The human ether-a-go-go-related gene (hERG) current inhibition selectively prolongs action potential of midmyocardial cells to augment transmural dispersion.
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 μM 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 I(Kr) 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.
Department of Human and Engineered Environmental Studies, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan.
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Yasuda
Department of Cardiovascular Medicine, School of Medicine, The University of Tokyo, Tokyo, Japan.
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Yasuda
Department of Cardiovascular Medicine, School of Medicine, The University of Tokyo, Tokyo, Japan.
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Yamashita
Department of Human and Engineered Environmental Studies, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan.
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Okada
Department of Human and Engineered Environmental Studies, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan.
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Hisada
Department of Human and Engineered Environmental Studies, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan. sugiura@k.u-tokyo.ac.jp.
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Sugiura
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004206:Disopyramide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D004699:Endocardium / Q000166:cytology / Q000187:drug effects; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects / Q000235:genetics*; D006321:Heart / Q000187:drug effects*; D006801:Humans; D032383:Myocytes, Cardiac / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D010496:Pericardium / Q000166:cytology / Q000187:drug effects; D026902:Potassium Channel Blockers / Q000494:pharmacology*
D000889:Anti-Arrhythmia Agents; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D026902:Potassium Channel Blockers; D004206:Disopyramide