Background— Ranolazine is a novel antianginal agent capable of producing antiischemic effects at plasma concentrations of 2 to 6 μmol/L without reducing heart rate or blood pressure. The present study examines its electrophysiological effects in isolated canine ventricular myocytes, tissues, and arterially perfused left ventricular wedge preparations.

Methods and Results— Transmembrane action potentials (APs) from epicardial and midmyocardial (M) regions and a pseudo-ECG were recorded simultaneously from wedge preparations. APs were also recorded from epicardial and M tissues. Whole-cell currents were recorded from epicardial and M myocytes. Ranolazine inhibited I_Kr (IC₅₀=11.5 μmol/L), late I_Na, late I_Ca, peak I_Ca, and I_Na-Ca (IC₅₀=5.9, 50, 296, and 91 μmol/L, respectively) and I_Ks (17% at 30 μmol/L), but caused little or no inhibition of I_to or I_K1. In tissues and wedge preparations, ranolazine produced a concentration-dependent prolongation of AP duration of epicardial but abbreviation of that of M cells, leading to reduction or no change in transmural dispersion of repolarization (TDR). At [K⁺]_o=4 mmol/L, 10 μmol/L ranolazine prolonged QT interval by 20 ms but did not increase TDR. Extrasystolic activity and spontaneous torsade de pointes (TdP) were never observed, and stimulation-induced TdP could not be induced at any concentration of ranolazine, either in normal or low [K⁺]_o. Ranolazine (5 to 20 μmol/L) suppressed early afterdepolarizations (EADs) and reduced the increase in TDR induced by the selective I_Kr blocker d-sotalol.

Conclusions— Ranolazine produces ion channel effects similar to those observed after chronic amiodarone (reduced I_Kr, I_Ks, late I_Na, and I_Ca). The actions of ranolazine to suppress EADs and reduce TDR suggest that, in addition to its antianginal actions, the drug may possess antiarrhythmic activity.