Beneficial Effects of Inhibition of Angiotensin-Converting Enzyme on Ischemic Myocardium During Coronary Hypoperfusion in Dogs

Abstract

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 ω -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.