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Mechanism of preconditioning against myocardial infarction

预处理抗心肌梗死的机制

基本信息

批准号：
04670547
负责人：
MIURA Tetsuji
金额：
$ 1.15万
依托单位：
Sapporo Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1992
资助国家：
日本
起止时间：
1992 至 1993
项目状态：
已结题

项目摘要

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.

包括我们在内的先前研究表明，A1 受体的激活会触发缺血预适应 (PC) 的心脏保护作用。然而，A1 受体激活后的机制仍不清楚。本研究旨在测试 Na-H 交换器、ATP 敏感钾通道 (KATP) 和蛋白激酶 C 在预处理中的作用。在戊巴比妥麻醉下，通过阻断冠状动脉30分钟并再灌注来诱导家兔心肌梗塞。 5 分钟缺血/5 分钟再灌注预处理将梗塞面积限制为对照值的约 40%。在 PC 前 60 分钟给予 Na-H 交换剂抑制剂阿米洛利（1.3 mg/kg 和 3.0 mg/kg）未能阻止预处理，尽管该药物显着降低动脉 pH 值和 HCO3^-，表明抑制肾脏中的 Na-H 交换剂。 KATP 的特异性阻断剂格列本脲 (0.3 mg/kg) 可减弱戊巴比妥/赛拉嗪麻醉的兔子的 PC，但在单独给予戊巴比妥的兔子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 微克/千克) 和多粘菌素 B (2.5 毫克/千克)，完全消除了 A1 受体激动剂 R-苯基异丙基腺苷的梗死面积限制作用，它模拟了预处理。这些剂量的星形孢菌素和多粘菌素 B 被证明可以阻断兔子对 4β-12-肉豆蔻酸 13-乙酸酯的正性肌力反应，表明 PKC 抑制剂的剂量足以阻断体内 PKC。这些结果表明，A1 受体激活后 PKC 的激活通过兔的预处理介导梗塞面积限制。 KATP 也可能有助于预处理，但其作用可能会因麻醉剂而改变。 PKC 和 KATP 之间的关系值得进一步调查。