- Email: [email protected]
Systemic and regional hemodynamic effects of perindopril in experimental heart failure
Meduedeu
14.
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19. 20.
21.
September 1993 American Heart Journal
and Gorodetshaya
by acetylcholine in atherosclerotic coronary arteries. N Engl J Med 1986;315:1046-51. Zeiher AM, Drexler H, Wollschlager H, Just H. Modulation of coronary vasomotor tone in humans: progressive endothelial dysfunction with different early stages of coronary atherosclerosis. Circulation 1991;83:39-l-401. Chester AH. O’Neil GS. Moncada S. Taikarimi K. Yacoub MH. Low basal and stimulated release of nitric oxide in atherosclerotic epicardial coronary arteries. Lancet 1990;336:897900. Tardy Y, Meister JJ, Perret F, Brunner HR, Arditi M. Noninvasive estimate of the mechanical properties of peripheral arteries from ultrasonic and photoplethysmographic measurements. Clin Phys Physiol Meas 1991;12:39-54. Perret F, Mooser V, Hayoz D, Tardy Y, Meister JJ, Etienne JD, Farine PA, Marazzi A, Burnier M, Nussberger J, Waeber B, Brunner HR. Evaluation of arterial compliance-pressure curves: effect of antihypertensive drugs. Hypertension 1991;18:11-77-83. Hirooka Y, Takeshita A, Imaizumi T, Suzuki S, Yoshida M, Ando S, Nakamura M. Attenuated forearm vasodilative response to intra-arterial natriuretic peptide in patients with heart failure. Circulation 1990;82:147-53. Henderson AH. Endothelium in control. Br Heart J 1991; 65:116-25. Miller VM, Vanhoutte PM. Enhanced release of endotheliumderived factor(s) by chronic increases in blood flow. Am J Physiol 1988;255:H446-51. Aoki N, Siegfried M, Lefer AM. Anti-EDRF effect of tumor
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necrosis factor in isolated, perfused cat carotid arteries. Am J Physiol 1989;256:H1509-12. Levine B, Kalman J, Mayer L, Fillit HM, Packer M. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med 1990;323:236-41. Hayoz D, Drexler H, Miinzel T, Hornig B, Zeiher AM, Just H, Brunner HR, Zelis R. Flow mediated arterial dilation is abnormal in congestive heart failure. Circulation (in press). Holtz J, Forstermann U, Pohl U, Giesler M, Bassenge E. Flow-dependent, endothelium-mediated dilation of epicardial coronary arteries in conscious dogs: effects of cyclooxygenase inhibition. J Cardiovasc Pharmacol 1984:6:1161-7. Cooke JP, Stamler J, Andon N, Davies PF, McKinley G, Loscalzo J. Flow stimulates endothelial cells to release a nitrovasodilator that is potentiated by reduced thiol. Am J Physiol 1990;259:H804-12. Ontkean MT, Gay R, Greenberg B. Effects of chronic captopril therapy on endothelium-derived relaxing factor activity in heart failure. [Abstract]. J Am Co11 Cardiol1992;19:207A. Wiemer G. Scholkens BA. Becker RHA. Busse R. Ramiorilat enhances endothelial autacoid formation by inhibiting breakdown of endothelium-derived bradykinin. Hypertension 1991;18:558-63. Drexler H, Banhardt U, Meinertz T, Wollschlager H, Lehmann M, Just H. Contrasting peripheral short-term and longterm effects of converting enzyme inhibition in patients with congestive heart failure. A double-blind, placebo-controlled trial. Circulation 1989;79:491-502.
Systemtic and reg.ional hemodynamic effects of perindopril in exp.erimentaI heart fa.ilure The effects of converting-enzyme inhibition. by perindoprilat (0.5 mglkg, intravenously, short-term administration) or perindopril (2 mglkg, orally, long-term administration once a day for 21 days) on systemic and regional hemoclynamics were studied.on a new rat model of heart failure, which was induced by microembolization of coronary vessels by 15 jrrn plastic microspheres. Cardiac output and regional blood flows were measured by microsphere technique; the tone of the venous vessels was determined as mean circulatory filling pressure in conscious, freely moving rats. Perindoprilat evoked a much more prominent increase in kidneys, adrenal glands, intestine, and skin blood flows in embolized rats than in sham-operated rats. The differences between the effects of long-term treatment with perindopril in sham-operated and embolized rats were highly significant. Mean circulatory filling pressure was decreased by short-term and long-term administration of an angiotensin-converting enzyme inhibitor. It is concluded that venous vessels could be one of the target sites for the effects of perindopril-like drugs. (AM HEART J 1993;126: 764-9.)
Oleg S. Medvedev,
From the Laboratory Center.
MD, PhD, and Eugenia A. Gorodetskaya,
of Experimental
Pharmacology,
Cardiology
Research
Reprint requests: Oleg S. Medvedev, MD, PhD, Laboratory of Experimental Pharmacology, Cardiology Research Center, 3 Cherepkovskaya 15A, Moscow 121552, Russia. Copyright ,C’ 1993 by Mosby-Year Book, 0002-8703/93/$1.00 + .lO 4/O/48688
764
Inc.
