Comparison of Dobutamine and Dopamine in

Acute Myocardial Infarction

Effects 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 two
agents at a dose of 10 gpg/kg/min i.v. to two groups of chronically instrumented conscious dogs, beginning 40
minutes after coronary artery occlusion and continuing for 24 hours thereafter. A control group that was
given an infusion of 5% dextrose was also studied. During the first 30 minutes of infusion, both dobutamine
and dopamine produced similar increases in cardiac output, left ventricular dP/dt and dP/dt/P, without
significant changes in heart rate, mean arterial blood pressure or regional myocardial blood flow. At 24
hours, cardiac output and left ventricular dP/dt and dP/dt/P continued to be greater in the dobutamine
group than in the control group. The acute positive inotropic effects of dopamine were no longer apparent at
24 hours. Epicardial blood flow in the dobutamine-treated group also was higher than that in the control
group. There were, however, no differences between groups in the ischemic-to-nonischemic myocardial
blood flow ratio. In addition, infarct size, measured by nitroblue tetrazolium staining, was smaller in the
dobutamine 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 postocclusion
baseline 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 transmyocardial
gradient (coronary sinus minus arterial difference) of 1.48 + 0.27 ng/mI. The results show that dobutamine
increases collateral flow to the ischemic myocardium, enhances left ventricular performance, and reduces
infarct size. None of these effects were produced by dopamine under these experimental conditions. The
difference between the effects of the two drugs probably is related, at least in part, to the detrimental effects
of local myocardial release of norepinephrine by dopamine.

DOBUTAMINE is a cardioselective adrenergic agent chemic myocardium because it has both /3-receptor-
Downloaded from http://ahajournals.org by on December 11, 2019

