Inhibition of voltage-gated Na+ currents by eleclazine in rat atrial and ventricular myocytes

Rachel E Caves,Stéphanie C Choisy,Ben Clennell,Alexander Carpenter,Jules C Hancox,Cameron Mcniff,Andrew F James,Brendan Mann,Hongwei Cheng,James T Milnes

doi:10.1016/j.hroo.2020.05.006

Rachel E Caves, Stéphanie C Choisy + Show 8 more

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https://doi.org/10.1016/j.hroo.2020.05.006

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Abstract

BackgroundAtrial-ventricular differences in voltage-gated Na+ currents might be exploited for atrial-selective antiarrhythmic drug action for the suppression of atrial fibrillation without risk of ventricular tachyarrhythmia. Eleclazine (GS-6615) is a putative antiarrhythmic drug with properties similar to the prototypical atrial-selective Na+ channel blocker ranolazine that has been shown to be safe and well tolerated in patients.ObjectiveThe present study investigated atrial-ventricular differences in the biophysical properties and inhibition by eleclazine of voltage-gated Na+ currents.MethodsThe fast and late components of whole-cell voltage-gated Na+ currents (respectively, INa and INaL) were recorded at room temperature (∼22°C) from rat isolated atrial and ventricular myocytes.ResultsAtrial INa activated at command potentials ∼5.5 mV more negative and inactivated at conditioning potentials ∼7 mV more negative than ventricular INa. There was no difference between atrial and ventricular myocytes in the eleclazine inhibition of INaL activated by 3 nM ATX-II (IC50s ∼200 nM). Eleclazine (10 μM) inhibited INa in atrial and ventricular myocytes in a use-dependent manner consistent with preferential activated state block. Eleclazine produced voltage-dependent instantaneous inhibition in atrial and ventricular myocytes; it caused a negative shift in voltage of half-maximal inactivation and slowed the recovery of INa from inactivation in both cell types.ConclusionsDifferences exist between rat atrial and ventricular myocytes in the biophysical properties of INa. The more negative voltage dependence of INa activation/inactivation in atrial myocytes underlies differences between the 2 cell types in the voltage dependence of instantaneous inhibition by eleclazine. Eleclazine warrants further investigation as an atrial-selective antiarrhythmic drug.

Highlights

Atrial fibrillation (AF) is characterized by a rapid and irregular electrical activation of the atria and is associated with significant morbidity and mortality, principally through an elevated risk of thromboembolism and ischemic stroke.[1]
Differences exist between rat atrial and ventricular myocytes in the biophysical properties of inactivation of fast Na1 current (INa)
- Differences exist between rat atrial and ventricular myocytes in the voltage dependence of activation and inactivation of fast Na1 current (INa)

Summary

Introduction

Atrial fibrillation (AF) is characterized by a rapid and irregular electrical activation of the atria and is associated with significant morbidity and mortality, principally through an elevated risk of thromboembolism and ischemic stroke.[1] AF is the most common clinical arrhythmia and its prevalence can be expected to rise with aging of the population, with consequent increase in socioeconomic burden of the disease.[2] The elevated atrial rate during AF causes electrical and structural remodeling that stabilizes the arrhythmia, establishing a progressive nature to the condition.[1] Effective early intervention to prevent and/or control the arrhythmia is desirable.[1]. Atrial-ventricular differences in voltage-gated Na1 currents might be exploited for atrial-selective antiarrhythmic drug action for the suppression of atrial fibrillation without risk of ventricular tachyarrhythmia. Eleclazine (GS-6615) is a putative antiarrhythmic drug with properties similar to the prototypical atrial-selective Na1 channel blocker ranolazine that has been shown to be safe and well tolerated in patients

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