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

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. 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. The present study investigated atrial-ventricular differences in the biophysical properties and inhibition by eleclazine of voltage-gated Na+ currents. The 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. Atrial 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. Differences 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.