that augments myocardial contractility, cardiac output
and myocardial blood flow with only minimal changes
in heart rate or arterial blood pressure. '-5 It may be used
clinically to improve depressed cardiac function with-
out further impairment of oxygen balance or metabo-
lism of the ischemic heart.6` Dobutamine not only
improves the global performance of the heart, but also
reduces infarct size during acute experimental myocar-
dial infarction.9 These salutary effects probably are
causally related to the increase in ischemic myocardial
blood flow produced by dobutamine. However, Tut-
tle'0 showed that a reduction of myocardial necrosis by
dobutamine was accompanied not only by an increase
in myocardial blood flow, but also by a reduction in the
amount of norepinephrine released from cardiac sym-
pathetic fibers that was facilitated after myocardial
ischemia. 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 the
Department of Medicine and Thorndike Memorial Laboratory, Boston
City 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 of
Rochester Medical Center, Cardiology Unit, Box 679, Rochester, New
York 14642.
Received September 16, 1982; accepted November 15, 1982.
Circulation 67, No. 4, 1983.
750
mediated inotropic and metabolic effects that would
increase 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 protective
effect of dobutamine on ischemic myocardium.
Like dobutamine, dopamine is a commonly used
inotropic agent. Although dobutamine and dopamine
have similar acute cardiac effects,513' '4 it probably is
not appropriate to generalize the salutary effects of
dobutamine on infarct size to dopamine, because their
mechanisms of actions as sympathomimetic amines
are different.1l 1'-' Dobutamine acts directly on adren-
ergic receptors, whereas dopamine exerts its adrener-
gic action both directly on adrenergic receptors and
indirectly by releasing norepinephrine from sympa-
thetic nerve endings.20 Dopamine's potential action of
releasing norepinephrine from the heart is in contrast to
the reduction in myocardial release of norepinephrine
produced by dobutamine.'0 Therefore, it appears that
dopamine may not have the same salutary effects as
dobutamine in acute myocardial infarction. Indeed,
dopamine has been shown to increase ischemic injury,
as measured by epicardial ST-segment elevation.21 22
The effects of dopamine on infarct size have never
been studied.
In the present study, we compared the effects of
dobutamine and dopamine on systemic hemodynam-
ics, myocardial blood flow, and infarct size in the
conscious dog with acute myocardial infarction.
 DOBUTAMINE AND DOPAMINE IN ACUTE MI/Maekawa et al.
Methods
Adult beagle dogs that weighed 6.9-17.8 kg were
studied in a conscious state. Two to 3 weeks before the
experiment, a sterile left thoracotomy was made under
anesthesia 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 left
anterior descending coronary artery isolated for im-
plantation of a Silastic balloon occluder (3.5 mm i.d.)
immediately distal to the first diagonal branch. Normal
saline was infused transiently into the balloon, and the
amount of saline that caused complete occlusion of the
coronary artery was determined. Heparin-filled Tygon
catheters (1.02 mm i.d.) were inserted into the main
pulmonary artery, left atrium and descending thoracic
aorta. The catheters and the occluder tubing were then
tunneled through the interscapular space and secured
externally at the back of the neck. After the wound was
closed, the dog was returned to the animal quarters and
given 400,000 U of procaine penicillin and 500 mg of
dihydrostreptomycin sulfate (Combiotics, i.m.; Pfizer
Pharmaceutical 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 ECG
was 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 the
coronary sinus through an external jugular vein and a
Downloaded from http://ahajournals.org by on December 11, 2019
high-fidelity transducer-tip catheter (Millar Instru-
ments Inc.) in the left ventricular cavity through a
femoral 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 Calculations
The intravascular catheters were connected to Sta-
tham P23Db pressure transducers and a Brush 480
eight-channel recorder (Gould, Inc., Instrument Sys-
tem Division). The Millar catheter was also connected
to the Brush 480 recorder for measuring left ventricular
pressure, and electronically differentiated maximal
rate of left ventricular pressure rise (dP/dt). In addi-
tion, the ratio of left ventricular dP/dt to a developed
left ventricular pressure of 50 mm Hg occurring during
isovolumic systole was calculated using a PDP- 11/10
minicomputer (Digital Equipment Corporation). Heart
rate was calculated from the ECG. Cardiac output was
measured by the indocyanine green (Cardio-Green;
Hynson, Westcott and Dunning, Inc.) dilution method
with a Gilford model 140 cardiac output system (Gil-
ford Instrument Laboratories, Inc.). Stroke volume
and total peripheral vascular resistance were calculated
using conventional formulas.
Organ blood flows were measured by the radio-
active microsphere method.23 24 Radioactive micro-
spheres (New England Nuclear), 15 + 3 mg in
diameter and labeled with cerium- 141, tin- 113, ruthen-
ium-103, and scandium-46 at a specific activity of 10
751
mCi/g, were suspended in a 10% dextran solution con-
taining 0.01% Tween-80 and adequately sonicated
before use. For flow measurements before coronary
artery occlusion, 500,000-750,000 microspheres were
injected into the left atrium followed by a 10-ml normal
saline flush over a 30-second period; 1-1.5 million
microspheres were used after coronary artery occlu-
sion. Arterial reference blood was collected for 90
seconds at a rate of 7.75 ml/min using a Harvard pump
beginning 10 seconds before the commencement of
microsphere injection. After the experiment, coronary
angiography was performed; the dog was given hep-
arin and killed with a lethal dose of a sodium pentobar-
bital. Organs were removed, cleaned, weighed, and
prepared for radioactivity counting. Tissue and blood
samples were counted for radioactivity using a Packard
gamma spectrometer at window settings correspond-
ing to the peak energies of the nuclides used. The
activity of each isotope was corrected for background
and crossover activities from other isotopes. Organ
blood flow was calculated on the PDP- 1 1/10 minicom-
puter using the reference sample method: organ blood
flow (m1l1O0g/min) = (arterial reference blood flow
[ml/min] X tissue nuclide activity x 100)/ (arterial
reference blood nuclide activity x tissue weight [g]).
Mean aortic blood pressure was divided by organ
blood flow to obtain the regional organ vascular
resistance.
