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Pathophysiological gignificance of endothelin receptor-mediated regulation of the cardiac ATP-sensitive K channel

内皮素受体介导的心脏 ATP 敏感 K 通道调节的病理生理学意义

基本信息

批准号：
06670099
负责人：
NAKAYA Haruaki
金额：
$ 1.28万
依托单位：
Chiba 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：
1994
资助国家：
日本
起止时间：
1994 至 1995
项目状态：
已结题

项目摘要

Recently the number of patients suffering from ischemic heart disease such as angina pectoris and myocardial infarction is increasing in Japan. For the establihsment of the pharmacological strategy, it is important to understand the pathophysiology of ischemic cell damage and ventricular arrhythmias in acute myocardial infarction.In the ischemic myocytes ATP-sensitive K^+ (K_<ATP>) channels are activated by a decrease in intracellular ATP,resulting in action potential shortening. Activation of K_<ATP> channels may protect ischemic myocardium by indirectly reducing transmembrane Ca^<++> influx. However, K_<ATP> channel opening may lead to occurrence of lethal ventricular arrhythmias due to decreases in action potential duration (APD) and effective refractory period. It has been reported that endogenous endothelin-1 (ET-1) in plasma and sympathetic activity are increased during acute myocardial ischemia. This study was undertaken to examine the effects of ET receptor and alpha_1-adreoceptor stimulation on cardiac K_<ATP> channels by using standard microelectrode and patch clamp techniques. I hoped that by so doing we would gain greater insight into the underlying mechanisms of ischem., cell injuries by these neurohumoral factors than was available from previous studies.In isolated guinea-pig ventricular cells, stimulation of ET_A receptors and alpha_<1A>-receptors in common inhibited the ATP-sensitive K^+ current (I_<K.ATP>) activated by K^+ channel opener (KCO) , nicorandil or cromakalim. These receptor stimulation also partially reversed the action potential shortening induced by KCO.In addition, alpha_1-adrenergic stimulation inhibited the action potential shortening under an ischemia-simulating condition. Thus, the inhibition of I_<K.ATP> mdiated by ET_A-or alpha_<1A>-receptors may be deleterious for ischemic myocytes because it may produce intracellular Ca^<++> overload.

近年来，在日本，患有缺血性心脏病如心绞痛和心肌梗塞的患者数量正在增加。在急性心肌梗死中，心肌细胞ATP敏感性K^+（K_<ATP>）通道由于细胞内ATP减少而被激活，导致动作电位缩短。钾通道的激活<ATP>可能通过间接减少跨膜Ca^++内流而保护缺血心肌。然而，钾<ATP>通道开放可能导致动作电位时程（APD）和有效不应期缩短，从而导致致死性室性心律失常的发生。研究表明，急性心肌缺血时血浆内皮素-1（ET-1）水平升高，交感神经活性增强。本研究采用标准微电极和膜片钳技术观察了ET受体和α 1肾上腺素受体刺激对心脏钾通道的影响<ATP>。我希望通过这样做，我们可以更深入地了解缺血的潜在机制，在离体豚鼠心室肌细胞中，ET_A受体和α<1A>_受体共同抑制<K.ATP>由K^+通道开放剂（KCO）、尼可地尔或克罗卡林激活的ATP敏感性K^+电流（I_）。这些受体刺激也部分逆转了KCO引起的动作电位缩短，此外，α_1-肾上腺素能刺激也抑制了模拟缺血条件下的动作电位缩短。因此，抑制<K.ATP>ET_A或α受体介导的I_2<1A>可能对缺血心肌细胞有害，因为它可能产生细胞内Ca ~（++）超载。