Electrophysiological effects of ranolazine, a novel antianginal agent with antiarrhythmic properties

Background - Ranolazine is a novel antianginal agent capable of producing antiischemic effects at plasma concentrations of 2 to 6 mumol/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 mumol/L), late I-Na, late I-Ca, peak I-Ca, and INa-Ca (IC50 = 5.9, 50, 296, and 91 mumol/L, respectively) and I-Ks (17% at 30 mumol/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 mumol/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 mumol/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.