Published Online
on September 4, 2007

A more recent version of this article appeared on September 25, 2007

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Submitted on March 22, 2007
Accepted on July 11, 2007

Atrium-Selective Sodium Channel Block as a Strategy for Suppression of Atrial Fibrillation. Differences in Sodium Channel Inactivation Between Atria and Ventricles and the Role of Ranolazine

Alexander Burashnikov PhD^*, José M. Di Diego MD, Andrew C. Zygmunt PhD, Luiz Belardinelli MD, and Charles Antzelevitch PhD^*

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

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

Background—The development of selective atrial antiarrhythmic agents is a current strategy for suppression of atrial fibrillation (AF).

Methods and Results—Whole-cell patch clamp techniques were used to evaluate inactivation of peak sodium channel current (I_Na) in myocytes isolated from canine atria and ventricles. The electrophysiological effects of therapeutic concentrations of ranolazine (1 to 10 µmol/L) and lidocaine (2.1 to 21 µmol/L) were evaluated in canine isolated coronary-perfused atrial and ventricular preparations. Half-inactivation voltage of I_Na was 15 mV more negative in atrial versus ventricular cells under control conditions; this difference increased after exposure to ranolazine. Ranolazine produced a marked use-dependent depression of sodium channel parameters, including the maximum rate of rise of the action potential upstroke, conduction velocity, and diastolic threshold of excitation, and induced postrepolarization refractoriness in atria but not in ventricles. Lidocaine also preferentially suppressed these parameters in atria versus ventricles, but to a much lesser extent than ranolazine. Ranolazine produced a prolongation of action potential duration (APD₉₀) in atria, no effect on APD₉₀ in ventricular myocardium, and an abbreviation of APD₉₀ in Purkinje fibers. Lidocaine abbreviated both atrial and ventricular APD₉₀. Ranolazine was more effective than lidocaine in terminating persistent AF and in preventing the induction of AF.

Conclusions—Our study demonstrates important differences in the inactivation characteristics of atrial versus ventricular sodium channels and a striking atrial selectivity for the action of ranolazine to produce use-dependent block of sodium channels, leading to suppression of AF. Our results point to atrium-selective sodium channel block as a novel strategy for the management of AF.

Key words: action potentials • antiarrhythmia agents • atrial fibrillation • electrophysiology • pharmacology

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