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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.

最近，日本患有心绞痛和心肌梗塞等缺血性心脏病的患者数量正在增加。了解急性心肌梗死时缺血细胞损伤和室性心律失常的病理生理学机制对于制定药物治疗策略具有重要意义。在缺血心肌细胞中，细胞内ATP含量的降低激活了ATP敏感性钾通道，导致动作电位缩短。激活K&lt；ATP&gt；通道可能通过间接减少跨膜钙内流对缺血心肌产生保护作用。然而，由于动作电位时程和有效不应期的缩短，K&lt；ATP&gt；通道开放可能导致致死性室性心律失常的发生。有报道称，急性心肌缺血时，血浆内源性内皮素-1(ET-1)和交感神经活性增加。本研究采用标准微电极和膜片钳技术，观察ET受体和α_1受体对心肌K_lt；ATP&gt通道的影响。我希望通过这样做，我们将比以前的研究更深入地了解这些神经体液因子对缺血细胞损伤的潜在机制。在分离的豚鼠心室细胞中，ET_A受体和α_1受体共同地抑制由K~+通道开放剂(KCO)、尼可地尔或克罗卡林激活的ATP敏感性钾电流(I_&lt；K.ATP&gt；)。这些受体的刺激也部分逆转了KCO引起的动作电位缩短。此外，在模拟缺血的条件下，α_1肾上腺素能刺激抑制动作电位的缩短。因此，ET_A-或α_lt；1A&gt；受体抑制心肌细胞内钙超载，对缺血心肌细胞可能是有害的。