Characterization of recombinant hERG K+ channel inhibition by the active metabolite of amiodarone desethyl-amiodarone

• Published in: Journal of electrocardiology Vol. 43; no. 5; pp. 440 - 448
• Main Authors: Zhang, Yi H., PhD, Cheng, Hongwei, PhD, Alexeenko, Vadim A., PhD, Dempsey, Christopher E., PhD, Hancox, Jules C., PhD
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2010
• Subjects: Amiodarone; Amiodarone - analogs & derivatives; Amiodarone - pharmacology; Analysis of Variance; Anti-Arrhythmia Agents - pharmacology; Antiarrhythmic; Cardiovascular; Class III; Desethyl-amiodarone; Ether-A-Go-Go Potassium Channels - drug effects; hERG; human ether-à-go-go-related gene; Humans; IKr; Patch-Clamp Techniques; Potassium channel; QT interval; Antiarrhythmic; QT interval; hERG; Class III; Amiodarone; Desethyl-amiodarone; human ether-à-go-go-related gene; Potassium channel; I Kr; IKr
• ISSN: 0022-0736; 1532-8430
• DOI: 10.1016/j.jelectrocard.2010.04.007

Abstract The aim of this study was to determine the effects of desethyl-amiodarone (DEA), the major metabolite of the class III antiarrhythmic drug amiodarone, on human ether-à-go-go-related gene ( hERG ) encoded potassium channel current. Materials and methods Whole-cell patch clamp recordings were made at 37°C of ionic current ( I hERG ) carried by recombinant hERG channels expressed in HEK-293 cells. Results Desethyl-amiodarone inhibited I hERG with a half-maximal inhibitory concentration of approximately 158 nmol/L, compared with approximately 47 nmol/L for amiodarone. The inhibitory action of DEA on I hERG was contingent on channel gating, showing significant time and voltage dependence. Desethyl-amiodarone also produced an approximately −9 mV shift in the voltage dependence of activation of I hERG ; however, there was no significant preference for activated over inactivated channels. Conclusions Because hERG underlies native cardiac “ I Kr ” channels, hERG / I Kr inhibition by DEA as well as amiodarone may contribute to the overall effects of amiodarone administration on cardiac repolarization.