Amiodarone Irrecoverably Impairs the Function of hERG Potassium Channels

Abstract

Amiodarone (AMIO) is a class III antiarrhythmic drug (AAD) that blocks the human ether-a-go-go-related (hERG) channel which conducts the rapidly activating delayed rectifier potassium current, IKr. While effective in the treatment of certain arrhythmias, like other class III AADs, AMIO presents a significant risk of inducing long QT syndrome (LQTS). The present study investigates the inhibitory effects of AMIO on hERG channels heterologously expressed in HEK293 as well as rat cardiomyocyte-derived H9c2 cells. Acute application of AMIO or desethylamiodarone (DEA) inhibited the hERG current (IhERG) in a concentration-dependent manner with an IC50 of 0.22 µM or 0.95 µM, respectively. Surprisingly, upon washout of the compounds and recording IhERG in a drug-free bath solution, no current recovery was observed from either the AMIO- or DEA-induced inhibition. Furthermore, after overnight (16 h) treatment of cells with the drugs and recordings were made in the absence of drugs, AMIO or DEA treatment resulted in a concentration-dependent IhERG reduction with an EC50 of 0.32 µM or 0.85 µM, respectively. Western blot analysis of hERG channel expression revealed that although AMIO overnight treatment did not affect hERG protein expression, it accelerated the degradation rate of mature hERG protein when AMIO-treated cells were further cultured in the absence of the drug. This suggests that the fundamental properties of these channels, such as membrane stability and function, are affected by AMIO treatment. Our results indicate that both AMIO and DEA irrecoverably impair hERG function, with IhERG recovery is dependent on the forward trafficking of newly made channels, which takes place in hours. Thus, it would be imperative to monitor electrophysiology of the heart in patients discontinuing AMIO therapy due to LQTS.