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CARDIOVASCULAR

Antiarrhythmic Effects of Ranolazine in a Guinea Pig in Vitro Model of Long-QT Syndrome

Pharmacological Sciences, CV Therapeutics, Inc., Palo Alto, California (L.W., Y.L., L.B.); Department of Medicine, University of Florida, Gainesville, Florida (J.C.S., Y.S.); and Masonic Medical Research Laboratory, Utica, New York (C.A.)

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 µM) prolonged monophasic APD at 90% repolarization (MAPD₉₀) 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 µM) significantly attenuated increases in MAPD₉₀ and reduced episodes of EADs and VT produced by ATX-II. Ranolazine also attenuated the synergistic effect of MAPD₉₀ 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.

Address correspondence to: Dr. Lin Wu, CV Therapeutics, Inc., 3172 Porter Dr., Palo Alto, CA 94304. E-mail: lin.wu{at}cvt.com

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