PhD Moscow,
Russia
Both experimentall and clinical studiesse4 have confirmed that the renin-angiotensin system plays an important role in the development of congestive heart failure, which is responsible for the increase in total peripheral resistance (TPR). Activation of the renin-angiotensin system in congestive heart failure
Volume 126, Number 3, Part 2 American Heart Journal
is followed by an uneven increase in regional vascular resistance in various zones of the body, and one of the most important pathophysiologic factors is a decrease in fractional renal blood flow (renal fraction of the cardiac output). 3, 5j 6 Arterial circulation is not the only target of the renin-angiotensin system; it also increases the tone of venous vessels and is followed by an increase in left ventricular end-diastolic pressure (LVEDP) in humans and in different experimental models of heart failure.7, 8 The goal of the present study was to investigate the short-term (perindoprilat, 0.5 mg/kg, intravenously) and long-term (perindopril, 2 mg/kg, orally, daily for 21 days) effects of angiotensin I converting-enzyme inhibition on systemic and regional hemodynamics on the new experimental rat model of heart failure, which was induced by selective embolization of coronary vessels with 15 pm plastic microspheres. All measurements were performed in conscious, unrestrained rats to avoid the effects of anesthesia to depress compensatory reflex mechanisms.g METHOk Embolization
of the coronary vessels. Heart failure in rats was induced by coronary vessel embolization as described previously. lo Briefly, Wistar rats weighing 270 to 350 gm were anesthetized with pentobarbital (Nembutal) (40 mg/kg, intraperitoneally) and polyethylene catheters (PE-10 and PE-50, Clay Adams) containing saline solution with heparin (50 units/ml) were placed into the left ventricle by way of the external right carotid artery. A suspension of 15 ym microspheres in saline solution with 0.05% Tween-80 containing about 150,000 to 200,000 microspheres was injected into the left ventricle during IO-second occlusion of the ascending aorta. Occlusion of the ascending aorta was performed by pressing the aorta to the vertebral column with the L-shaped wire. After injection of the microspheres, the occlusion device was removed, and skin incision was closed with sutures. The sham-operated group was subjected to the same procedures except for injection of microspheres. Subsequent experimental procedures began 20 days after embolization or sham operation. Measurement of tiemodynamic parameters. Twenty days after embolization or sham operation, animals were anesthetized with Nembutal (40 mg/kg intraperitoneally), and polyethylene catheters were placed into the abdominal aorta by way of the femoral artery, into the left ventricle by way of the right carotid artery, into the jugular vein. Peripheral ends of the catheters were passed subcutaneously to the interscapular region and exteriorized there. The experiments were performed the next day. Arterial and left ventricular pressures were monitored by Statham 231D pressure transducers. Heart rate was determined with a cardiotachometer triggered by a wave of arterial pulse pressure; dP/d&,,, of left ventricular pressure was measured by the differentiator (type 562, Hugo Sachs Elektronik, Germany). Measurement of the regional hemodynamics. The la-
Medvedev and Gorodetskaya
765
beled 15 km microspheres (Co-57, Sn-113; New England Nuclear, Wilmington, Del.) were used to measure changes in the systemic and regional hemodynamics.ll A detailed description of the technique used in this study was given previously.12 Briefly, a catheter placed in the left ventricle was used to measure left ventricular pressure and to inject the microspheres; an arterial catheter was used to withdraw the reference sample of blood and to measure arterial pressure. Approximately 100,000 radioactive microspheres suspended in saline solution containing 0.05 % of Tween-80 (Serva) were injected over a 20-second period into the left ventricle. Withdrawal of the arterial reference blood samples began 5 seconds before the microsphere .injection with a pump at a rate of 0.97 ml/min. Blood was withdrawn for 60 seconds. Fluid replacement consisted of 6.54 ml of 13.4% Ficoll-‘70 (Pharmacia Fine Chemicals) saline mixture. At the end of the experiment, the animals were killed by an overdose of Nembutal. Samples of organs and tissues (skin, muscles, kidneys, adrenal glands, lungs, stomach, liver, brain, and small intestine) were removed and weighed. The number of microspheres in the reference’blood samples and tissue samples was determined by a y-counter (CompuGamma 1282, LKB-Wallac, Finland).. An adequate mixture of microspheres and blood was confirmed by equal numbers in paired organs (kidneys and testis). Cardiac output and blood flows were calculated with standard equations.ll Venous tone determination. Total-body .venous tone was determined by measuring mean circulatory filling pressure (MCFP).13 Twenty days after embolization, the rats were anesthetized with Nembutal (40 mg/kg, intraperitoneally) and polyethylene catheters welded from PE-10 and PE-50 (Clay Adams) were inserted into the abdominal aorta through the femoral artery and into the femoral vein for blood pressure measurement and intravenous administration of the drug, respectively. A silicone rubber catheter was inserted into the caudal vena cava by way of the femoral vein for the measurement of central venous pressure. A saline-filled latex balloon-tipped catheter was inserted into the right atrium through the right external jugular vein. All catheters were filled with heparinized saline solution and tunneled subcutaneously to the back of the neck and fixed. Animals were allowed to recover 24 hours after operation. Arterial and central venous pressures were monitored by a Statham P23ID transducers. MCFP measurements were made by temporally stopping the circulation by inflating the balloon that was inserted into the right atrium. Within 5 seconds after inflation of the balloon with saline solution, mean arterial pressure decreased whereas venous pressure increased to a plateau level. Central venous pressure measured within 5 seconds of circulation arrest is referred to as venous,plateau pressure (VPP). Blood pressure, heart rate, and central venous pressure were measured continuously throughout the whole experiment. MCFP was calculated with the equation of Samar and Colemanf4 and a coefficient l/60, reflecting the arterial-to-venous compliance ratioi3: MCFP = VPP plus l/60 (FAP - VPP), where FAP represents the final arterial pressure (mm Hg) obtained within 5 seconds after circulatory arrest.
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September 1993 American Heart Journal
Medvedev qnd Gorodetskaya
Table I. Systemic hemodynamics of sham-operated and embolized rats before and after perindoprilat Sham-operated Hemodynamics
Base
MAP (mm Hg) HR (beats/min) CI (ml/min/lOO gm)
level
rats After
101 f 3.0 386 ? 5.0
TPR (mm Hg/ml/min/lOO gm) LVEDP (mm Hg) +dP/d&,,, (mm Hg/sec) -dP/dt,,, (mm Hg/sec)
0.35 * 0.01 2.54 + 0.09 6.2 r 0.5
6890 + 290 5454
+ 264
MAP, Mean arterial pressure; HR, heart rate; CI, cardiac *p < 0.05 vs corresponding base level. tp < 0.05 vs sham-operated rats.
perindoprilat 95 414 43.2 0.36 2.22 5.7 6708 5396
39.9 + 1.0
SV (ml)
index;
Embolized
* k zk i * + I! k
3* 7* 1.7% 0.01 0.09* 0.5 295 274
Base 98 363 30.2 0.27 3.28 13.2 6248 5454
level i. F rt + + i k t
injection rats
After
3 St 1.3t 0.01-F 0.13t 1.17 281 217
perindoprilat 88 401 38.6 0.31 2.36 9.5 6402 5396
+ ir k 2 k + + ?I
4* 12* 2.4* 0.02* 0.12* O.S*,t 315 824
SV, stroke volume.
