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

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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.