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

Background: 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.

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

Methods: The fast and late components of whole-cell voltage-gated Na⁺ currents (respectively, I _Na and I _NaL) were recorded at room temperature (∼22°C) from rat isolated atrial and ventricular myocytes.

Results: Atrial I _Na activated at command potentials ∼5.5 mV more negative and inactivated at conditioning potentials ∼7 mV more negative than ventricular I _Na. There was no difference between atrial and ventricular myocytes in the eleclazine inhibition of I _NaL activated by 3 nM ATX-II (IC₅₀s ∼200 nM). Eleclazine (10 μM) inhibited I _Na 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 I _Na from inactivation in both cell types.

Conclusions: Differences exist between rat atrial and ventricular myocytes in the biophysical properties of I _Na. The more negative voltage dependence of I _Na 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.