Blood samples were taken simultaneously from the
aorta and coronary sinus for measuring plasma cate-
cholamine concentrations, using a radioenzymatic
method.25
The heart was removed for determination of risk
zone and infarct size. The left anterior descending
coronary artery was cannulated at the site of the bal-
loon occluder and the left main and right coronary
arteries were cannulated through their respective ostia.
The heart was then perfused for 15 minutes under a
constant pressure of 100 mm Hg with a 1% Monastral
Red dye solution (E.I. du Pont, de Nemours & Co.,
Inc.) into the left anterior descending artery and a
0.5% Monastral Blue dye solution into the other two
catheters. 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 the
heart and cut transversely into six or seven slices ap-
proximately 6-7 mm thick. Each slice was weighed
and photographed and immersed in a nitroblue tetrazo-
lium solution for 15 minutes at 37°C. (Nitroblue tetra-
zolium is a marker for tissue dehydrogenase27 that
stains noninfarcted viable tissue blue and leaves in-
farcted areas unstained.) Both sides of the left ventric-
ular slices were then rephotographed. The risk and
infarct zones were planimetered on each photograph,
and the percent risk or infarct size relative to the entire
slice was determined by averaging the percent values
for both the apical and basal sections of that slice. The
weight for the risk or infarcted portion of the slice was
obtained by multiplying the average percent value and
 752 CIRCULATION
the weight of the slice. The weights for all the slices
were than added up to determine the total risk region
and infarct size. Finally, left ventricular slices were cut
into 42-50 myocardial segments, which were divided
into endocardial and epicardial halves. These pieces
were then weighed and counted for radioactivity and
regional blood flow measurements. Left ventricular
transmural segments were grouped into four regions
according to their endocardial blood flows determined
40 minutes after coronary artery occlusion. Trans-
mural segments with endocardial blood flow less than
25 ml/100 g/min were designated as severely ische-
mic. Segments with endocardial blood flows of 25-50
ml/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 Protocol
Dogs were divided into three groups according to
drug assignments: dobutamine (10 ,ug/kg/min), dopa-
mine (10 ,ug/ml/min), and 5% dextrose solution. The
drugs were administered randomly to dogs. The rest of
the protocols was identical in the three groups.
After a 30-minute control period, the left anterior
descending coronary artery was occluded by inflating
the previously implanted balloon occluder with a pre-
determined amount of normal saline. Systemic hemo-
dynamics, including cardiac output, heart rate, aortic
blood pressure, left atrial pressure, and left ventricular
dP/dt and dP/dt/P, were measured at 5-10-minute in-
Downloaded from http://ahajournals.org by on December 11, 2019
tervals during the control period and in the first 40
minutes after coronary artery occlusion. Microsphere
organ blood flows and plasma catecholamine levels
were measured immediately before and 40 minutes
after coronary artery occlusion.
Beginning 40 minutes after coronary artery occlu-
sion, one of the three drug solutions was infused in
each group at a rate of 0.19 ml/min for 30 minutes
using 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 additional
23 hours at a rate of 0.9 ml/hour, using a battery-
operated Sigmamotor mobile infusion pump (Sigma-
motor, Inc.) as previously described.9
On 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. The
amount of the drug delivered from the infusion bag
over the experimental period was verified by subtract-
ing the weight of the bag after the infusion from that
before the infusion.
Statistical Analysis
The experimental results are given as mean ± SEM.
The statistical significance of the difference between
VOL 67, No 4, APRIL 1983
the three experimental groups was determined by two-
way analysis of variance for independent groups with
repeated measures.28 Dunnett's test29 was used to de-
termine the significance of differences between the
preocclusion control and the serial repeated measure-
ments after coronary artery occlusion in each group.
The t test was used to analyze the difference between
two means; p < 0.05 was considered significant.
Results
Coronary artery occlusion was successfully pro-
duced in 31 dogs, as shown by coronary angiography
and postmortem examination on the second day of the
experiment. All dogs showed evidence of acute myo-
cardial ischemia in the first hour after coronary artery
occlusion, including electrocardiographic ST-segment
elevation and decreased left ventricular dP/dt. Five
dogs were excluded from the study: one dog died
shortly after coronary artery occlusion, before the drug
infusion, and four dogs died during the drug infusion
(two dogs received dobutamine, one dopamine and
one 5% dextrose). Eight of the remaining dogs (1 1 ± 1
kg) received dobutamine, eight (12 ± 1 kg) dopamine
and 10 (11 ±- 1 kg) 5% dextrose.
Systemic Hemodynamics
Acute coronary artery occlusion produced similar
changes in systemic hemodynamics in all three groups
(figs. 1-3). There was a decrease in cardiac output and
left ventricular dP/dt and dP/dt/P, and an increase in
heart rate. Mean aortic blood pressure did not change
significantly, while total peripheral vascular resistance
increased 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 hemodynamic
variables 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 in
both groups. Cardiac output also increased slightly
above the values before drug infusion (fig. 4), but did
not differ significantly from the preocclusion controls.
The changes in cardiac output and left ventricular dP/dt
and dP/dt/P were of similar magnitude in the two
groups (fig. 4). In addition, total peripheral vascular
resistance did not change significantly from the preoc-
clusion controls in two groups. Heart rate also did not
change significantly from the preocclusion control
during dobutamine infusion, but was higher than the
control value during dopamine infusion. Dextrose in-
fusion did not affect any of the hemodynamic re-
sponses to acute coronary occlusion. Mean left atrial
pressure decreased from 4.7 ± 1.0 to 3.4 ± 0.9 mm
Hg (p < 0.05) during dobutamine infusion, but did
not change significantly during dopamine infusion
(6.7 + 1.4 to 7.6 ± 2.2 mm Hg) or 5% dextrose
infusion (4.0 ± 1.0 to 3.7 + 0.8 mm Hg). Stroke
volume increased only during dobutamine infusion
(18 ± I to 20 ± 1 ml, p <0.05).
At 24 hours after coronary artery occlusion, all dogs
 DOBUTAMINE AND DOPAMINE IN ACUTE MI/Maekawa et al. 753

