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 bradykinin and contribute to accumulation of bradykinin and NO, both of which may be beneficial for diseased hearts. To test this idea, we administered imidaprilat and cilazaprilat, respectively to the canine ischemic myocardium. In the open chest dogs with low constant coronary perfusion pressure (CPP, 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 LER with increases in cardiac bradykinin and NO levels. The beneficial effects of ACE inhibitors were blunted by either L-NAME (an inhibitor of NO synthase) and HOE140 (an inhibitor of bradykinin receptors), respectively. ACE inhibitors, on the other hand, are reported to attenuate the severity of myocardial stunning, which effect is partially attributable to bradykinin- and NO-dependent mechanisms. Further, ACE inhibitors limited infarct size following coronary occlusion and reperfusion. This infarct size-limitation was blunted by either L-NAME and IBTX (the antagonist of K(Ca) channels). Bradykinin is also reported to close K(Ca) channels. Thus, we concluded that ACE inhibitors attenuate both reversible and irreversible myocardial cellular injury via bradykinin/NO-dependent mechanisms. In experimental and clinical settings, the cardioprotective effects of ACE inhibitors on the diseased heart may be attributable to these mechanisms.
Kitakaze
M
M
Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Suita, Japan.
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K
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Takashima
S
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Minamino
T
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Kuzuya
T
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Hori
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M
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001920:Bradykinin / Q000502:physiology*; D006801:Humans; D017202:Myocardial Ischemia / Q000188:drug therapy*; D017682:Myocardial Stunning; D009206:Myocardium / Q000378:metabolism; D009569:Nitric Oxide / Q000502:physiology*
D000806:Angiotensin-Converting Enzyme Inhibitors; D009569:Nitric Oxide; D001920:Bradykinin