Correlation between human ether-a-go-go-related gene channel inhibition and action potential prolongation

Saxena, P. et al. (2017) Correlation between human ether-a-go-go-related gene channel inhibition and action potential prolongation. British Journal of Pharmacology, 174(18), pp. 3081-3093. (doi:10.1111/bph.13942) (PMID:28681507) (PMCID:PMC5573420)

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Abstract

Background and Purpose: Human ether-a-go-go-related gene (hERG; Kv11.1) channel inhibition is a widely accepted predictor of cardiac arrhythmia. hERG channel inhibition alone is often insufficient to predict pro-arrhythmic drug effects. This study used a library of dofetilide derivatives to investigate the relationship between standard measures of hERG current block in an expression system and changes in action potential duration (APD) in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). The interference from accompanying block of Cav1.2 and Nav1.5 channels was investigated along with an in silico AP model. Experimental Approach: Drug-induced changes in APD were assessed in hiPSC-CMs using voltage-sensitive dyes. The IC50 values for dofetilide and 13 derivatives on hERG current were estimated in an HEK293 expression system. The relative potency of each drug on APD was estimated by calculating the dose (D150) required to prolong the APD at 90% (APD90) repolarization by 50%. Key Results: The D150 in hiPSC-CMs was linearly correlated with IC50 of hERG current. In silico simulations supported this finding. Three derivatives inhibited hERG without prolonging APD, and these compounds also inhibited Cav1.2 and/or Nav1.5 in a channel state-dependent manner. Adding Cav1.2 and Nav1.2 block to the in silico model recapitulated the direction but not the extent of the APD change. Conclusions and Implications: Potency of hERG current inhibition correlates linearly with an index of APD in hiPSC-CMs. The compounds that do not correlate have additional effects including concomitant block of Cav1.2 and/or Nav1.5 channels. In silico simulations of hiPSC-CMs APs confirm the principle of the multiple ion channel effects.

Item Type:Articles
Additional Information:This work is supported by Austrian Science Fund (FWF; http://www.fwf.ac.at). PS was supported by a doctoral programme ‘molecular drug targets’ funded by FWF W1232. MPHV is recipient of Fundacion Alfonso Martin Escudero (SPAIN) postdoctoral fellowship. SB is supported by FWF grant P27729.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Smith, Professor Godfrey and Saxena, Ms Priyanka and Hortigon, Dr Maria
Authors: Saxena, P., Hortigon-Vinagre, M.P., Beyl, S., Baburin, I., Andranovits, S., Iqbal, S.M., Costa, A., IJzerman, A.P., Kügler, P., Timin, E., Smith, G.L., and Hering, S.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:British Journal of Pharmacology
Publisher:Wiley
ISSN:0007-1188
ISSN (Online):1476-5381
Published Online:06 July 2017
Copyright Holders:Copyright © 2017 The Authors
First Published:First published in British Journal of Pharmacology 174(18): 3081-3093
Publisher Policy:Reproduced under a Creative Commons license

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