Table II. Systemic hemodynamics of sham-operated and embolized rats receiving long-term treatment with saline or perindopril, 2 mglkg, by gavage Sham-operated Saline
Hemodynamics
MAP (mm Hg) HR (beatdmin) CI (ml/min/lOO gm) SV (ml) TPR (mm Hg/ml/min/lOO
LVEDP (mm Hg) +dP/dt,,, (mm Hghec) -dP/dt,ax (mm Hg/sec)
gm)
97 390 40.2 0.30 2.44 7.8 12131 7863
+ +t i -+ zk k k
rats
Embolized
Perindopril 3 11 1.5 0.01 0.15 0.5 423 473
MAP, Mean arterial pressure; HR, heart rate; Cl, cardiac index; SV, stroke *p < 0.05 vs corresponding level in the saline group. Tp< 0.05 vs corresponding values in sham-operated group.
Statistical analysis. Data are reported as mean rt SEM. Statistical analysis of the data was performed by the Student paired and unpaired t tests. Experimental protocol. Animals were divided into two groups: one group received short-term administration of perindoprilat and the second group received long-term treatment with perindopril. Each group was divided into four subgroups: (1) subgroup I (sham-operated rats receiving saline); (2) subgroup II (sham-operated rats receiving angiotensin-converting enzyme inhibitor); (3) subgroup III (rats with heart failure receiving saline); and (4) subgroup IV (rats with heart failure receiving angiotensin-converting enzyme inhibitor). In each subgroup 12 animals were used for microsphere measurement of hemodynamics and 12 were used for measurement of MCFP. Drugs. Perindoprilat and perindopril were kindly provided by Institut de Recherches Internationales Servier, Courbevoie, France. RESULTS Perindopril-induced changes in systemic hemodynamics Acute effects. Perindoprilat injection (Table I) in sham-operated rats was followed by a 6 % decrease in
81 355 30.4 0.25 2.78 4.3 8685 6140
3~ 5” f 16 k 2.3* t 0.02 + 0.25 t 0.8* i 607* Z!I 568*
Saline 102 369 37.0 0.33 2.74 12.0 10948 7875
F k ix 1 I+ 25 f +
rats Perindopril
4 11 0.5 0.02 0.15 1.5t 678 508
82 377 44.2 0.31 1.90 6.7 10977 6872
rt t & k + f I +
5% 8 2.0* 0.01 0.16* O.S*,t 587 310
volume.
mean arterial pressure (p < 0.05), a 12.5% decrease in TPR (p < 0.05), a 7.2% increase in heart rate (p < 0.05), and an 8.2% increase in cardiac index (p < 0.05). In contrast, perindoprilat injection induced more prominent changes in embolized rats (Table I). In fact mean arterial pressure decreased by 9.8% @ < 0.05) and heart rate increased by 10.2 % (p < 0.05). Changes in TPR (by 28%) p < 0.05) were twice as much (p < 0.05) as those in sham-operated animals. The 27 % increase in cardiac index (p < 0.05) was threefold higher (p < 0.05) than that in shamoperated rats. At the same time perindoprilat injection significantly decreased LVEDP by 25% (p < 0.05) and increased stroke volume by 13 % (p < 0.05) in embolized rats only. Chronic effects. Perindopril-treated sham-operated rats reduced mean arterial pressure by 16% (p < 0.05). An unexpected finding was that 21-day treatment with perindopril was followed by a 24% decrease in cardiac index in sham-operated rats (p < 0.05). The effects of perindopril on mean arterial pressure or heart rate were similar in both groups
Volume 126, Number 3, Part 2 American Heart Journal
Medvedev
Table III. Perindoprilat
flow
Base
(mllminlgm)
Skin Skeletal muscles Kidneys Adrenals Lungs Stomach Liver Brain Small intestine *p < 0.05 vs corresponding ‘rp < 0.05 vs sham-operated
767
(5 mg/kg) induced changes in regional blood flows in sham-operated and embolized rats Sham-operated
Blood
and Gorodetskaya
0.20 0.20 5.54 5.22 1.50 1.29 0.15 1.44 2.84
level f tk t + f + f f
Embolized
rats After
0.02 0.04 0.36 0.65 0.45 0.13 0.08 0.08 0.33
perindoprilat 0.24 0.18 6.61 6.49 1.00 1.36 0.20 1.39 3.44
k f + ir rt f f t "
Base 0.12 0.10 3.18 3.28 0.75 0.92 0.10 0.95 1.88
0.02* 0.04 0.45* 0.91* 0.16 0.19
0.10 0.11 0.34*
After
level * + * f * k * 2 +
rats
0.01t O.OlT 0.32t 0.77 0.12 0.17 0.04 0.07.f 0.207
perindoprilat 0.16 0.11 5.62 5.93 1.31 1.19 0.14 1.21 3.40
f f i. k zk rt jr f f
0.02* 0.01 0.33 1.26* 0.25* 0.13 0.05 0.16 0.29*
base level. rats.
Table IV. Regional blood flows in sham-operated and embolized rats receiving long-term treatment with saline or perindopril Sham-operated Blood
flow
(mllminlgm)
Skin Skeletal muscles Kidneys Adrenals Lungs Stoma& Liver Brain Small intestine *p < 0.05 vs corresponding
values in saliie-treated
Saline 0.21 0.14 5.40 5.83 3.92 1.29 0.19 1.29 3.20
3+ 2 r + * + r +
rats
Embolized
Perindopril 0.10 0.09 0.55 1.06 2.16 0.23 0.10 0.15 0.38
0.11 0.08 6.39 4.56 0.38 0.75 0.21 1.00 3.03
+ + 2 t + f + F k
Saline 0.09 0.09 0.59 0.55 0.14 0.12 0.10 0.14 0.22
0.16 0.15 5.13 6.68 1.28 1.15 0.19 1.26 3.63
k * f I!I zk f f + +-
rats Perindopril
0.09 0.09 0.28 1.47 0.36 0.14 0.11 0.13 1.05
0.14 0.15 7.56 5.07 0.62 1.40 0.17 1.40 4.08
f i: t f + t * * Ik
0.09 0.09 0.56* 0.51 0.17 0.16 0.09 0.14 0.53
group.
