. Sonnenblick EH, Frishman WH, LeJemtel TH: Dobutamine: a newsynthetic cardioactive sympathetic amine. N Engl J Med 300: 17,1979

20. Nash CW, Wolff SA, Ferguson BA: Release of tritiated noradrena-line from perfused rat hearts by sympathomimetic amines. Can JPhysiol Pharmacol 46: 35, 1968

21. Reid P, Pitt B, Kelly D: Effects of dopamine on increasing infarctarea in acute myocardial infarction. (abstr) Circulation 46 (supplII): 11-210. 1972

22. Lekven J, Semb G: Effect of dopamine and calcium on lipolysisand myocardial ischemic injury following acute coronary occlusionin the dog. Circ Res 34: 349, 1974

23. Heymann MA, Payne BD, Hoffman Jl, Rudolph AM: Blood flowmeasurements with radionuclide-labeled particles. Prog Cardio-vasc Dis 20: 55, 1977

24. Liang C: Metabolic control of circulation. Effects of iodoacetateand fluoroacetate. J Clin Invest 60: 61, 1977

25. Peuler JD, Johnson GA: Simultaneous single isotope radioenzyma-tic assay of plasma norepinephrine, epinephrine and dopamine.Life Sci 21: 625, 1977

26. Lowe JE, Reimer KA, Jennings RB: Experimental infarct size as afunction of the amount of myocardium at risk. Am J Pathol 90:363, 1978

27. Nachlas MM, Shnitka TK: Macroscopic identification of earlymyocardial infarcts by alterations in dehydrogenase activity. Am JPathol 42: 379, 1963

28. Winer BT: Statistical Principles in Experimental Design, 2nd ed.New York, McGraw-Hill, pp 261, 1971

29. Dunnett CW: New tables for multiple comparisons with a control.Biometrics 20: 482, 1964

30. Reimer KA, Jennings RB: The "wavefront phenomenon" of myo-cardial ischemic cell death. II. Transmural progression of necrosiswithin the framework of ischemic bed size (myocardium at risk)and collateral flow. Lab Invest 40: 633, 1979

31. Schaper W: The morphology of collaterals and anastomoses inhuman, canine and porcine hearts. In The Collateral Circulation ofthe Heart, edited by DAK Black. New York, American ElsevierPublishing, 1971, pp 5-18

32. Iversen LL: Catecholamine uptake processes. Br Med Bull 29:130, 1973

33. Mathes P, Cowan C. Gudbjarnason S: Storage and metabolism ofnorepinephrine after experimental myocardial infarction. Am JPhysiol 220: 27, 1971

34. Glick G, Epstein SE, Wechsler AS, Braunwald E: Physiologicaldifferences between the effects of neuronally released and blood-borne norepinephrine on beta adrenergic receptors in the arterialbed of the dog. Circ Res 21: 217, 1967

35. Russell MP, Moran NC: Evidence for lack of innervation of /3-2adrenoceptors in the blood vessels of the gracilis muscle of the dog.Circ Res 46: 344, 1980

36. Mohrman DE, Feigl EO: Competition between sympathetic vaso-constriction and metabolic vasodilation in the canine coronary cir-culation. Circ Res 42: 79, 1978

37. Waldenstrom AP, Hjalmarson AC, Thornell L: A possible role of

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LV FUNCTION AND INFARCT SIZE BY CTT/Slutsky et al.

noradrenaline in the development of myocardial infarction. Anexperimental study in the isolated rat heart. Am Heart J 95: 43,1978

38. Vokonas PS, Malsky PM, Paul SJ, Robbins SL, Hood WB Jr:Radioautographic studies in experimental myocardial infarction:profiles of ischemic blood flow and quantification of infarct size inrelation to magnitude of ischemic zone. Am J Cardiol 42: 67, 1978

39. Unverferth DV, Leier CV, Magorien RD, Croskery R, SvirbelyJR, Kolibash AJ, Dick MR, Meacham JA, Baba N: Improvementof human myocardial mitochondria after dobutamine: a quantita-

tive ultrastructural study. J Pharmacol Exp Ther 215: 527, 198040. Spann JF, Sonnenblick EH, Cooper T, Chidsey CA, William VL,

Braunwald E: Cardiac norepinephrine stores and the contractilestate of heart muscle. Circ Res 19: 317, 1966

41. Loeb HS, Bredakis J, Gunnar RM: Superiority of dobutamine overdopamine for augmentation of cardiac output in patients withchronic low output cardiac failure. Circulation 55: 375, 1977

42. Keung ECH, Siskind SJ, Sonnenblick EH, Ribner HS, SchwartzWJ, LeJemtel TH: Dobutamine therapy in acute myocardial infarc-tion. JAMA 245: 144, 1981

In Vivo Estimation of Myocardial Infarct Size andLeft Ventricular Function by Prospectively Gated

Computerized Transmission TomographyROBERT A. SLUTSKY, M.D., ROBERT F. MATTREY, M.D., STEPHEN A. LONG,

AND CHARLES B. HIGGINS, M.D.

