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


METHODS
Whole-cell patch clamp recordings were made at 37 degrees 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.
Zhang
Yi H
YH
Department of Physiology and Pharmacology and Cardiovascular Research Laboratories, School of Medical Sciences, University of Bristol, University Walk, Bristol, UK.
Cheng
Hongwei
H
Alexeenko
Vadim A
VA
Dempsey
Christopher E
CE
Hancox
Jules C
JC
D000638:Amiodarone / Q000031:analogs & derivatives* / Q000494:pharmacology; D000704:Analysis of Variance; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects*; D006801:Humans; D018408:Patch-Clamp Techniques
D000889:Anti-Arrhythmia Agents; D051638:Ether-A-Go-Go Potassium Channels; C092509:KCNH6 protein, human; C036116:desethylamiodarone; D000638:Amiodarone