of rats (Table II). In contrast, embolized rats had quite different changes incardiac index. In fact, an 18% increase in cardiac index (p < 0.01) was observed compared with saline-treated embolized rats. The difference was even higher when compared with the sham-operated perindopril-treated group (+31%, p < 0.001). The 46% decrease in TPR (p < 0.05) was observed in the perindopril-treated embolized group but not in perindopril sham-operated animals. Effects of perindopril on regional hemodynamics Acute effects. Perindoprilat-induced acute changes in regional blood flow are shown in Table III. In sham-operated rats, 0.5 mg/kg of perindoprilat increased blood flow in the skin by 25% 0, < 0.05), in the small intestine by 27 % (p < 0.05), in the adrenals by 29.5% (p c 0.05), and in the kidneys by 21% (p < 0.05) and decreased vascular resistance in the small intestine by 22% (p < 0.05), adrenals by 22% (p < 0.05), and kidneys by 19% (p < 0.05). Similar changes also occurred in embolized animals, but they
were much greater. Blood flow was increased in the skin by 66 % (p < 0.05), in the small intestine by 92 % 03 < 0.05), in the adrenals by 123 % (p < 0.05), and in the kidneys by 90% (p < 0.05); vascular resistance was reduced in the small intestine by 48 % (p < 0.05), in the adrenals by 47 % (p < 0.05), and in the kidneys by 49% (p < 0.05). In addition, in embolized rats blood flow was increased in the lungs by 74% (JI < 0.05), and vascular resistance was reduced in the skin by 39.5% (p < 0.05), in the stomach by 21% (p < 0.05), in the brain by 21.5% (p < 0.05), and in the lungs by 33% (p < 0.05). Chronic effects. The measurements of blood flow (Table IV) in various organs has not revealed significantly lower blood flow or higher vascular resistance in any organ in the embolized group when compared with the sham-operated group. Changes in regional blood flow after perindopril treatment are shown in Table IV. In most of the organs studied in sham-operated rats, perindopril treatment did not influence the level of blood flow. There was a tendency for
September 1993 American Heart Journal
76% Medvedev and Gorodetskaya
a
sham
m
embolized
10
0
DISCUSSION
a cz 0
vs 7.4 + 0.2 mm Hg, p < 0.05). Perindoprilat was potent in decreasing MCFP only in rats with coronary embolization (Fig. 1). Chronic effects. In sham-operated animals perindopril produced a strong and highly significant decrease in MCFP (by 13 %, p < 0.01) (Fig. 1). In rats with coronary embolization, perindopril treatment was followed by a decrease in MCFP (by 26%) p < 0.01).
-10
s
-20
-30 Acute admin.
Chronic
admin.
Fig. 1.8 Effects of snort-term administration of perindoprilat (0.5 mgl/kg, intravenously;bolus) and long-term treatment with perindopril (2 mg/kg, orally, once a day for 21 days) on MCFP in sham-operated and embolized rats. (*p < 0.05 compared with saline-treated control rats; #p < 0.05 compared with sham-operated group; up < 0.05 compared with appropriate group of rats receiving shortterm treatment with perindoprilat.)
blood flow to increase in the kidney (NS); only the heart had a decrease in blood flow from 6.97 _t 0.89 (saline-treated group) to 4.41 4 0.80 ml/min/gm (in perindopril-treated rats) that is, a decrease of 37% (p < 0.05). Perindopril-treated sham-operated rats had significantly lower vascular resistance only in the kidney (-31%; p < 0.05). Effects of perindopril on cardiovascular function in embolized’rats were quite different. Perindopril-treated rats had significantly higher, blood flow in the kidney (+47 % , p < 0.05) and lower vascular resistance in the’kidney, stomach, and brain compared with saline-treated animals. Vascular’resistance in the stomach and the brain was significantly lower and significantly higher in the small intestine when compared with the respective values in the perindopril-treated, sham-operated rats. Perindoprii-induced
changes
in MCFP
Acute egects. Rats with the embolized coronary vessels had significantly higher baseline levels of MCFP compared with sham-operated’rats (8.5 + 0.2
In rats with coronary vessel embolization the main signs of experimental heart failure were clearly distinguished: high LVEDP and high venous tone (high preload) compared with sham-operated rats. They had slightly higher TPR and lower cardiac index. Thus depressed cardiac performance indicating chronic heart failure is documented by hemodynamic data, which are similar to the signs of heart insufliciency reported previously.8J 15-r7 In the preliminary short-term study, perindoprilat improved hemodynamic function of the heart, regional blood flows, and venous tone. The manifestation of some of these features was somewhat less prominent in the long-term study with perindopril but could be explained by a development of more moderate level of heart failure (no increase in TPR and no decrease in regional blood in the saline embolized group). However, perindopril-treated rats had a higher level of cardiac index, lower mean circulatory filling pressure, and TPR compared with salinetreated animals. These findings resemble those of captopril.8p 18-21In rats with congestive heart failure caused by large myocardial infarction21 captopril decreased TPR, mean arterial pressure, and left ventricular systolic pressure. The most prominent effect occurred in the renal circulation; the increase in renal flow was more pronounced in heart failure group than in sham-operated animals. It is important that the main results of our study closely resemble those of clinical trials on angiotensin-converting enzyme inhibitors. In patients with congestive heart failure captopril significantly increased cardiac index, reduced blood pressure and TPR,18, 2o and enhanced renal flow by 60 % .18Results of our experiments are close to the earlier findings of Raya et a1.,8 which showed that captopsil treatment decreased MCFP and blood volume whereas venous compliance increased in rats with chronic left ventricular dysfunction after myocardial infarction. We assume that the increase in venous tone is one of the most sensitive criteria for the development of experimental heart failure;,.which is dependent on the activation of renin-angiotensin system. AS a result of
Volume 126, Number 3, Part 2
American
Medvedev
Heart Journal
the above, venous vessels might be one of the main targets for the perindopril-like drugs in patients with CHF.
12.
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September 1993 American Heart Journal
and Gorodetshaya
by acetylcholine in atherosclerotic coronary arteries. N Engl J Med 1986;315:1046-51. Zeiher AM, Drexler H, Wollschlager H, Just H. Modulation of coronary vasomotor tone in humans: progressive endothelial dysfunction with different early stages of coronary atherosclerosis. Circulation 1991;83:39-l-401. Chester AH. O’Neil GS. Moncada S. Taikarimi K. Yacoub MH. Low basal and stimulated release of nitric oxide in atherosclerotic epicardial coronary arteries. Lancet 1990;336:897900. Tardy Y, Meister JJ, Perret F, Brunner HR, Arditi M. Noninvasive estimate of the mechanical properties of peripheral arteries from ultrasonic and photoplethysmographic measurements. Clin Phys Physiol Meas 1991;12:39-54. Perret F, Mooser V, Hayoz D, Tardy Y, Meister JJ, Etienne JD, Farine PA, Marazzi A, Burnier M, Nussberger J, Waeber B, Brunner HR. Evaluation of arterial compliance-pressure curves: effect of antihypertensive drugs. Hypertension 1991;18:11-77-83. Hirooka Y, Takeshita A, Imaizumi T, Suzuki S, Yoshida M, Ando S, Nakamura M. Attenuated forearm vasodilative response to intra-arterial natriuretic peptide in patients with heart failure. Circulation 1990;82:147-53. Henderson AH. Endothelium in control. Br Heart J 1991; 65:116-25. Miller VM, Vanhoutte PM. Enhanced release of endotheliumderived factor(s) by chronic increases in blood flow. Am J Physiol 1988;255:H446-51. Aoki N, Siegfried M, Lefer AM. Anti-EDRF effect of tumor
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23.
