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

肿胀诱导的氯离子通道激活可能参与了心肌缺血再灌注性心律失常的发生。为了评价氯离子通道的病理生理作用，寻找氯离子通道的特异性阻断剂是很重要的，因为已知包括二苯乙烯衍生物在内的其他氯离子通道阻滞剂也会影响其他离子通道。用膜片钳技术观察了多种喹诺酮类化合物对低渗溶液(54-63%渗透压)诱导的豚鼠心房肌细胞氯离子电流的影响。在所研究的多种化合物中，OPC 18360(1-甲基-4-(1-哌嗪基)-2(1H)喹啉酮盐酸盐)在100um时显著抑制肿胀引起的氯离子电流，而对1um异丙肾上腺素所激活的cAMP依赖的氯离子电流有轻微的增强作用。相同浓度的化合物不影响L型钙离子通道电流和…内向整流K~+电流(I_t；K_1&>t；)略有降低，延迟整流K~+电流(I_K)和Na~+电流(I_t；Na&>t；)略有降低。该药略微延长了在电流钳制模式下记录的心房细胞动作电位。在豚鼠乳头肌，OPC 18360使已形成的张力略有增加。在麻醉开胸犬模型上，还观察了欧普克18360对缺血和再灌注性心律失常的影响。静脉注射OPC 18360 1 mg/kg对平均血压、心率和心电参数无明显影响。OPC 18360可减少冠脉闭塞30min时的室性早搏总数。然而，该药物未能防止冠状动脉闭塞和再灌流期间的室颤。因此，可以推断OPC-18360是一种特异性的溶胀诱导的氯离子通道阻断剂。然而，为了开发一种临床适用的抗心律失常药物，可能需要进一步寻找更有效的氯离子通道阻滞剂。较少

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