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(Na)) were recorded at room temperature (∼22°C) from rabbit isolated left atrial and right ventricular myocytes. RESULTS: I(Na) conductance density was ∼1.8-fold greater in atrial than in ventricular cells. Atrial I(Na) was activated at command potentials ∼7 mV more negative and inactivated at conditioning potentials ∼11 mV more negative than ventricular I(Na). The onset of inactivation of I(Na) was faster in atrial cells than in ventricular myocytes. Ranolazine (30 μM) inhibited I(Na) 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(Na) 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(Na). The more negative voltage dependence of I(Na) activation and inactivation, together with trapping of the drug in the inactivated channel, underlies an atrial-selective action of ranolazine.