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

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 methodsWhole-cell patch clamp recordings were made at 37°C of ionic current (IhERG) carried by recombinant hERG channels expressed in HEK-293 cells. ResultsDesethyl-amiodarone inhibited IhERG 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 IhERG 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 IhERG; however, there was no significant preference for activated over inactivated channels. ConclusionsBecause hERG underlies native cardiac “IKr” channels, hERG/IKr inhibition by DEA as well as amiodarone may contribute to the overall effects of amiodarone administration on cardiac repolarization.