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，日本患有缺血性心脏病（如心绞痛和心肌梗塞）的患者人数正在增加。为了建立药理学策略，重要的是要了解急性心肌梗塞中缺血性细胞损伤和心室心律不齐的病理生理。在缺血性心肌细胞ATP敏感的K^+（K_ <ATP>）通道中，通过降低细胞内的ATP ATP ATP ATP ATP ATP敏感性K^+（K_ <ATP>）通道可能会导致细胞内ATP的降低。 K_ <ATP>通道的激活可以通过间接减少跨膜Ca^<++>涌入来保护缺血性心肌。但是，K_ <ATP>通道开口可能会导致由于动作电位持续时间降低（APD）和有效难治时期而导致致死性心律不齐。据报道，在急性心肌缺血期间，血浆中内源性内皮素-1（ET-1）增加。这项研究是为了检查ET受体和Alpha_1-Adreoceptor刺激对心脏K_ <ATP>通道的影响，并使用标准的微电极和斑块夹技术。 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或Cromakalim。这些受体刺激还部分逆转了kco.的作用潜在缩短，此外，α_1-肾上腺素能刺激抑制了在减少缺血状态下的作用势缩短。因此，由et_a-or alpha_ <1a> - 受体受体对I_ <k.atp> MD抑制可能对缺血性心肌细胞有害，因为它可能会产生细胞内Ca^<++>过载。