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Electrophysiologic Properties and Antiarrhythmic Actions of a Novel Antianginal Agent

Masonic Medical Research Laboratory, 2150 Bleecker Street, Utica, NY 13501; ca{at}mmrl.edu

Luiz Belardinelli, MD

Lin Wu, MD

Heather Fraser, PhD

CV Therapeutics, Inc., Palo Alto, CA

Andrew C. Zygmunt, PhD

Alexander Burashnikov, PhD

José M. Di Diego, MD

Jeffrey M. Fish, DVM

Jonathan M. Cordeiro, PhD

Robert J. Goodrow, Jr

Fabiana Scomik, PhD

Guillermo Perez, PhD

Masonic Medical Research Laboratory, Utica, NY

Ranolazine is a novel antianginal agent capable of producing anti-ischemic effects at plasma concentrations of 2 to 6 µM without a significant reduction of heart rate or blood pressure. This review summarizes the electrophysiologic properties of ranolazine. Ranolazine significantly blocks I_Kr (IC₅₀ = 12 µM), late I_Na, late I_Ca, peak I_Ca, I_Na-Ca (IC₅₀ = 5.9, 50, 296, and 91 µM, respectively) and I_Ks (17% at 30,uM), but causes little or no inhibition of I_to or I_Kl. In left ventricular tissue and wedge preparations, ranolazine produces a concentration-dependent prolongation of action potential duration (APD) in epicardium, but abbreviation of APD of M cells, leading to either no change or a reduction in transmural dispersion of repolarization (TDR). The result is a modest prolongation of the QT interval. Prolongation of APD and QT by ranolazine is fundamentally different from that of other drugs that block I_Kr and induce torsade de pointes in that APD prolongation is rate-independent (ie, does not display reverse rate-dependent prolongation of APD) and is not associated with early afterdepolarizations, triggered activity, increased spatial dispersion of repolarization, or polymorphic ventricular tachycardia. Torsade de pointes arrhythmias were not observed spontaneously nor could they be induced with programmed electrical stimulation in the presence of ranolazine at concentrations as high as 100 µM. Indeed, ranolazine was found to possess significant antiarrhythmic activity, acting to suppress the arrhythmogenic effects of other QT-prolonging drugs. Ranolazine produces ion channel effects similar to those observed after chronic exposure to amiodarone (reduced late I_Na, I_Ks, I_KS, and I_Ca). Ranolazine's actions to reduce TDR and suppress early afterdepolarization suggest that in addition to its anti-anginal actions, the drug possesses antiarrhythmic activity.

Key Words: ranolazine • anti-ischemic • IKr blocker • transmural dispersion of repolarization • QT prolongation • early afterdepolarizations • antiarrhythmic

Journal of Cardiovascular Pharmacology and Therapeutics, Vol. 9, No. 1 suppl, S65-S83 (2004)
DOI: 10.1177/107424840400900106


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