Search for a cardiac Cl^- channel blocker : Development of a novel type of antiarrhythmic drug

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Activation of swelling-induced Cl^- channels may be involved in the genesis of cardiac arrhythmias during myocardial ischemia and reperfusion. In order to evaluate the pathophysiological role of the Cl^- channel, it would be important to find a specific blocker of the Cl^- channels, because other Cl^- channel blockers including stilben derivatives are known to affect other ion channels. We examined effects of many chemical compounds having quinolinone structures on the Cl^- current induced by exposure to a hypotonic solution (54-63 % osmolarity) in isolated guinea pig atrial cells using patch clamp techniques. Among many chemical compounds examined, OPC 18360 (1-methyl-4- (1-piperazinyl) -2 (1H) quinolinone hydrochloride) at a concentration of 100 muM significantly inhibited the swelling-induced Cl^- current whereas it slightly enhanced the cAMP-dependent Cl^- current activated by 1 muM isoproterenol. The compound at the same concentration failed to affect the L-type Ca^<++> current an … More d the inward rectifier K^+ current (I_<K1>) although it slightly decreased the delayd rectifier K^+ current (I_K) and the Na^+ current (I_<Na>). The drug slightly prolonged the action potential recorded from atrial cells in the current clamp mode. In isolated papillary muscles of guinea pigs OPC 18360 slightly increased the developed tension. Effects of OPC 18360 on the ischemia-and reperfusion-induced arrhythmias were also evaluated in anesthetized open chest dogs. Intravenous administration of 1 mg/kg OPC 18360 did not significantly affect the mean blood pressure, heart rate and ECG parameters. OPC 18360 decreased the number of total ventricular premature contractions during coronary occlusion of 30 min. However, the drug failed to prevent ventricular fibrillation during coronary occlusion and reperfusion. Thus, it can be concluded that OPC 18360 is a specific blocker of the swelling-induced Cl^- channel. However, further search for more potent Cl^- channel blocker may be needed for the development of a clinically applicable antiarrhythmic drug. Less