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

• Published in: Journal of electrocardiology 2010-10, Vol.43 (5), p.440-448
• Main Authors: Zhang, Yi H, Cheng, Hongwei, Alexeenko, Vadim A, Dempsey, Christopher E, Hancox, Jules C
• Format: Article
• Language: English
• ISSN: 0022-0736
• DOI: 10.1016/j.jelectrocard.2010.04.007

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-a-go-go-related gene (hERG) encoded potassium channel current. Materials and methods: Whole-cell patch clamp recordings were made at 37C of ionic current (I sub(hERG)) carried by recombinant hERG channels expressed in HEK-293 cells. Results: Desethyl-amiodarone inhibited I sub(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 sub(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 sub(hERG); however, there was no significant preference for activated over inactivated channels. Conclusions: Because hERG underlies native cardiac "I sub(Kr)" channels, hERG/I sub(Kr) inhibition by DEA as well as amiodarone may contribute to the overall effects of amiodarone administration on cardiac repolarization.