(Circulation. 1995;92:950-961.)
© 1995 American Heart Association, Inc.
Articles |
Beneficial Effects of Inhibition of Angiotensin-Converting Enzyme on Ischemic Myocardium During Coronary Hypoperfusion in Dogs
From The First Department of Medicine (M.K., T.M., K.N., K.K., M.H., T.K.), Osaka University School of Medicine, Osaka; Department of Physiology (Y.S., H.M.), Tokai University School of Medicine, Isehara; Department of Physiology (H.K.), Osaka University School of Medicine, Osaka; and Department of Information Science (M.I.), Osaka University School of Medicine, Osaka, Japan.
Correspondence to Masafumi Kitakaze, MD, PhD, The First Department of Medicine, Osaka University School of Medicine, 2-2 Yamadaoka, Suita 565, Japan.
Background Angiotensin-converting enzyme (ACE) produces angiotensin II, causing vasoconstriction of coronary arteries and reduction of coronary blood flow. The present study was undertaken to test the hypothesis that an ACE inhibitor increases coronary blood flow and improves myocardial metabolic and contractile functions of ischemic myocardium.
Methods and Results In 65 open-chest dogs, the left anterior
descending coronary artery was perfused through an
extracorporeal bypass tube from the left carotid artery. When
cilazaprilat (3 µg/kg per minute) was infused into the bypass tube
for 10 minutes after reduction of coronary blood flow due to
partial occlusion of the bypass tube, coronary blood flow
increased from 30±1 to 43±2 mL/100 g per minute despite there
being
no changes in coronary perfusion pressure (43±1 mm Hg). The
ratio of myocardial endocardial flow to epicardial flow increased
during an infusion of cilazaprilat. Both fractional shortening and
lactate extraction ratio of the perfused area were increased
(fractional shortening: 4.1±0.6% to 8.9±0.6%,
P<.001;
lactate extraction ratio: -55.7±3.3% to -36.7±3.9%,
P<.001). During an infusion of cilazaprilat, the bradykinin
concentration of coronary venous blood was markedly increased.
The increased coronary blood flow due to cilazaprilat was
attenuated by HOE-140 (an inhibitor of bradykinin
receptors; coronary blood flow: 35±2 mL/100 g per minute), and
by N
-nitro-L-arginine methyl
ester (an inhibitor of nitric oxide synthase;
coronary blood flow: 34±2 mL/100 g per minute).
Intracoronary administration of bradykinin mimicked the
beneficial effects of cilazaprilat. Cyclic GMP content of the
coronary artery was increased by cilazaprilat compared with the
untreated condition in the ischemic myocardium. In
the denervated hearts, the increased coronary blood flow due to
cilazaprilat was not attenuated. On the other hand, CV11974, an
inhibitor of angiotensin II receptors, slightly
increased coronary blood flow to 34±2 from 30±1 mL/100 g per
minute.
Conclusions We conclude that an inhibitor of ACE can increase coronary blood flow and ameliorate myocardial ischemia, primarily due to accumulation of bradykinin and production of nitric oxide from the ischemic myocardium. Inhibition of angiotensin II production due to inhibition of ACE partially contributes to coronary vasodilation in the ischemic myocardium.
Key Words: angiotensin-converting inhibitor • nitric oxide • cilazaprilat • myocardial ischemia • bradykinin
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