Bradykinin Mediation of Ca2+-Activated K+Channels Regulates Coronary Blood Flow in Ischemic Myocardium

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Abstract
BackgroundEndothelium-dependent hyperpolarizing factor relaxes vascular smooth muscles by opening the Ca2+-activated K+(KCa) channels. The role of the opening of KCachannels in coronary vasodilation during myocardial ischemia was investigated.Methods and ResultsThe left anterior descending coronary arteries of open-chest dogs were perfused with blood through an extracorporeal bypass tube from the carotid artery. Intracoronary administration of bradykinin increased coronary blood flow (CBF) in dogs treated withNG-nitro-l-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase; this effect was completely inhibited by the KCachannel blocker iberiotoxin. In dogs treated with L-NAME, the bypass tube was occluded to reduce CBF to one third of the baseline value, after which coronary perfusion pressure was maintained constant. Intracoronary administration of iberiotoxin for 20 minutes further decreased CBF (from 33±2 to 19±2 mL·100 g−1·min−1,P<.01), fractional shortening, and lactate extraction ratio during coronary hypoperfusion. Bradykinin was released, and the bradykinin receptor antagonist HOE-140 blocked the effects of iberiotoxin on coronary hemodynamic and metabolic parameters during myocardial ischemia. Although the combination of L-NAME and the adenosine receptor antagonist 8-sulfophenyltheophylline reduced reactive hyperemic flow after 20 seconds of coronary occlusion, the additional presence of iberiotoxin resulted in a further decrease in this parameter.ConclusionsThe opening of KCachannels in response to endogenous bradykinin contributed to coronary vasodilation and reduced contractile and metabolic dysfunction during myocardial ischemia in open-chest dogs.

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