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

最近，日本的心绞痛、心肌梗塞等缺血性心脏病患者正在增加。了解急性心肌梗死缺血性细胞损伤和室性心律失常的病理生理机制，对制定药物治疗策略具有重要意义。缺血肌细胞中，ATP敏感的K^+ (K_<ATP>)通道被激活，细胞内ATP减少，导致动作电位缩短。激活K_<ATP>通道可能通过间接减少跨膜Ca^<++>内流来保护缺血心肌。然而，K_<ATP>通道开度可导致动作电位持续时间（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。据报道，急性心肌缺血时血浆内源性内皮素-1 （ET-1）和交感神经活性升高。本研究采用标准微电极和膜片钳技术研究ET受体和α _1-肾上腺受体刺激对心脏K_<ATP>通道的影响。我希望通过这样做，我们能更深入地了解缺血的潜在机制。与之前的研究相比，这些神经体液因子对细胞损伤的影响更大。在离体豚鼠心室细胞中，共同刺激ET_A受体和α _<1A>受体可抑制K^+通道打开剂（KCO）、尼可地尔或克罗卡林激活的atp敏感K^+电流（I_<K. atp >）。这些受体刺激也部分逆转了KCO诱导的动作电位缩短。此外，在缺血模拟条件下，α _1-肾上腺素能刺激可抑制动作电位缩短。因此，I_<K。由et_a或α _<1A>受体介导的ATP>可能对缺血肌细胞有害，因为它可能产生细胞内Ca^<++>过载。

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.