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

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.

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

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

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 microM) 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.

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.