Synergistic Electrophysiologic and Antiarrhythmic Effects of the Combination of Ranolazine and Chronic Amiodarone in Canine Atria

Abstract

Background— Amiodarone and ranolazine have been characterized as inactivated- and activated-state blockers of cardiac sodium channel current (I Na ), respectively, and shown to cause atrial-selective depression of I Na -related parameters. This study tests the hypothesis that their combined actions synergistically depress I Na -dependent parameters in atria but not ventricles. Methods and Results— The effects of acute ranolazine (5 to 10 μmol/L) were studied in coronary-perfused right atrial and left ventricular wedge preparations and superfused left atrial pulmonary vein sleeves isolated from chronic amiodarone-treated (40 mg/kg daily for 6 weeks) and untreated dogs. Floating and standard microelectrode techniques were used to record transmembrane action potentials. When studied separately, acute ranolazine and chronic amiodarone caused atrial-predominant depression of I Na -dependent parameters. Ranolazine produced a much greater reduction in V max and much greater increase in diastolic threshold of excitation and effective refractory period in atrial preparations isolated from amiodarone-treated versus untreated dogs, leading to a marked increase in postrepolarization refractoriness. The drug combination effectively suppressed triggered activity in pulmonary vein sleeves but produced relatively small changes in I Na -dependent parameters in the ventricle. Acetylcholine (0.5 μmol/L) and burst pacing induced atrial fibrillation in 100% of control atria, 75% of ranolazine-treated (5 μmol/L) atria, 16% of atria from amiodarone-treated dogs, and in 0% of atria from amiodarone-treated dogs exposed to 5 μmol/L ranolazine. Conclusions— The combination of chronic amiodarone and acute ranolazine produces a synergistic use-dependent depression of I Na -dependent parameters in isolated canine atria, leading to a potent effect of the drug combination to prevent the induction of atrial fibrillation.