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 anti-arrhythmic 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 & 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). 10 μM eleclazine 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 two cell types in the voltage-dependence of instantaneous inhibition by eleclazine. Eleclazine warrants further investigation as an atrial-selective anti-arrhythmic drug.