Abstract

Inhibitors of bradykinin (BK)-inactivating enzymes protect from myocardial ischemia/reperfusion injury after short periods of reperfusion. However, protection after 2 to 3 h of reperfusion does not mean that myocardium remains viable for an extended time. Therefore, we examined the effects of inhibitors of angiotensin-converting enzyme (ramiprilat), EP24.11 (cFP-F-pAB), and EP24.15 (cFP-AAF-pAB) in a chronic model of myocardial ischemia/reperfusion injury. A left descending coronary artery was occluded for 30 min in anesthetized rabbits. Saline, ramiprilat, or endopeptidase inhibitors were given after 27 min of occlusion. The BK₂ receptor antagonist HOE140 was administered in certain experiments. After ischemia, the occlusion was released, and the animal allowed to recover for 3 or 7 days. Surgery was then repeated, and the heart removed for determination of infarct size. In separate experiments, the heart was removed after 2 h of reperfusion for determination of BK tissue levels. Ramiprilat and endopeptidase inhibitors reduced infarct size at 3 and 7 days. Combining inhibitors further reduced infarct size after 3 days. The protective effect of the endopeptidase inhibitors was blocked by HOE140. Infarct sizes at 7 days were larger than at 3 days. The additive effect of multiple inhibitors was absent at 7 days. Ramiprilat and cFP-F-pAB significantly increased tissue BK levels. We conclude that inhibition of BK-inactivating enzymes protects endogenous BK from degradation and provides long-lasting protection from myocardial ischemia/reperfusion injury. A single treatment at the time of reperfusion does not prevent extension of the infarction between 3 and 7 days.