THE HUMAN ETHER-A-GO-GO-RELATED GENE (hERG) CURRENT INHIBITION SELECTIVELY PROLONGS ACTION POTENTIAL OF MIDMYOCARDIAL CELLS TO AUGMENT TRANSMURAL DISPERSION

被引:0
作者
Yasuda, C. [1 ]
Yasuda, S. [2 ]
Yamashita, H. [2 ]
Okada, J. [1 ]
Hisada, T. [1 ]
Sugiura, S. [1 ]
机构
[1] Univ Tokyo, Grad Sch Frontier Sci, Dept Human & Engineered Environm Studies, Kashiwa, Chiba 2778563, Japan
[2] Univ Tokyo, Sch Med, Dept Cardiovasc Med, Tokyo 113, Japan
来源
JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY | 2015年 / 66卷 / 04期
基金
日本学术振兴会;
关键词
arrhythmia; human ether-a-go-go-related gene current; action potential; action potential clamp; transmural dispersion; M-cells; I-Kr; disopyramide; LONG QT SYNDROME; TORSADE-DE-POINTES; INACTIVATION KINETICS; SODIUM-CHANNEL; POTASSIUM; REPOLARIZATION; MODELS; DISOPYRAMIDE; ACTIVATION; MYOCYTES;
D O I
暂无
中图分类号
Q4 [生理学];
学科分类号
071003 ;
摘要
The majority of drug induced arrhythmias are related to the prolongation of action potential duration following inhibition Of rapidly activating delayed rectifier potassium current (I-Kr) mediated by the hERG channel. However, for arrhythmias to develop and be sustained, not only the prolongation of action potential duration but also its transmural dispersion are required. Herein, we evaluated the effect of hERG inhibition on transmural dispersion of action potential duration using the action potential clamp technique that combined an in silico myocyte model with the actual I-Kr measurement. Whole cell I-Kr current was measured in Chinese hamster ovary cells stably expressing the hERG channel. The measured current Was coupled with models of ventricular endocardial, M-, and epicardial cells to calculate the action potentials. Action Potentials were evaluated under control condition and in the presence of 1, 10, or 100 mu M disopyramide, an hERG inhibitor. Disopyramide dose-dependently increased the action potential durations of the three cell types. However, action Potential duration of M-cells increased disproportionately at higher doses, and was significantly different from that of epicardial and endocardial cells (dispersion of repolarization). By contrast, the effects of disopyramide on peak In. and instantaneous current-voltage relation were similar in all cell types. Simulation study suggested that the reduced repolarization reserve of M-cell with smaller amount of slowly activating delayed rectifier potassium current levels off at longer action potential duration to make such differences. The action potential clamp technique is useful for studying the mechanism of arrhythmogenesis by hERG inhibition through the transmural dispersion of repolarization.
引用
收藏
页码:599 / 607
页数:9
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