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 anti-anginal 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. CONCLUSIONS 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.