Cellular mechanisms of cardioprotection afforded by inhibitors of angiotensin converting enzyme in ischemic hearts: Role of bradykinin and nitric oxide

Angiotensin converting enzyme (ACE) inhibitors inhibit the degradation of b radykinin and contribute to accumulation of bradykinin and NO, both of whic h may be beneficial for diseased hearts. To test this idea, we administered imidaprilat and cilazaprilat, respectively to the canine ischemic myocardi um. In the open chest dogs with law constant coronary perfusion pressure (C PP, from 104+/-3 to 42+/-3 mmHg), coronary blood flow (CBF, 91+/-1 to 32+/- 2 ml/100 g/min), fractional shortening (FS), and lactate extraction ratio ( LER) decreased. Either imidaprilat or cilazaprilat increased CBF, FS, and L ER with increases in cardiac bradykinin and NO levels. The beneficial effec ts of ACE inhibitors were blunted by either L-NAME (an inhibitor of NO synt hase) and HOE140 (an inhibitor of bradykinin receptors), respectively. ACE inhibitors, on the other hand, are reported to attenuate the severity of my ocardial stunning, which effect is partially attributable to bradykinin- an d NO-dependent mechanisms. Further, ACE inhibitors limited infarct size fol lowing coronary occlusion and reperfusion. This infarct size-limitation was blunted by either L-NAME and IBTX (the antagonist of K-Ca channels). Brady kinin is also reported to close K-Ca channels. Thus, we concluded that ACE inhibitors attenuate both reversible and irreversible myocardial cellular i njury via bradykinin\NO-dependent mechanisms. In experimental and clinical settings, the cardioprotective effects of ACE inhibitors on the diseased he art may be attributable to these mechanisms.