Atrial-ventricular differences in rabbit cardiac voltage-gated Na currents: Basis for atrial-selective block by ranolazine.

Background: Class 1 antiarrhythmic drugs are highly effective in restoring and maintaining sinus rhythm in atrial fibrillation patients but carry a risk of ventricular tachyarrhythmia. The antianginal agent ranolazine is a prototypic atrial-selective voltage-gated Na channel blocker but the mechanisms underlying its atrial-selective action remain unclear.

Objective: The present study examined the mechanisms underlying the atrial-selective action of ranolazine.

Methods: Whole-cell voltage-gated Na currents (I) were recorded at room temperature (∼22°C) from rabbit isolated left atrial and right ventricular myocytes.

Results: I conductance density was ∼1.8-fold greater in atrial than in ventricular cells. Atrial I was activated at command potentials ∼7 mV more negative and inactivated at conditioning potentials ∼11 mV more negative than ventricular I. The onset of inactivation of I was faster in atrial cells than in ventricular myocytes. Ranolazine (30 μM) inhibited I in atrial and ventricular myocytes in a use-dependent manner consistent with preferential activated/inactivated state block. Ranolazine caused a significantly greater negative shift in voltage of half-maximal inactivation in atrial cells than in ventricular cells, the recovery from inactivation of I was slowed by ranolazine to a greater extent in atrial myocytes than in ventricular cells, and ranolazine produced an instantaneous block that showed marked voltage dependence in atrial cells.

Conclusion: Differences exist between rabbit atrial and ventricular myocytes in the biophysical properties of I. The more negative voltage dependence of I activation and inactivation, together with trapping of the drug in the inactivated channel, underlies an atrial-selective action of ranolazine.