DOBUTAMINE Myocardial Blood Flows

0_---,2 D Myocardial blood flow decreased transmurally after
fl200 scoronary
| :] occlusion; the greater decline was in the en-
\ 3 Io150.t docardial segment. There was no difference between
} ;-,;1125 i
e _4> 100-
the three groups. During the first 30 minutes of infu-
sion, neither dobutamine nor dopamine significantly
i~ 2 t'- __ 2 I ' altered myocardial blood flow (fig. 6). At 24 hours,
' however, myocardial blood flow increased markedly
and was significantly higher in the dobutamine group
25 in all ischemic epicardial segments and in nonischemic
myocardium than in the control group (fig. 7). There
5000 * |was no difference in myocardial blood flow between
50000 T \ I 0 the dopamine group and the control group.
The ischemic/nonischemic myocardial blood flow
W
| 4000Lk
4000
{|. N
1/l/ /\ I\; \ MQ 50 t M
\
ratio
Eat
Z24|
did differ in the three
50nogrus
hours, except for the mildly
not
either ateyr
ischemic region
or
at 24
roups acutely
40
\ 4 lhours, when the ratio was greater in the dobutamine
> -Yz-?d

15 . 3 :tsa --
1C, 3000 40 group (0.78 + 0.03) than in the dextrose group (0.58
+0.07,p <0.05).