24.
25.
26.
27.
28.
necrosis factor in isolated, perfused cat carotid arteries. Am J Physiol 1989;256:H1509-12. Levine B, Kalman J, Mayer L, Fillit HM, Packer M. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med 1990;323:236-41. Hayoz D, Drexler H, Miinzel T, Hornig B, Zeiher AM, Just H, Brunner HR, Zelis R. Flow mediated arterial dilation is abnormal in congestive heart failure. Circulation (in press). Holtz J, Forstermann U, Pohl U, Giesler M, Bassenge E. Flow-dependent, endothelium-mediated dilation of epicardial coronary arteries in conscious dogs: effects of cyclooxygenase inhibition. J Cardiovasc Pharmacol 1984:6:1161-7. Cooke JP, Stamler J, Andon N, Davies PF, McKinley G, Loscalzo J. Flow stimulates endothelial cells to release a nitrovasodilator that is potentiated by reduced thiol. Am J Physiol 1990;259:H804-12. Ontkean MT, Gay R, Greenberg B. Effects of chronic captopril therapy on endothelium-derived relaxing factor activity in heart failure. [Abstract]. J Am Co11 Cardiol1992;19:207A. Wiemer G. Scholkens BA. Becker RHA. Busse R. Ramiorilat enhances endothelial autacoid formation by inhibiting breakdown of endothelium-derived bradykinin. Hypertension 1991;18:558-63. Drexler H, Banhardt U, Meinertz T, Wollschlager H, Lehmann M, Just H. Contrasting peripheral short-term and longterm effects of converting enzyme inhibition in patients with congestive heart failure. A double-blind, placebo-controlled trial. Circulation 1989;79:491-502.
Systemtic and reg.ional hemodynamic effects of perindopril in exp.erimentaI heart fa.ilure The effects of converting-enzyme inhibition. by perindoprilat (0.5 mglkg, intravenously, short-term administration) or perindopril (2 mglkg, orally, long-term administration once a day for 21 days) on systemic and regional hemoclynamics were studied.on a new rat model of heart failure, which was induced by microembolization of coronary vessels by 15 jrrn plastic microspheres. Cardiac output and regional blood flows were measured by microsphere technique; the tone of the venous vessels was determined as mean circulatory filling pressure in conscious, freely moving rats. Perindoprilat evoked a much more prominent increase in kidneys, adrenal glands, intestine, and skin blood flows in embolized rats than in sham-operated rats. The differences between the effects of long-term treatment with perindopril in sham-operated and embolized rats were highly significant. Mean circulatory filling pressure was decreased by short-term and long-term administration of an angiotensin-converting enzyme inhibitor. It is concluded that venous vessels could be one of the target sites for the effects of perindopril-like drugs. (AM HEART J 1993;126: 764-9.)
Oleg S. Medvedev,
From the Laboratory Center.
MD, PhD, and Eugenia A. Gorodetskaya,
of Experimental
Pharmacology,
Cardiology
Research
Reprint requests: Oleg S. Medvedev, MD, PhD, Laboratory of Experimental Pharmacology, Cardiology Research Center, 3 Cherepkovskaya 15A, Moscow 121552, Russia. Copyright ,C’ 1993 by Mosby-Year Book, 0002-8703/93/$1.00 + .lO 4/O/48688
764
Inc.
PhD Moscow,
Russia
Both experimentall and clinical studiesse4 have confirmed that the renin-angiotensin system plays an important role in the development of congestive heart failure, which is responsible for the increase in total peripheral resistance (TPR). Activation of the renin-angiotensin system in congestive heart failure
Volume 126, Number 3, Part 2 American Heart Journal
is followed by an uneven increase in regional vascular resistance in various zones of the body, and one of the most important pathophysiologic factors is a decrease in fractional renal blood flow (renal fraction of the cardiac output). 3, 5j 6 Arterial circulation is not the only target of the renin-angiotensin system; it also increases the tone of venous vessels and is followed by an increase in left ventricular end-diastolic pressure (LVEDP) in humans and in different experimental models of heart failure.7, 8 The goal of the present study was to investigate the short-term (perindoprilat, 0.5 mg/kg, intravenously) and long-term (perindopril, 2 mg/kg, orally, daily for 21 days) effects of angiotensin I converting-enzyme inhibition on systemic and regional hemodynamics on the new experimental rat model of heart failure, which was induced by selective embolization of coronary vessels with 15 pm plastic microspheres. All measurements were performed in conscious, unrestrained rats to avoid the effects of anesthesia to depress compensatory reflex mechanisms.g METHOk Embolization
of the coronary vessels. Heart failure in rats was induced by coronary vessel embolization as described previously. lo Briefly, Wistar rats weighing 270 to 350 gm were anesthetized with pentobarbital (Nembutal) (40 mg/kg, intraperitoneally) and polyethylene catheters (PE-10 and PE-50, Clay Adams) containing saline solution with heparin (50 units/ml) were placed into the left ventricle by way of the external right carotid artery. A suspension of 15 ym microspheres in saline solution with 0.05% Tween-80 containing about 150,000 to 200,000 microspheres was injected into the left ventricle during IO-second occlusion of the ascending aorta. Occlusion of the ascending aorta was performed by pressing the aorta to the vertebral column with the L-shaped wire. After injection of the microspheres, the occlusion device was removed, and skin incision was closed with sutures. The sham-operated group was subjected to the same procedures except for injection of microspheres. Subsequent experimental procedures began 20 days after embolization or sham operation. Measurement of tiemodynamic parameters. Twenty days after embolization or sham operation, animals were anesthetized with Nembutal (40 mg/kg intraperitoneally), and polyethylene catheters were placed into the abdominal aorta by way of the femoral artery, into the left ventricle by way of the right carotid artery, into the jugular vein. Peripheral ends of the catheters were passed subcutaneously to the interscapular region and exteriorized there. The experiments were performed the next day. Arterial and left ventricular pressures were monitored by Statham 231D pressure transducers. Heart rate was determined with a cardiotachometer triggered by a wave of arterial pulse pressure; dP/d&,,, of left ventricular pressure was measured by the differentiator (type 562, Hugo Sachs Elektronik, Germany). Measurement of the regional hemodynamics. The la-