SUMMARY We evaluated 11 dogs using computerized transmission tomography (CTT); eight werestudied after coronary occlusion and three served as sham controls. Ungated scans (1 cm deep) of the leftventricle (LV) were obtained from LV apex to base to determine infarct size (IS). At the middle LV level,prospectively gated scans were obtained to determine LV function. In all infarct dogs, contrast mediumenhancement of the entire infarct or the periphery of the infarct occurred. Autopsy IS was compared withthe IS by CTT using either the inner (IM) or outer margin (OM) of the contrast-enhanced periphery of theinfarcts as the border of the infarct. IS by both CTT techniques correlated well with autopsy IS (r = 0.89 forIM; r = 0.93 for OM). The estimate usingOM (26.5 + 12 g) gave IS sizes similar to autopsy values (25.5 +11.7 g), but IS derived using IM (14.1 8.0 g) underestimated autopsy values by approximately 45% (p <0.01). From the prospectively gated CTT images, we calculated mid-LV end-diastolic (EDA) and end-systolic areas (ESA) as well as percent area change before and after coronary occlusion. EDA increasedfrom 17.0 + 5.3 cm2 to 23.7 + 7.6 cm2 (p < 0.05). ESA increased from 12.1 + 4.1 cm2 to 18.6 7.2 cm2 (p< 0.05), and percent area change decreased from 29.3 5.0% to 21.7 9.9% (p < 0.05).We conclude that CTT imaging can reliably estimate IS, particularly when the area of rim enhancement

of the infarct is included within the presumed infarct region. Estimates of chamber function can be madefrom gated CTT scans. Anterior myocardial infarctions produce left ventricular dilatation with reducedchamber function, which can be detected by gated CTT scans.

QUANTITATION of myocardial infarct size is impor-tant in assessing clinical prognosis after infarction andin evaluating the effects of interventions designed toreduce the myocardial damage during ischemia.'-5 Exvivo studies have shown that computerized transmis-sion tomography (CTT) can be used to accuratelyquantitate irreversibly damaged myocardial tissue.6-9Recent reports have also shown the ability of CTT toquantitate infarct size in vivo, though the method var-ied in each study.'0 1 The present study was designedto define the accuracy of CTT scans for quantitating

From the Department of Radiology, University of California, SanDiego Medical Center and the San Diego Veterans AdministrationMedical Center, San Diego, California.

Supported in part by the Research Service of the Veterans Adminis-tration and by grant (SCOR) HL-24922-01 from the NIH.

Dr. Higgins is recipient of USPHS Career Development Award K04HL-2001 from the NHLBI.

Address for correspondence: Robert A. Slutsky, M.D., VeteransAdministration Medical Center (114), 3350 La Jolla Village Drive, SanDiego, California 92161.

Received October 25, 1982; revision accepted November 23, 1982.Circulation 67, No. 4, 1983.

infarct volume and to compare two CTT methods ofassessing myocardial infarct size with autopsy values;we also used CTT to characterize middle left ventricu-lar (LV) chamber dynamics before and after coronaryocclusion by prospective ECG gating and evaluatedthe variability in estimates of cardiac function by pro-spective ECG gating of CTT images obtained on twodifferent days.

MethodsExperimental Model

Eleven conditioned mongrel dogs (mean weight 28± 4 kg) constituted the study population. Each dogwas given subcutaneous morphine sulfate, 3 mg/kg,and then anesthetized with i.v. pentobarbital, 25 mg/kg. Through a left thoracotomy, a hydraulic coronaryoccluder was placed around the proximal left anteriordescending artery, and in four dogs an injection cath-eter was placed into the left atrial appendage. Thecatheters were burrowed subcutaneously and external-ized. The wound was closed aseptically and the dogswere allowed to recover. Control CTT scans were ob-

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K Maekawa, C S Liang and W B Hood, Jrsystemic hemodynamics, plasma catecholamines, blood flows and infarct size.

Comparison of dobutamine and dopamine in acute myocardial infarction. Effects of

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