1. Effects of oroar areryocluson nddobta2

FIGURE
-~~~~ ~~~ cI.c,~~~~~~~~~~.
150 i
~ ~ ~~

600-
I

I
- ~~~~~~~~~~~~~~~~~~~DOPAMINE

I
Lj~~~~~~.~~~~125
~~~~~~~~~~~~~~~~~~~~~~~~~~~
100

0 06 0 X2200
Zk ~~~~~~~~~~~~~~~75
50~~~~~~~~~~~~~50
Downloaded from http://ahajournals.org by on December 11, 2019

mine infusion on cardiac output, heart rate, left ventricular dPI } 4''')1
I \
dtanddP/dt/P,meanaorticbloodpressureandtotalperipheral 5000
vascular resistance. The abscissa denotes time after coronary K \'s t
artery occlusion, and the baseline values are shown at zero 404000
'
time. Bars indicate SEM. Asterisks show the values that differ
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 not
differ from the preocclusion or preinfusion controls in
the dextrose and dopamine groups, but it was higher in
the dobutamine group (figs. 1-3 and 5). Left ventricu- E
ol6000
o So
E
lar dP/dt and dP/dtIP fell below the levels seen during&
the initial infusion of the drugs in all three groups and 100 I!0
lower than the preocclusion control in the dextrose and
dopamine groups. Similary, left ventricular dP/dt de- 4000
creased below preocclusion values in the dobutamine
group, but left ventricular dP/dt/P did not fall below its
preocclusion control (fig. 1). The absolute values of I I
left ventricular dP/dt and dP/dt/P were lowest in the 10 20 30 40 50 60 70 24
0
group infused with 5% dextrose (fig. 3). When these MINUTES HRS
values at 24 hours of infusion were calculated as a FIGURE 2. Effects of coronary artery occlusion and dopamine
percentage of preinfusion controls, the values in the infusion on cardiac output, heart rate, left ventricular dPIdt
dobutamine group were significantly higher than those and dPIdtIP, mean aortic blood pressure and total peripheral
in the dopamine and control groups (fig. 5). vascular resistance. Format and symbols are as in figure 1.
 754 CIRCULATION VOL 67, No 4, APRIL 1983

M 5% Dextrose

0 Dobutomine

a Dopomine T
150
Li)

*r

tz,
010
'io
(.0

M 50

FIGURE 4. Effects of 5% dextrose, dobutamine and dopamine

on cardiac output, left ventricular dPIdt, and dP/dt!P during the
'
first 30 minutes of infusion. The effects are expressed as a
percentage ofpreinfusion control values (averages of the four
3000
values obtained 25-40 minutes after coronary artery occlu-
sion). Bars show SEM. Asterisks indicate values that differ sig-
2000 nificantly from the dextrose group at p < 0.05.

30 Myocardial Infarct Size

There were no differences in the weight of either the
left ventricle or the risk zone between the dextrose,
dobutamine and dopamine groups (table 2). Infarct
size was smaller in the dobutamine group, regardless
100 ---X{-+i--4 _- }
I >-
50
6000oLC
rit of whether infarct size was expressed in terms of the
K~~~~~~~~~~~~~~~~~~~~~K actual weight of the infarcted region or as a percentage
of the whole left ventricle or of the risk zone.
Downloaded from http://ahajournals.org by on December 11, 2019

Regional Blood Flows

Coronary artery occlusion resulted in a decrease in
blood flow to kidney, lung, and the splanchnic circula-
0 10 20 30 40 50 60 70 24
MINUTES lIPS tion (table 3). Dobutamine infusion increased blood
flow and decreased vascular resistance in skeletal mus-
FIGURE 3. Effects of coronary artery occlusion and 5% dex-
trose infusion on cardiac oultput, left ventricular dP/dt and dPI
dt/P, mean aortic blood pressure, and total peripheral vascular 5 % Dextrose
resistance. Format and symbols are as in figure 1. M Dobutomine
U Dopomine
,e 150
Arterial and Coronary Sinus Plasma
Catecholamine Concentrations
Plasma norepinephrine and epinephrine levels in-
creased after coronary artery occlusion in both arterial 100

and coronary sinus blood (table 1). Subsequent infu-

sions of dobutamine and dextrose did not alter the
catecholamine concentrations. In contrast, dopamine \ 50

significantly increased arterial and coronary sinus con-

centrations of catecholamines (table 1, fig. 8). The
increments at 24 hours after coronary artery occlusion, O-
however, were smaller than those found 30 minutes Cardioc Output Left Ventriculor dP/dt Left Ventricular dPIdt/P

after occlusion. Figure 8 also shows that the difference
between coronary sinus and arterial concentrations of
norepinephrine was acutely increased only by dopa-
mine, suggesting a net release of norepinephrine from
the heart. In contrast, the difference between coronary
sinus and arterial concentrations of epinephrine sug-
gests a net uptake in the heart. There were no differ-
ences between the three groups.
FIGURE 5. Effects of 5% dextrose, dobutamine and dopamine
on cardiac output, left ventricular dPIdt, and dPldt/P 24 hours
after coronary artery occlusion. The effects are expressed as a
percentage of preinfusion control values obtained 25-40 min-
utes after coronary artery occlusion. Bars show SEM. Asterisks
indicate values that differ significantly from the dextrose group
at p < 0.05. Dagger signs denote values that differ significantly
from the dobutamine group.
 DOBUTAMINE AND DOPAMINE IN ACUTE MllMaekawa et al. 755

