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on August 9, 2004

A more recent version of this article appeared on August 24, 2004

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Submitted on February 19, 2004
Revised on May 12, 2004
Accepted on May 21, 2004

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

Charles Antzelevitch PhD^*, Luiz Belardinelli MD, Andrew C. Zygmunt PhD, Alexander Burashnikov PhD, José M. Di Diego MD, Jeffrey M. Fish DVM, Jonathan M. Cordeiro PhD, and George Thomas PhD

From the Masonic Medical Research Laboratory, Utica, NY (C.A., A.C.Z., A.B., J.M.D., J.M.F., J.M.C., G.T.), and CV Therapeutics, Inc, Palo Alto, Calif (L.B.).

^* To whom correspondence should be addressed. E-mail: ca{at}mmrl.edu.

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.

Key words: ischemia • ion channels • intervals • depolarization

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