Turgeon J, Fiset C, Kingma M L, Lacoursière L, Kingma J G
Quebec Heart Institute, Laval Hospital, Ste-Foy, Quebec, Canada.
J Cardiovasc Pharmacol. 1995 Oct;26(4):518-23. doi: 10.1097/00005344-199510000-00002.
The delayed rectifier potassium current (IK) is a major repolarizing current in guinea pig ventricular myocytes. Blockade of IK or other repolarizing currents is of increasing interest for development of antiarrhythmic drugs; however, these interventions may also be proarrhythmic. In the present study, we compared the potential antiarrhythmic properties of indapamide and chlorthalidone, two structurally related sulfonamide diuretics which differ in their ability to block the slow component of the delayed rectifier (IKs) in isolated, buffer-perfused guinea pig hearts. Hearts underwent 30-min global no-flow ischemia and 10-min reperfusion. Dose-response (10(-7)-10(-4) M) effects of indapamide or chlorthalidone on reperfusion-induced arrhythmias, coronary flow, and heart rate (HR) were evaluated in a randomized blinded fashion. There was no significant difference in the incidence of ventricular fibrillation (VF) for either compound as compared with untreated controls. However, VF duration was reduced to < 40 s in all hearts treated with indapamide 10(-4) M). Mean VF duration with indapamide 10(-4) M was 31 +/- 4 versus 70 +/- 40 s in controls (p < 0.05). Chlorthalidone did not protect against reperfusion-induced arrhythmias. HR was unchanged with either compound; coronary flow during the control perfusion period increased approximately 43% with indapamide 10(-4) M (p < 0.05 vs. all treatment groups). These results demonstrate that indapamide, but not chlorthalidone, confers significant protection against reperfusion-induced VF in this experimental preparation and suggest that selective block of IKs may be antiarrhythmic.
延迟整流钾电流（IK）是豚鼠心室肌细胞中的主要复极电流。阻断IK或其他复极电流在抗心律失常药物研发中越来越受到关注；然而，这些干预措施也可能促发心律失常。在本研究中，我们比较了吲达帕胺和氯噻酮这两种结构相关的磺胺类利尿剂的潜在抗心律失常特性，它们在分离的、缓冲灌注的豚鼠心脏中阻断延迟整流器慢成分（IKs）的能力有所不同。心脏经历30分钟的全心无血流缺血和10分钟的再灌注。以随机双盲方式评估吲达帕胺或氯噻酮对再灌注诱导的心律失常、冠状动脉血流和心率（HR）的剂量反应（10^(-7)-10^(-4) M）效应。与未治疗的对照组相比，两种化合物的心室颤动（VF）发生率均无显著差异。然而，在所有用10^(-4) M吲达帕胺治疗的心脏中，VF持续时间缩短至<40秒。10^(-4) M吲达帕胺组的平均VF持续时间为31±4秒，而对照组为70±40秒（p<0.05）。氯噻酮不能预防再灌注诱导的心律失常。两种化合物对HR均无影响；在对照灌注期，10^(-4) M吲达帕胺使冠状动脉血流增加约43%（与所有治疗组相比，p<0.05）。这些结果表明，在该实验制剂中，吲达帕胺而非氯噻酮能显著保护心脏免受再灌注诱导的VF，并提示选择性阻断IKs可能具有抗心律失常作用。