EP/CARD/UM probably was related to the different doses. The dose of

300 F dobutamine in the present study was only half that in
5 % Dextrose the earlier study. The increase in blood flow to ische-
E Dobutomine
T
mic epicardium in preference to endocardium is con-
f0 200k Dopomine sistent with the observation that native collateral ves-
sels are more abundant in the epicardium than in the
*~
Q0
endocardium.31 Furthermore, dobutamine increased
t4Z~ 100_ blood flow to both ischemic and nonischemic myocar-
dium, without effects on the ratio of ischemic to
300
F. nonischemic blood flow. This finding suggests that
dobutamine did not cause a "coronary steal" as it
FEA/LOCARi2/UM increased blood flow to normal myocardium. Thus,
czi the reduction in infarct size by dobutamine appears to
0; 200k be causally related, at least in part, to the increase in
collateral flow to ischemic myocardium. The mecha-
nisms by which dobutamine increases collateral flow
100o are not known. Dobutamine has /3-receptor-mediated
vasodilator effects.4 In addition, the well-maintained
aortic blood pressure in the dobutamine group may
SEVERELY MODERATELY MILULY N4UN - have contributed to the relatively higher coronary per-
ISCHEMIC REG/ON fusion pressure for the coronary circulation compared
FIGURE 6. Epicardial and endocardial blood flows obtained with that of the dextrose group.
30 minutes into the infusion of 5% dextrose, dobutamine, or Neither coronary sinus norepinephrine concentra-
dopamine. The left ventricle was divided into four regions, tion nor the transmyocardial (coronary sinus minus
according to the endocardial blood flow immediately before aortic) norepinephrine concentration gradient de-
drug infusions. Bars show SEM. There are no significant differ- creased during dobutamine infusion. Our results, how-
ences in flow values between the three groups. ann.s ,
EP/CARL//M T
cle. In contrast, dopamine infusion did not change
skeletal muscle blood flow (fig. 9). Instead, dopamine 300k
D] 5 % Dextrose
E Dobutomine
increased blood flow to kidney and adrenal gland, and
Downloaded from http://ahajournals.org by on December 11, 2019

decreased renal and adrenal vascular resistance. None a Dopamine

of these changes occurred in the group receiving 5% 200k
dextrose. No significant vascular changes occurred in
the splanchnic circulation.
0r 100k
Discussion 0z0~
The present study confirms our earlier report9 that -Ih

dobutamine improves global mechanical function of Q: E//DOCARD/UM

the heart during acute myocardial infarction, and fur- 01~ 400k T*
ther shows that the beneficial effects on cardiac func-
tion persist during dobutamine infusion for 24 hours
after the coronary occlusion. These salutary effects of 300k
dobutamine are accompanied by increases in blood
flow to ischemic epicardium and a reduction in infarct 200t
size. Our earlier study0 showed that blood flow in-
creased to ischemic myocardium shortly after dobuta-
mine infusion was started. In the present study, dobu- 100
tamine did not produce an immediate increase in
ischemic myocardial blood flow. It was accompanied
by an increase in blood flow to the ischemic epicardi- T
SEVERELY MOD3ERATELY MILDLY
um 24 hours after coronary artery occlusion, but when
1llISCHEM/C REG/ON
myocardial blood flow began to increase cannot be
determined. However, since infarcts are usually com- FIGURE 7. Epicardial and endocardial blood flows obtained
pleted within 6 hours after coronary artery occlusion,30 24 hours after coronary artery occlusion in the three groups that
it appears likely that the collateral flow must have received 5% dextrose, dobutamine, or dopamine. The left ven-
increased by dobutamine within the first several hours tricle was divided intofour regions, according to their endocar-
of dobutamine infusion in our study. Later changes in dial blood flow values obtained immediately before drug infu-
flow are not likely to have significant effects on reduc- sion. Bars show SEM. Asterisks indicate values that differ
ing infarct size. The discrepancy in the timing of onset significantly from the dextrose group; dagger signs indicate
of myocardial blood flow rise between the two studies values that differ significantly from the dobutamine group.
 756 CIRCULATION VOL 67, No 4, APRIL 1983

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 - dobutamine
0 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 - dopamine
0 0.51 ±0.09 0.67±0.13 0.98±0.15 0.35±0.07
40 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±0.05
40 min 0.68±0.11* 0.78±0.22 1.58±0.39* 0.48±0.12
70 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) obtained
before coronary artery occlusion. The 40-minute values represent the effects of coronary artery occlusion, whereas the
effects of drug infusion are shown by the values obtained at 70 minutes and 24 hours after coronary artery occlusion.

