title: Cyclovirobuxine D inhibits the currents of HERG potassium channels stably expressed in HEK293 cells.
abstract: 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.
authors.affiliation: 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.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.forename: Qiaoxu
authors.initials: Q
authors.lastname: Wang
authors.forename: Jiang
authors.initials: J
authors.lastname: Xu
authors.forename: Jun
authors.initials: J
authors.lastname: Zhao
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.forename: Shuangqing
authors.initials: S
authors.lastname: Peng
mesh_terms: D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D000072237:ERG1 Potassium Channel; D004553:Electric Conductivity; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D057809:HEK293 Cells; D006801:Humans; D007700:Kinetics; D026902:Potassium Channel Blockers / Q000494:pharmacology*
chemical_list: D004365:Drugs, Chinese Herbal; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D026902:Potassium Channel Blockers; C032939:cyclovirobuxine D