Medvedev and Gorodetskaya
765
beled 15 km microspheres (Co-57, Sn-113; New England Nuclear, Wilmington, Del.) were used to measure changes in the systemic and regional hemodynamics.ll A detailed description of the technique used in this study was given previously.12 Briefly, a catheter placed in the left ventricle was used to measure left ventricular pressure and to inject the microspheres; an arterial catheter was used to withdraw the reference sample of blood and to measure arterial pressure. Approximately 100,000 radioactive microspheres suspended in saline solution containing 0.05 % of Tween-80 (Serva) were injected over a 20-second period into the left ventricle. Withdrawal of the arterial reference blood samples began 5 seconds before the microsphere .injection with a pump at a rate of 0.97 ml/min. Blood was withdrawn for 60 seconds. Fluid replacement consisted of 6.54 ml of 13.4% Ficoll-‘70 (Pharmacia Fine Chemicals) saline mixture. At the end of the experiment, the animals were killed by an overdose of Nembutal. Samples of organs and tissues (skin, muscles, kidneys, adrenal glands, lungs, stomach, liver, brain, and small intestine) were removed and weighed. The number of microspheres in the reference’blood samples and tissue samples was determined by a y-counter (CompuGamma 1282, LKB-Wallac, Finland).. An adequate mixture of microspheres and blood was confirmed by equal numbers in paired organs (kidneys and testis). Cardiac output and blood flows were calculated with standard equations.ll Venous tone determination. Total-body .venous tone was determined by measuring mean circulatory filling pressure (MCFP).13 Twenty days after embolization, the rats were anesthetized with Nembutal (40 mg/kg, intraperitoneally) and polyethylene catheters welded from PE-10 and PE-50 (Clay Adams) were inserted into the abdominal aorta through the femoral artery and into the femoral vein for blood pressure measurement and intravenous administration of the drug, respectively. A silicone rubber catheter was inserted into the caudal vena cava by way of the femoral vein for the measurement of central venous pressure. A saline-filled latex balloon-tipped catheter was inserted into the right atrium through the right external jugular vein. All catheters were filled with heparinized saline solution and tunneled subcutaneously to the back of the neck and fixed. Animals were allowed to recover 24 hours after operation. Arterial and central venous pressures were monitored by a Statham P23ID transducers. MCFP measurements were made by temporally stopping the circulation by inflating the balloon that was inserted into the right atrium. Within 5 seconds after inflation of the balloon with saline solution, mean arterial pressure decreased whereas venous pressure increased to a plateau level. Central venous pressure measured within 5 seconds of circulation arrest is referred to as venous,plateau pressure (VPP). Blood pressure, heart rate, and central venous pressure were measured continuously throughout the whole experiment. MCFP was calculated with the equation of Samar and Colemanf4 and a coefficient l/60, reflecting the arterial-to-venous compliance ratioi3: MCFP = VPP plus l/60 (FAP - VPP), where FAP represents the final arterial pressure (mm Hg) obtained within 5 seconds after circulatory arrest.
766
September 1993 American Heart Journal
Medvedev qnd Gorodetskaya
Table I. Systemic hemodynamics of sham-operated and embolized rats before and after perindoprilat Sham-operated Hemodynamics
Base
MAP (mm Hg) HR (beats/min) CI (ml/min/lOO gm)
level
rats After
101 f 3.0 386 ? 5.0
TPR (mm Hg/ml/min/lOO gm) LVEDP (mm Hg) +dP/d&,,, (mm Hg/sec) -dP/dt,,, (mm Hg/sec)
0.35 * 0.01 2.54 + 0.09 6.2 r 0.5
6890 + 290 5454
+ 264
MAP, Mean arterial pressure; HR, heart rate; CI, cardiac *p < 0.05 vs corresponding base level. tp < 0.05 vs sham-operated rats.
perindoprilat 95 414 43.2 0.36 2.22 5.7 6708 5396
39.9 + 1.0
SV (ml)
index;
Embolized
* k zk i * + I! k
3* 7* 1.7% 0.01 0.09* 0.5 295 274
Base 98 363 30.2 0.27 3.28 13.2 6248 5454
level i. F rt + + i k t
injection rats
After
3 St 1.3t 0.01-F 0.13t 1.17 281 217
perindoprilat 88 401 38.6 0.31 2.36 9.5 6402 5396
+ ir k 2 k + + ?I
4* 12* 2.4* 0.02* 0.12* O.S*,t 315 824
SV, stroke volume.
Table II. Systemic hemodynamics of sham-operated and embolized rats receiving long-term treatment with saline or perindopril, 2 mglkg, by gavage Sham-operated Saline
Hemodynamics
MAP (mm Hg) HR (beatdmin) CI (ml/min/lOO gm) SV (ml) TPR (mm Hg/ml/min/lOO
LVEDP (mm Hg) +dP/dt,,, (mm Hghec) -dP/dt,ax (mm Hg/sec)
gm)
97 390 40.2 0.30 2.44 7.8 12131 7863
+ +t i -+ zk k k
rats
Embolized
Perindopril 3 11 1.5 0.01 0.15 0.5 423 473
MAP, Mean arterial pressure; HR, heart rate; Cl, cardiac index; SV, stroke *p < 0.05 vs corresponding level in the saline group. Tp< 0.05 vs corresponding values in sham-operated group.
