Electrophysiological Effects of Ranolazine, a Novel Antianginal Agent With Antiarrhythmic Properties

Abstract

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 (IC ₅₀ =11.5 μmol/L), late I _Na , late I _Ca , peak I _Ca , and I _Na-Ca (IC ₅₀ =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.