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

寻找心脏Cl^-通道阻滞剂：新型抗心律失常药物的开发

基本信息

批准号：
07557173
负责人：
NAKAYA Haruaki
金额：
$ 7.3万
依托单位：
Chiba University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1997
项目状态：
已结题

项目摘要

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

肿胀诱导的 Cl^- 通道的激活可能与心肌缺血和再灌注期间心律失常的发生有关。为了评估 Cl^- 通道的病理生理作用，找到一种特异性的 Cl^- 通道阻断剂非常重要。 ^- 通道，因为已知其他 Cl^- 通道阻滞剂（包括二苯乙烯衍生物）会影响其他离子通道，我们研究了许多具有喹啉酮结构的化合物对通道的影响。 Cl^- 使用膜片钳技术在分离的豚鼠心房细胞中暴露于低渗溶液（54-63% 渗透压）诱导的电流。在检查的许多化合物中，OPC 18360（1-甲基-4-（1-哌嗪基）-）。 100 μM 浓度的 2 (1H) 喹啉酮盐酸盐）显着抑制肿胀诱导的 Cl^- 电流，同时略微增强 cAMP 依赖性1 μM 异丙肾上腺素激活的 Cl^- 电流虽然略有影响，但未能影响 L 型 Ca^<++> 电流和内向整流器 K^+ 电流 (I_<K1>)。在电流钳模式下，延迟整流K^+电流（I_K）和Na^+电流（I_<Na>）略有延长心房细胞记录的动作电位。还在麻醉的开胸狗中评估了 OPC 18360 轻微增加的张力。静脉注射 1 mg/kg OPC 18360 不会显着影响平均血压。 OPC 18360 减少了冠状动脉期间的心率和心电图参数。然而，该药物未能预防冠状动脉闭塞和再灌注期间的心室颤动。因此，可以得出结论，OPC 18360是肿胀诱导的Cl^-通道的特异性阻断剂。但是，还需要进一步寻找更有效的药物。开发临床适用的抗心律失常药物可能需要Cl^-通道阻滞剂。