Jo Su-Hyun, Hong Hee-Kyung, Chong Seon Ha, Won Kwang Hee, Jung Sung Jun, Choe Han
Department of Physiology, Institute of Bioscience and Biotechnology, Kangwon National University College of Medicine, Chuncheon 200-701, Korea.
Eur J Pharmacol. 2008 Sep 11;592(1-3):19-25. doi: 10.1016/j.ejphar.2008.06.094. Epub 2008 Jul 2.
Clomipramine is a tricyclic antidepressant for psychiatric disorders that can induce QT prolongation, which may lead to torsades de pointes. Since blockade of cardiac human ether-a-go-go-related gene (hERG) channels is an important cause of acquired long QT syndrome, we investigated the acute effects of clomipramine on hERG channels to determine the electrophysiological basis for its proarrhythmic potential. We examined the effects of clomipramine on the hERG channels expressed in Xenopus oocytes and HEK293 cells using two-microelectrode voltage-clamp and patch-clamp techniques. Clomipramine induced a concentration-dependent decrease in the current amplitude at the end of the voltage steps and hERG tail currents. The IC50 for clomipramine needed to block the hERG current in Xenopus oocytes decreased progressively relative to the degree of depolarization. The fractional electrical distance was estimated to be delta=0.83. The IC50 for the clomipramine-induced blockade of the hERG currents in HEK293 cells at 36 degrees C was 0.13 microM at +20 mV. Clomipramine affected the channels in the activated and inactivated states but not in the closed states. The clomipramine-induced blockade of hERG was found to be use-dependent, exhibiting a more rapid onset and a greater steady-state block at the higher frequencies of activation. The S6 domain mutations, Y652A and F656A partially attenuated (Y652A) or abolished (F656A) the hERG-current blockade. These results suggest that clomipramine is a blocker of the hERG channels, providing a molecular mechanism for the arrhythmogenic side effects during the clinical administration of clomipramine.
氯米帕明是一种用于治疗精神疾病的三环类抗抑郁药，可导致QT间期延长，进而可能引发尖端扭转型室性心动过速。由于心脏人ether-a-go-go相关基因（hERG）通道的阻断是获得性长QT综合征的一个重要原因，我们研究了氯米帕明对hERG通道的急性影响，以确定其致心律失常潜力的电生理基础。我们使用双微电极电压钳和膜片钳技术，研究了氯米帕明对非洲爪蟾卵母细胞和HEK293细胞中表达的hERG通道的影响。氯米帕明在电压阶跃结束时和hERG尾电流处诱导电流幅度呈浓度依赖性降低。相对于去极化程度，阻断非洲爪蟾卵母细胞中hERG电流所需的氯米帕明的半数抑制浓度（IC50）逐渐降低。分数电距离估计为δ=0.83。在36℃时，氯米帕明诱导阻断HEK293细胞中hERG电流的IC50在+20 mV时为0.13 microM。氯米帕明影响处于激活和失活状态的通道，但不影响处于关闭状态的通道。发现氯米帕明诱导的hERG阻断具有使用依赖性，在较高激活频率下表现出更快的起效和更大的稳态阻断。S6结构域突变Y652A和F656A部分减弱（Y652A）或消除（F656A）了hERG电流阻断。这些结果表明，氯米帕明是hERG通道的阻断剂，为氯米帕明临床应用期间的致心律失常副作用提供了分子机制。
