Mechanism of preconditioning against myocardial infarction

包括我们在内的研究表明，A1受体的激活触发了缺血预处理（PC）的心脏保护作用。然而，A1受体激活后的机制仍不清楚。本研究旨在探讨钠-氢交换体、ATP敏感性钾通道（KATP）和蛋白激酶C在预适应中的作用。在戊巴比妥钠麻醉下，结扎家兔冠状动脉30分钟再灌注，造成心肌梗塞。5分钟缺血/5分钟再灌注预处理将梗死面积限制在对照值的约40%。在PC前60分钟给予Na-H交换抑制剂阿米洛利（1.3 mg/kg和3.0 mg/kg）未能阻断预处理，尽管这种药物显著降低动脉pH和HCO 3 ^-，表明肾脏中的Na-H交换抑制。KATP的特异性阻断剂格列本脲（0.3 mg/kg）在戊巴比妥/甲苯噻嗪麻醉的家兔中减弱PC，但在单独给予戊巴比妥的家兔中未观察到这种抑制作用。两种不同的PKC抑制剂，星形孢菌素（50 μ g/kg）和多粘菌素B（2.5 mg/kg）完全消除了A1受体激动剂R-苯基异丙基腺苷（模拟预处理）的梗死面积限制作用。这些剂量的星形孢菌素和多粘菌素B显示阻断兔对4 β-12-肉豆蔻酸酯13-乙酸酯的变力性反应，表明PKC抑制剂的剂量足以阻断体内PKC。这些结果表明，激活A1受体激活后的PKC介导的心肌梗死范围的限制预处理在兔。KATP也可能有助于预处理，但其作用可能被麻醉剂改变。PKC与KATP的关系有待进一步研究。

Previous studies, including ours, demonstrated that activation of A1 receptor triggers the cardioprotective effect of ischemic preconditioning (PC). However, mechanism subsequent to the A1 receptor activation remains unclear. The present study aimed to test the roles of Na-H exchanger, ATP sensitive potassium channel (KATP), and protein kinase C in preconditioning. Under pentobarbital anesthesia, myocardial infarction was induced in the rabbit by occluding coronary artery for 30 min and reperfusion. Preconditioning with 5 min ischemia/5 min reperfusion limited infarct size to approximately 40% of thecontrol values. An inhibitor of Na-H exchanger, amiloride (1.3 mg/kg and 3.0 mg/kg) given 60 min before PC failed to block preconditioning, though this agent significantly reduces arterial pH and HCO3^-, suggesting inhibition of Na-H exchanger in the kidneys. A specific blocker of KATP,glibenclamide (0.3 mg/kg) attenuated PC in the rabbit anesthetized with pentobarbital/xylazine, but such inhibitory effect was not observed in those given pentobarbital alone. Two different PKC inhibitors, staurosporine (50 mug/kg) and polymyxin B (2.5 mg/kg) completely abolished infarct size-limiting effect of an A1 receptor agonist, R-phenylisopropyladenosine, which mimics preconditioning. Those doses of staurosporine and polymyxin B were shown to block inotropic response to 4beta-12-myristate 13-acetate in the rabbits, suggesting that the dose of the PKC inhibitors were sufficient to block PKC in vivo. These results suggest that activation of PKC subsequent to A1 receptor activation mediates infarct size limitation by preconditioning in the rabbit. KATP may also contribute to preconditioning, but its role may be modified by anesthetics. Relationship between PKC and KATP warrants further investigation.