Antiarrhythmic effects of ranolazine in a guinea pig in vitro model of long-QT syndrome

Prolongation of the QT interval of the ECG is associated with increased risk of torsades de pointes ventricular tachycardia. Ranolazine, a novel antianginal agent, is reported to decrease the delayed rectifier potassium current, I-Kr, and to increase action potential duration (APD) and the QT interval. However, ranolazine is also reported to reduce late sodium current ( late I-Na), a depolarizing current that contributes to prolongation of the plateau of the ventricular action potential. We hypothesized that ranolazine would decrease APD and the occurrence of arrhythmias when late I-Na is increased. Therefore, we measured the effects of ranolazine alone and in the presence of anemone toxin (ATX)-II, whose action mimics the sodium channelopathy associated with long-QT3 syndrome, on epicardial monophasic action potentials and ECGs recorded from guinea pig isolated hearts. Ranolazine (0.1 - 50 muM) prolonged monophasic APD at 90% repolarization (MAPD(90)) by up to 22% but did not cause either early afterdepolarizations (EADs) or ventricular tachycardia (VT). ATX-II (1 - 20 nM) markedly increased APD and caused EADs and VT. Ranolazine ( 5 - 30 muM) significantly attenuated increases in MAPD 90 and reduced episodes of EADs and VT produced by ATX-II. Ranolazine also attenuated the synergistic effect of MAPD 90 increase caused by combinations of ATX-II and blockers of I-K [ E- 4031; 1-[2-(6-methyl-2- pyridyl) ethyl]-4-methylsulfonylaminobenzoyl) piperidine]. Thus, although ranolazine alone prolonged APD, it reduced APD and ventricular arrhythmias caused by agents that increased late I-Na and decreased I-K.