Statistical analysis. Data are reported as mean rt SEM. Statistical analysis of the data was performed by the Student paired and unpaired t tests. Experimental protocol. Animals were divided into two groups: one group received short-term administration of perindoprilat and the second group received long-term treatment with perindopril. Each group was divided into four subgroups: (1) subgroup I (sham-operated rats receiving saline); (2) subgroup II (sham-operated rats receiving angiotensin-converting enzyme inhibitor); (3) subgroup III (rats with heart failure receiving saline); and (4) subgroup IV (rats with heart failure receiving angiotensin-converting enzyme inhibitor). In each subgroup 12 animals were used for microsphere measurement of hemodynamics and 12 were used for measurement of MCFP. Drugs. Perindoprilat and perindopril were kindly provided by Institut de Recherches Internationales Servier, Courbevoie, France. RESULTS Perindopril-induced changes in systemic hemodynamics Acute effects. Perindoprilat injection (Table I) in sham-operated rats was followed by a 6 % decrease in
81 355 30.4 0.25 2.78 4.3 8685 6140
3~ 5” f 16 k 2.3* t 0.02 + 0.25 t 0.8* i 607* Z!I 568*
Saline 102 369 37.0 0.33 2.74 12.0 10948 7875
F k ix 1 I+ 25 f +
rats Perindopril
4 11 0.5 0.02 0.15 1.5t 678 508
82 377 44.2 0.31 1.90 6.7 10977 6872
rt t & k + f I +
5% 8 2.0* 0.01 0.16* O.S*,t 587 310
volume.
mean arterial pressure (p < 0.05), a 12.5% decrease in TPR (p < 0.05), a 7.2% increase in heart rate (p < 0.05), and an 8.2% increase in cardiac index (p < 0.05). In contrast, perindoprilat injection induced more prominent changes in embolized rats (Table I). In fact mean arterial pressure decreased by 9.8% @ < 0.05) and heart rate increased by 10.2 % (p < 0.05). Changes in TPR (by 28%) p < 0.05) were twice as much (p < 0.05) as those in sham-operated animals. The 27 % increase in cardiac index (p < 0.05) was threefold higher (p < 0.05) than that in shamoperated rats. At the same time perindoprilat injection significantly decreased LVEDP by 25% (p < 0.05) and increased stroke volume by 13 % (p < 0.05) in embolized rats only. Chronic effects. Perindopril-treated sham-operated rats reduced mean arterial pressure by 16% (p < 0.05). An unexpected finding was that 21-day treatment with perindopril was followed by a 24% decrease in cardiac index in sham-operated rats (p < 0.05). The effects of perindopril on mean arterial pressure or heart rate were similar in both groups
Volume 126, Number 3, Part 2 American Heart Journal
Medvedev
Table III. Perindoprilat
flow
Base
(mllminlgm)
Skin Skeletal muscles Kidneys Adrenals Lungs Stomach Liver Brain Small intestine *p < 0.05 vs corresponding ‘rp < 0.05 vs sham-operated
767
(5 mg/kg) induced changes in regional blood flows in sham-operated and embolized rats Sham-operated
Blood
and Gorodetskaya
0.20 0.20 5.54 5.22 1.50 1.29 0.15 1.44 2.84
level f tk t + f + f f
Embolized
rats After
0.02 0.04 0.36 0.65 0.45 0.13 0.08 0.08 0.33
perindoprilat 0.24 0.18 6.61 6.49 1.00 1.36 0.20 1.39 3.44
k f + ir rt f f t "
Base 0.12 0.10 3.18 3.28 0.75 0.92 0.10 0.95 1.88
0.02* 0.04 0.45* 0.91* 0.16 0.19
0.10 0.11 0.34*
After
level * + * f * k * 2 +
rats
0.01t O.OlT 0.32t 0.77 0.12 0.17 0.04 0.07.f 0.207
perindoprilat 0.16 0.11 5.62 5.93 1.31 1.19 0.14 1.21 3.40
f f i. k zk rt jr f f
0.02* 0.01 0.33 1.26* 0.25* 0.13 0.05 0.16 0.29*
base level. rats.
Table IV. Regional blood flows in sham-operated and embolized rats receiving long-term treatment with saline or perindopril Sham-operated Blood
flow
(mllminlgm)
Skin Skeletal muscles Kidneys Adrenals Lungs Stoma& Liver Brain Small intestine *p < 0.05 vs corresponding
values in saliie-treated
Saline 0.21 0.14 5.40 5.83 3.92 1.29 0.19 1.29 3.20
3+ 2 r + * + r +
rats
Embolized
Perindopril 0.10 0.09 0.55 1.06 2.16 0.23 0.10 0.15 0.38
0.11 0.08 6.39 4.56 0.38 0.75 0.21 1.00 3.03
+ + 2 t + f + F k
Saline 0.09 0.09 0.59 0.55 0.14 0.12 0.10 0.14 0.22
0.16 0.15 5.13 6.68 1.28 1.15 0.19 1.26 3.63
k * f I!I zk f f + +-
rats Perindopril
0.09 0.09 0.28 1.47 0.36 0.14 0.11 0.13 1.05
0.14 0.15 7.56 5.07 0.62 1.40 0.17 1.40 4.08
f i: t f + t * * Ik
0.09 0.09 0.56* 0.51 0.17 0.16 0.09 0.14 0.53
group.
of rats (Table II). In contrast, embolized rats had quite different changes incardiac index. In fact, an 18% increase in cardiac index (p < 0.01) was observed compared with saline-treated embolized rats. The difference was even higher when compared with the sham-operated perindopril-treated group (+31%, p < 0.001). The 46% decrease in TPR (p < 0.05) was observed in the perindopril-treated embolized group but not in perindopril sham-operated animals. Effects of perindopril on regional hemodynamics Acute effects. Perindoprilat-induced acute changes in regional blood flow are shown in Table III. In sham-operated rats, 0.5 mg/kg of perindoprilat increased blood flow in the skin by 25% 0, < 0.05), in the small intestine by 27 % (p < 0.05), in the adrenals by 29.5% (p c 0.05), and in the kidneys by 21% (p < 0.05) and decreased vascular resistance in the small intestine by 22% (p < 0.05), adrenals by 22% (p < 0.05), and kidneys by 19% (p < 0.05). Similar changes also occurred in embolized animals, but they
were much greater. Blood flow was increased in the skin by 66 % (p < 0.05), in the small intestine by 92 % 03 < 0.05), in the adrenals by 123 % (p < 0.05), and in the kidneys by 90% (p < 0.05); vascular resistance was reduced in the small intestine by 48 % (p < 0.05), in the adrenals by 47 % (p < 0.05), and in the kidneys by 49% (p < 0.05). In addition, in embolized rats blood flow was increased in the lungs by 74% (JI < 0.05), and vascular resistance was reduced in the skin by 39.5% (p < 0.05), in the stomach by 21% (p < 0.05), in the brain by 21.5% (p < 0.05), and in the lungs by 33% (p < 0.05). Chronic effects. The measurements of blood flow (Table IV) in various organs has not revealed significantly lower blood flow or higher vascular resistance in any organ in the embolized group when compared with the sham-operated group. Changes in regional blood flow after perindopril treatment are shown in Table IV. In most of the organs studied in sham-operated rats, perindopril treatment did not influence the level of blood flow. There was a tendency for
September 1993 American Heart Journal
76% Medvedev and Gorodetskaya
a
sham
m
embolized
10
0
DISCUSSION
a cz 0
vs 7.4 + 0.2 mm Hg, p < 0.05). Perindoprilat was potent in decreasing MCFP only in rats with coronary embolization (Fig. 1). Chronic effects. In sham-operated animals perindopril produced a strong and highly significant decrease in MCFP (by 13 %, p < 0.01) (Fig. 1). In rats with coronary embolization, perindopril treatment was followed by a decrease in MCFP (by 26%) p < 0.01).
