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

ABSTRACT: BACKGROUND AND PURPOSE:Human ether-a-go-go-related gene (hERG; Kv 11.1) 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 Cav 1.2 and Nav 1.5 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 Cav 1.2 and/or Nav 1.5 in a channel state-dependent manner. Adding Cav 1.2 and Nav 1.2 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 Cav 1.2 and/or Nav 1.5 channels. In silico simulations of hiPSC-CMs APs confirm the principle of the multiple ion channel effects.

SUBMITTER: Saxena P

PROVIDER: S-EPMC5573420 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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

Saxena P P Hortigon-Vinagre M P MP Beyl S S Baburin I I Andranovits S S Iqbal S M SM Costa A A IJzerman A P AP Kügler P P Timin E E Smith G L GL Hering S S

British journal of pharmacology 20170811 18

<h4>Background and purpose</h4>Human ether-a-go-go-related gene (hERG; K<sub>v</sub> 11.1) 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-de ...[more]

PMID: 28681507

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Project description:Current regulatory guidelines for assessing the risk of QT prolongation include in vitro assays assessing drug effects on the human ether-à-go-go-related (hERG; also known as Kv11.1) channel expressed in cell lines. These assays are typically conducted at room temperature to promote the ease and stability of recording hERG currents. However, the new Comprehensive in vitro Proarrhythmia Assay (CiPA) paradigm proposes to use an in silico model of the human ventricular myocyte to assess risk, requiring as input hERG channel pharmacology data obtained at physiological temperatures. To accommodate current industry safety pharmacology practices for measuring hERG channel activity, an in silico model of hERG channel that allows for the extrapolation of hERG assay data across different temperatures is desired. Because temperature may have an effect on both channel gating and drug binding rate, such models may need to have two components: a base model dealing with temperature-dependent gating changes without drug, and a pharmacodynamic component simulating temperature-dependent drug binding kinetics. As a first step, a base mode that can capture temperature effects on hERG channel gating without drug is needed.To meet this need for a temperature-dependent base model, a Markov model of the hERG channel with state transition rates explicitly dependent on temperature was developed and calibrated using data from a variety of published experiments conducted over a range of temperatures. The model was able to reproduce observed temperature-dependent changes in key channel gating properties and also to predict the results obtained in independent sets of new experiments.This new temperature-sensitive model of hERG gating represents an attempt to improve the predictivity of safety pharmacology testing by enabling the translation of room temperature hERG assay data to more physiological conditions. With further development, this model can be incorporated into the CiPA paradigm and also be used as a tool for developing insights into the thermodynamics of hERG channel gating mechanisms and the temperature-dependence of hERG channel block by drugs.

Dataset Information

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

Publications

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

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