Eleclazine Inhibition of Voltage-gated Sodium Currents in Rat Atrial and Ventricular Myocytes

Abstract

Atrial-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 side-effects. Eleclazine (GS-6615) is a putative antiarrhythmic drug that has been shown to be safe and well-tolerated in patients and has properties similar to the prototypical atrial-selective Na+ channel blocker, ranolazine.Atrial-ventricular differences in the biophysical properties of voltage-gated Na+ currents and their inhibition by eleclazine were investigated.The fast and late components of whole-cell voltage-gated Na+ currents (respectively, INa & INaL) were recorded at room temperature (∼22 °C) from rat isolated atrial and ventricular myocytes. Atrial INa activated at command potentials ∼5.5 mV more negative and inactivated at conditioning potentials ∼7 mV more negative than ventricular INa. Under control conditions, INaL density was ∼2-fold greater in atrial than in ventricular myocytes. There was no difference between the two cell types in block of INaL by eleclazine (IC50s ∼200 nM) in the presence of the INaL activator, ATX-II (3 nM). 10 μM eleclazine inhibited INa in atrial and ventricular myocytes in a use-dependent manner consistent with preferential activated state block. Eleclazine produced an instantaneous inhibition of INa in atrial but not ventricular myocytes; the drug caused a negative shift in voltage of half-maximal inactivation and slowed the recovery of INa from inactivation in both cell types. Thus, differences exist between rat atrial and ventricular myocytes in the biophysical properties of INa. The more negative voltage-dependence of INa activation/inactivation underlies the instantaneous block by eleclazine in atrial myocytes. Eleclazine warrants further investigation as an atrial-selective antiarrhythmic drug.