Norepinephrine Epinephrine ever, do not disprove Tuttle's hypothesis'0 that the

Es1 myocardial salvage by dobutamine may result partly
rEs from diminished release of norepinephrine from the
'a.0i ischemic myocardium, because most of the coronary
q) sinus blood came from nonischemic myocardium and
Downloaded from http://ahajournals.org by on December 11, 2019

'4
C'a only a small fraction from the ischemic region. Signifi-
'R (3- cant changes in the amount of norepinephrine released
from the ischemic myocardium might have been
masked by norepinephrine-containing blood returning
from nonischemic regions.
Our results further indicate that unlike dobutamine,
dopamine affected neither cardiac function nor isch-
t01.5 t 35% Dextrose emic myocardial blood flow 24 hours after coronary
c
'a, : 5 llDobutamine arterial occlusion, although the acute cardiovascular
~~~~Dopamine effects of dobutamine and dopamine during the initial
infusion were similar. Infarct size also was unaffected
0.5

TABLE 2. Effects of Dobutamine, Dopamine and 5% Dextrose on

0 Infarct Size
Dobuta- Dopa- 5% dex-
-0. 5 mine mine trose
(n = 7) (n = 7) (n = 8) F
Left ventricle
Weight (g) 46±4 55±4 55±4 1.63
X-1 . 5- Risk zone
Weight (g) 13 ± 1 18 ± 1 17± 1 3.13
FIGURE 8. Acute effects of5% dextrose, dobutamine and dopa- % left ventricle 30±3 34±3 31±2 0.57
mine infusion upon plasma catecholamines. (top) Changes in
arterial plasma concentrations of norepinephrine and epineph- Infarct size
rine, obtained after 30 minutes of infusion, compared with Weight (g) 7±1* 14±2 13± 1 6.69
preinfusion values. (bottom) Coronary sinus minus arterial % left ventricle 16±2* 26 ± 3 23 ± 2 4.67
plasma concentration difference of norepinephrine and epi- % risk zone 55±4* 76±6 76±5 5.49
nephrine. Bars show SEM. Asterisks indicate values that differ Values are mean ± SEM. The F values show that only infarct size
significantly from the dextrose group; dagger signs indicate differed in the three groups. Asterisks indicate values that differ
values that differ significantly from the dobutamine group. significantly from the dextrose group.
 DOBUTAMINE AND DOPAMINE IN ACUTE MI/Maekawa et al. 757

TABLE 3. Effects of Acute Coronary Artery Occlusion on Organ and nonischemic myocardium, because tissue norepi-
Blood Flows nephrine was depleted in both of these regions after
Organ blood flow acute myocardial infarction.33 This endogenously re-
(mll 100g/min) leased norepinephrine may produce a greater vasocon-
Organ Control Occlusion strictor effect than circulating catecholamines .' Al-
Brain 58±3 55±3 pha-receptor-mediated vasoconstriction could have
Lungs (bronchial artery) 52 ± 7 34 ± 5* limited the increase in myocardial blood flow.36
Right ventricle 88 ± 7 85 ± 7
In addition, endogenously released norepinephrine
may exert deleterious effect on the ischemic myocardi-
Adrenal glands 295 ± 18 272 ± 20 um by its oxygen-wasting effects in the'mitochondria,
Kidneys 506± 22 396 ± 24* and its actions causing calcium accumulation in the
Liver (hepatic artery) 37 ± 4 30 + 3* cardiac cell.'1 12 Myocardial cellular damage may be
Stomach 41±4 31±5* produced in isolated rat heart by even small doses of
Small intestine 46±4 38±3* norepinephrine released by hypoxia or myocardial in-
farction.37 Furthermore, dopamine increases arterial
Large intestine 64+ 6 53±4* concentrations of free fatty acids22 'whereas dobuta-
Spleen 266 ± 21 260 ± 19 mine does not.4 Since myocardial lipolysis increases
Bladder 10±1 6±1* myocardial oxygen requirements, these effects of do-
Pancreas 35 ± 4 32 ± 3 pamine are detrimental in the setting of acute myocar-
Splanchnics 63 ±4 54 ± 3* dial ischemia.'2
Femoral muscle 5.1± 0.5 4.1± 0.5*
Earlier studies in anesthetized, open-chest dogs
showed that dopamine exaggerated the ischemic in-
Skin 3.0±0.3 3.4±0.4 jury, as evidenced by epicardial ST-segment eleva-
Bone 15±3 10±2* tions.21' 22 On the other hand, our results in conscious
Values are mean + SEM. N = 26. dogs indicate that infarct size was not significantly
*p < 0.05 vs control (paired t test). increased by dopamine. This apparent discrepancy
may be related in part to the use of anesthesia and
by dopamine infusion. The changes in plasma catechol- open-chest preparations by previous investigators. In
amine demonstrate that as expected, dopamine caused addition, epicardial ST-segment elevation was used to
a release of endogenous catecholamines from both detect acute effects of dobutamine in the earlier stud-
sympathetic nerves endings and adrenal medulla. In ies, whereas infarct size was measured 24 hours later
Downloaded from http://ahajournals.org by on December 11, 2019

contrast, dobutamine, which, like isoproterenol, has a
large N-substituent group,32 is not taken up into the
sympathetic nerve endings and does not cause release
of endogenous norepinephrine. Dopamine produced a
net release of norepinephrine from the heart. Norepi-
nephrine probably was released from both the ischemic
Adrenal Glands
r* t
150
100
50
_
150.
Splanchnics
100
50-
FIGURE 9. Changes (percentage of preinfusion values) in
blood flow and vascular resistance in skeletal muscle, adrenal
glands, kidneys, and splanchnics after 30 minutes ofinfusion of
5% dextrose, dobutamine, and dopamine. Bars show SEM. As-
terisks indicate values that differ significantlyfrom the dextrose
group; dagger signs indicate values that differ significantlyfrom
the dobutamine group.
in our experiments. Aggravation of ischemic insult
during the acute phase of myocardial ischemia might
not necessarily produce a greater infarct size in our
preparation because the infarct size, as expressed by
percent risk zone, was already nearly maximal in' the
control dextrose group (76%).38
Dobutamine improves myocardial mitochondrial ul-
trastructure in patients with congestive cardiomyo-
pathy.39 This may lead to better mitochondrial use of
oxygen 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 the
decrease in tissue catecholamine storage.33 Dopamine
might have enhanced the rate of norepinephrine deple-
tion in the heart. Although depletion of norepinephrine
by itself does not necessarily change intrinsic myocar-
dial contractility,33 40 it would attenuate the inotropic
response of the heart to indirectly acting adrenergic
agents like dopamine.
Dobutamine and dopamine exert different effects on
peripheral vasculature. Dobutamine increased skeletal
muscle blood flow. In contrast, dopamine increased
blood' flow to the kidneys and adrenal glands. The
increase in renal blood flow probably is caused by the
dopaminergic action of the drug.'6 The increase in
adrenal blood flow was accompanied'by increases in
plasma catecholamines, suggesting the blood flow re-
 758 CIRCULATION
sponse was closely coupled to the adrenal release of
catecholamines. The mechanism for this change is not
known.
Both dobutamine and dopamine are useful inotropic
agents in patients with heart failure. Dobutamine is a
preferred agent to improve depressed myocardial per-
4&
formance in patients with low output cardiac failure3
and patients with acute myocardial infarction.42 Dobu-
tamine produces favorable effects on hemodynamics in
most patients with acute myocardial infarction6 and in
heart failure complicating coronary artery disease'
without serious deleterious side effects. Nevertheless,
dopamine may increase renal perfusion by its unique
dopaminergic action, not present with dobutamine.
Our present study suggests that dobutamine is more
effective than dopamine in producing sustained cardiac
improvement after acute myocardial infarction, and
that the norepinephrine-releasing property of dopa-
mine may be detrimental to the ischemic myocardium.
Acknowledgment
The authors thank Samuel Rivers, Stephanie Arnold, Debra Gins-
burg, Catherine H. Mesner, and Chhanda Panda for their excellent
technical assistance. The following chemicals were generously supplied
by pharmaceutical companies: Indocyanine green (Cardio-Green) by
Hynson, Westcott and Dunning, Division of Becton, Dickinson and