-10
s
-20
-30 Acute admin.
Chronic
admin.
Fig. 1.8 Effects of snort-term administration of perindoprilat (0.5 mgl/kg, intravenously;bolus) and long-term treatment with perindopril (2 mg/kg, orally, once a day for 21 days) on MCFP in sham-operated and embolized rats. (*p < 0.05 compared with saline-treated control rats; #p < 0.05 compared with sham-operated group; up < 0.05 compared with appropriate group of rats receiving shortterm treatment with perindoprilat.)
blood flow to increase in the kidney (NS); only the heart had a decrease in blood flow from 6.97 _t 0.89 (saline-treated group) to 4.41 4 0.80 ml/min/gm (in perindopril-treated rats) that is, a decrease of 37% (p < 0.05). Perindopril-treated sham-operated rats had significantly lower vascular resistance only in the kidney (-31%; p < 0.05). Effects of perindopril on cardiovascular function in embolized’rats were quite different. Perindopril-treated rats had significantly higher, blood flow in the kidney (+47 % , p < 0.05) and lower vascular resistance in the’kidney, stomach, and brain compared with saline-treated animals. Vascular’resistance in the stomach and the brain was significantly lower and significantly higher in the small intestine when compared with the respective values in the perindopril-treated, sham-operated rats. Perindoprii-induced
changes
in MCFP
Acute egects. Rats with the embolized coronary vessels had significantly higher baseline levels of MCFP compared with sham-operated’rats (8.5 + 0.2
In rats with coronary vessel embolization the main signs of experimental heart failure were clearly distinguished: high LVEDP and high venous tone (high preload) compared with sham-operated rats. They had slightly higher TPR and lower cardiac index. Thus depressed cardiac performance indicating chronic heart failure is documented by hemodynamic data, which are similar to the signs of heart insufliciency reported previously.8J 15-r7 In the preliminary short-term study, perindoprilat improved hemodynamic function of the heart, regional blood flows, and venous tone. The manifestation of some of these features was somewhat less prominent in the long-term study with perindopril but could be explained by a development of more moderate level of heart failure (no increase in TPR and no decrease in regional blood in the saline embolized group). However, perindopril-treated rats had a higher level of cardiac index, lower mean circulatory filling pressure, and TPR compared with salinetreated animals. These findings resemble those of captopril.8p 18-21In rats with congestive heart failure caused by large myocardial infarction21 captopril decreased TPR, mean arterial pressure, and left ventricular systolic pressure. The most prominent effect occurred in the renal circulation; the increase in renal flow was more pronounced in heart failure group than in sham-operated animals. It is important that the main results of our study closely resemble those of clinical trials on angiotensin-converting enzyme inhibitors. In patients with congestive heart failure captopril significantly increased cardiac index, reduced blood pressure and TPR,18, 2o and enhanced renal flow by 60 % .18Results of our experiments are close to the earlier findings of Raya et a1.,8 which showed that captopsil treatment decreased MCFP and blood volume whereas venous compliance increased in rats with chronic left ventricular dysfunction after myocardial infarction. We assume that the increase in venous tone is one of the most sensitive criteria for the development of experimental heart failure;,.which is dependent on the activation of renin-angiotensin system. AS a result of
Volume 126, Number 3, Part 2
American
Medvedev
Heart Journal
the above, venous vessels might be one of the main targets for the perindopril-like drugs in patients with CHF.
12.
REFERENCES
1. Arnolda L, McGrath BP, Johnston CI. Vasopressin and angiotensin II contribute equally to the increased afterload in rabbits with heart failure. Cardiovasc Res 1991:25:68-72. 2. Borek M, Charlap S, Frishman WH. Angiotensin-converting enzyme inhibitors in heart failure. Med Clin North Am 1989; 73:315-38. 3. Giudicelli JF, Richer C, Richard C, Thuillez C. Angiotensin converting enzyme inhibition: systemic and regional hemodynamics inrats and humans. Am J Hypertens 1991;4:2588-629. 4. Nishimura H. Kubo S. Uevama M. Kubota J, Kawamura K. Peripheral hemodynamic effects of captopril in patients with congestive heart failure. AM HEART J 1989;117:100-5. 5. Heidland A, Teschner M, Gotz R. Changes in renal function in heart failure and their modification by conversion enzyme inhibitors. Klin Wochenschr 1991;69(suppl24):65-72. 6. Thuillez C, Richard C, Loueslati H, Auzepy P, Giudicclli JF. Systemic and regional hemodynamic effects of perindopril in congestive heart failure. J Cardiovasc Pharmacol1990;15:52735. 7. Muir AL, Nolan J. Modulation of venous tone in heart failure. AM HEART J 1991;121:1948-50. 8. Raya T, Gay RG, Aquirre M, Goldman S. Importance of venodilatation in prevention of left ventricular dilatation after chronic large myocardial infarction in rats. Circ Res 1989; 64:H330-H7. 9. Cox RH, Bagshaw FJ. Influence of anesthesia on the response to carotid hypotension in the dog. Am JPhysiol1979;237:H424H32. 10. Gorodetskaya EA, Dugin SF, Medvedev OS, Allabergenova EA. Simple method to produce acute heart failure by coronary vessel embolization in closed chest rats with microsphere. J Pharmacol Method 1990;24:43-51. 11. Heymann MA, Payne BD, Hoffman JIE, Rudolf AM. Blood
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