Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, Academy of Military Medical Sciences, 20 Dongdajie Street, Fengtai District, Beijing 100071, PR China.
Eur J Pharmacol. 2011 Jun 25;660(2-3):259-67. doi: 10.1016/j.ejphar.2011.03.039. Epub 2011 Apr 12.
Cyclovirobuxine D (CVB-D) has been widely used for treatment of cardiac insufficiency and arrhythmias in China. The antiarrhythmic and proarrhythmic potential of this drug might be concerned with prolongation of action potential duration and QT interval. Human-ether-a-go-go-related gene (HERG) has an important role in the repolarization of the cardiac action potential. This study investigated for the first time the effect of CVB-D on HERG channels stably expressed in HEK293 cells using the whole-cell patch-clamp technique. CVB-D inhibited HERG current (IHERG) in a concentration-dependent manner with an IC50 of 19.7 μM. IHERG blockade required channel activation and was time-dependent, suggesting an open channel block. Moreover, IHERG inhibition by CVB-D was relieved by depolarization to a highly positive membrane potential (+80 mV) that favored HERG channel inactivation. These findings suggested that CVB-D inhibit HERG channels in the open states. CVB-D had no effect on HERG current kinetics. Thus, we conclude that CVB-D inhibits HERG encoded potassium channels and this action might be a molecular mechanism for the previously reported APD prolongation and QT interval prolongation with this drug.
环维黄杨星 D（CVB-D）在中国被广泛用于治疗心功能不全和心律失常。这种药物的抗心律失常和致心律失常作用可能与动作电位持续时间和 QT 间期的延长有关。人 ether-a-go-go 相关基因（HERG）在心动作电位复极中起重要作用。本研究首次采用全细胞膜片钳技术研究了 CVB-D 对稳定表达于 HEK293 细胞的 HERG 通道的影响。CVB-D 呈浓度依赖性抑制 HERG 电流（IHERG），IC50 为 19.7 μM。IHERG 阻断需要通道激活并具有时间依赖性，提示为开放通道阻断。此外，CVB-D 对 IHERG 的抑制作用可被去极化至高度正膜电位（+80 mV）缓解，这有利于 HERG 通道失活。这些发现表明 CVB-D 在开放状态下抑制 HERG 通道。CVB-D 对 HERG 电流动力学没有影响。因此，我们得出结论，CVB-D 抑制 HERG 编码的钾通道，这一作用可能是先前报道的该药物 APD 延长和 QT 间期延长的分子机制。