Company, Baltimore, MD; dobutamine HCl (Dobutrex) by Lilly Re-
search Laboratories, Indianapolis, IN.
References
1. Tuttle RR, Mills J: Dobutamine. Development of a new catechol-
Downloaded from http://ahajournals.org by on December 11, 2019
amine to selectively increase cardiac contractility. Circ Res 36:
185, 1975
2. Hinds JE, Hawthorne EW: Comparative cardiac dynamic effects of
dobutamine and isoproterenol in conscious instrumented dogs. Am
J Cardiol 36: 894, 1975
3. Leier CV, Heban PT, Huss P, Bush CA, Lewis RP: Comparative
systemic and regional hemodynamic effects of dopamine and dobu-
tamine in patients with cardiomyopathic heart failure. Circulation
58: 466, 1978
4. Liang C, Hood WB Jr: Dobutamine infusion in conscious dogs
with and without autonomic nervous system inhibition: effects on
systemic 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 the
effects 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 Cardiol
39: 588, 1977
7. Tubau JF, Bourassa MG, Cote P: Hemodynamic and metabolic
changes 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, Fletcher
RD: 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 acute
myocardial 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 acute
myocardial infarction. In Proceedings: European Dobutamine
Symposium, edited by A Glynne, RA Lucas. London, Guy's Hos-
pital, 1978, pp 58-67
11. Ceremuzyfiski L: Hormonal and metabolic reactions evoked by
acute myocardial infarction. Circ Res 48: 767, 1981
VOL 67, No 4, APRIL 1983
12. Opie LH: Myocardial infarct size. Part I. Basic considerations. Am
Heart 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 for
treatment of heart failure and shock: an update on dopamine and a
first 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 plasma
concentrations of noradrenaline and renin in patients with low
cardiac output following acute myocardial infarction. Eur J Clin
Pharmacol 18: 213, 1980
18. Robie NW, Nutter DO, Moody C, McNay JL: In vivo analysis of
adrenergic receptor activity of dobutamine. Circ Res 34: 663, 1974
19. Sonnenblick EH, Frishman WH, LeJemtel TH: Dobutamine: a new
synthetic 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 J
Physiol Pharmacol 46: 35, 1968
21. Reid P, Pitt B, Kelly D: Effects of dopamine on increasing infarct
area in acute myocardial infarction. (abstr) Circulation 46 (suppl
II): 11-210. 1972
22. Lekven J, Semb G: Effect of dopamine and calcium on lipolysis
and myocardial ischemic injury following acute coronary occlusion
in the dog. Circ Res 34: 349, 1974
23. Heymann MA, Payne BD, Hoffman Jl, Rudolph AM: Blood flow
measurements with radionuclide-labeled particles. Prog Cardio-
vasc Dis 20: 55, 1977
24. Liang C: Metabolic control of circulation. Effects of iodoacetate
and 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 a
function of the amount of myocardium at risk. Am J Pathol 90:
363, 1978
27. Nachlas MM, Shnitka TK: Macroscopic identification of early
myocardial infarcts by alterations in dehydrogenase activity. Am J
Pathol 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 necrosis
within 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 in
human, canine and porcine hearts. In The Collateral Circulation of
the Heart, edited by DAK Black. New York, American Elsevier
Publishing, 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 of
norepinephrine after experimental myocardial infarction. Am J
Physiol 220: 27, 1971
34. Glick G, Epstein SE, Wechsler AS, Braunwald E: Physiological
differences between the effects of neuronally released and blood-
borne norepinephrine on beta adrenergic receptors in the arterial
bed of the dog. Circ Res 21: 217, 1967
35. Russell MP, Moran NC: Evidence for lack of innervation of /3-2
adrenoceptors 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
 LV FUNCTION AND INFARCT SIZE BY CTT/Slutsky et al.

noradrenaline in the development of myocardial infarction. An
experimental 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 in
relation to magnitude of ischemic zone. Am J Cardiol 42: 67, 1978
39. Unverferth DV, Leier CV, Magorien RD, Croskery R, Svirbely
JR, Kolibash AJ, Dick MR, Meacham JA, Baba N: Improvement
of human myocardial mitochondria after dobutamine: a quantita-
tive ultrastructural study. J Pharmacol Exp Ther 215: 527, 1980
40. Spann JF, Sonnenblick EH, Cooper T, Chidsey CA, William VL,
Braunwald E: Cardiac norepinephrine stores and the contractile
state of heart muscle. Circ Res 19: 317, 1966
41. Loeb HS, Bredakis J, Gunnar RM: Superiority of dobutamine over
dopamine for augmentation of cardiac output in patients with
chronic low output cardiac failure. Circulation 55: 375, 1977
42. Keung ECH, Siskind SJ, Sonnenblick EH, Ribner HS, Schwartz
WJ, LeJemtel TH: Dobutamine therapy in acute myocardial infarc-
tion. JAMA 245: 144, 1981

In Vivo Estimation of Myocardial Infarct Size and

Left Ventricular Function by Prospectively Gated
Computerized Transmission Tomography
ROBERT 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 were
studied after coronary occlusion and three served as sham controls. Ungated scans (1 cm deep) of the left
ventricle (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 medium
enhancement of the entire infarct or the periphery of the infarct occurred. Autopsy IS was compared with
the IS by CTT using either the inner (IM) or outer margin (OM) of the contrast-enhanced periphery of the
infarcts as the border of the infarct. IS by both CTT techniques correlated well with autopsy IS (r = 0.89 for
IM; r = 0.93 for OM). The estimate using OM (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 <
Downloaded from http://ahajournals.org by on December 11, 2019

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 increased
from 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 made
from gated CTT scans. Anterior myocardial infarctions produce left ventricular dilatation with reduced
chamber function, which can be detected by gated CTT scans.

QUANTITATION of myocardial infarct size is impor-
tant in assessing clinical prognosis after infarction and
in evaluating the effects of interventions designed to
reduce the myocardial damage during ischemia.'-5 Ex
vivo studies have shown that computerized transmis-
sion tomography (CTT) can be used to accurately
quantitate irreversibly damaged myocardial tissue.6-9
Recent reports have also shown the ability of CTT to
quantitate infarct size in vivo, though the method var-
ied in each study.'0 1 The present study was designed
to define the accuracy of CTT scans for quantitating
From the Department of Radiology, University of California, San
Diego Medical Center and the San Diego Veterans Administration
Medical 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 K04
HL-2001 from the NHLBI.
Address for correspondence: Robert A. Slutsky, M.D., Veterans
Administration Medical Center (114), 3350 La Jolla Village Drive, San
Diego, California 92161.
Received October 25, 1982; revision accepted November 23, 1982.
Circulation 67, No. 4, 1983.
759
infarct volume and to compare two CTT methods of
assessing myocardial infarct size with autopsy values;
we also used CTT to characterize middle left ventricu-
lar (LV) chamber dynamics before and after coronary
occlusion by prospective ECG gating and evaluated
the variability in estimates of cardiac function by pro-
spective ECG gating of CTT images obtained on two
different days.
Methods
Experimental Model
Eleven conditioned mongrel dogs (mean weight 28
± 4 kg) constituted the study population. Each dog
was given subcutaneous morphine sulfate, 3 mg/kg,
and then anesthetized with i.v. pentobarbital, 25 mg/
kg. Through a left thoracotomy, a hydraulic coronary
occluder was placed around the proximal left anterior
descending artery, and in four dogs an injection cath-
eter was placed into the left atrial appendage. The
catheters were burrowed subcutaneously and external-
ized. The wound was closed aseptically and the dogs
were allowed to recover. Control CTT scans were ob-