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 mol/L) were studied in coronary-perfused right atrial and left ventricular wedge preparations and superfused left atrial pulmonary vein sleeves isolated from chronic amiodaronetreated (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 mol/L) and burst pacing induced atrial fibrillation in 100% of control atria, 75% of ranolazine-treated (5 mol/L) atria, 16% of atria from amiodarone-treated dogs, and in 0% of atria from amiodarone-treated dogs exposed to 5 mol/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. (Circ Arrhythm Electrophysiol. 2010;3:88-95.)

Potassium Channel Blockade Enhances Atrial Fibrillation–Selective Antiarrhythmic Effects of Optimized State-Dependent Sodium Channel Blockade

“…Theoretical considerations and recent experimental work motivated the choice of NCB and KCB as potentially synergistic targets. Sicouri et al, 10 using ranolazine and chronic amiodarone, and Burashnikov et al, 11 using ranolazine and dronedarone, showed that combination therapy depressed atrial V max and AF inducibility more than either drug alone, similar to our findings. The superior efficacy of combination therapy was attributed to the blockade of Na + channels in both their open state by ranolazine and inactivated state by amiodarone or dronedarone, an alternative anti-AF strategy.…”

“…9 In recent experimental work, the combination of ranolazine (class I effect) and amiodarone or dronaderone (class III action) had superior antiarrhythmic efficacy compared with either drug alone. [10][11][12] Using realistic mathematical models of cardiac electrophysiology, we previously analyzed the exploitation of state-dependent Na + -channel blocking properties to produce channel blockade that is selective for the fibrillating atrium, aiming to define pharmacodynamic properties that maximize therapeutic effects on the fibrillating atrium and minimize ventricular proarrhythmic actions at the much slower rate of resting sinus rhythm. 13 Here, we tested the hypothesis Background-The development of effective and safe antiarrhythmic drugs for atrial fibrillation (AF) rhythm control is an unmet clinical need.…”

Atrial-selective sodium channel block by dronedarone: sufficient to terminate atrial fibrillation?

“…Under experimental conditions-particularly at faster rates-amiodarone and dronedarone, both of which are inactivated-state sodium channel blockers with rapid dissociation kinetics, have a greater potential to depress I Na properties in atria than in ventricles . Recently, a combination of ranolazine and dronedarone (two mechanistically different sodium channel blockers with additive effects on I Na properties, see above) were highly effective for AF termination and prevention and found the combination highly effective (Sicouri et al 2010). As hypothesized, both substances synergistically potentiated their antiarrhythmic efficacies, with the combination being much more effective than expected from the mathematical sum of the two separate efficacy values.…”

“…Atrial-selective inhibition of sodium channels has previously been demonstrated for several antiarrhythmic agents (Burashnikov et al 2007;Sicouri et al 2010) and represents a property likely contributing to dronedarone's antiarrhythmic effect. Atrial sodium channel blockade leads to alterations of various biophysical parameters of sodium current (I Na ) that produce post-repolarization refractoriness without a major effect on action potential duration (APD).…”

The Significance of the Late Na+ Current for Arrhythmia Induction and the Therapeutic Antiarrhythmic Potential of Ranolazine

“…123,124 Such findings have led to the idea that a multidrug approach for the treatment of AF may hold considerable potential. Dronedarone is a noniodinated derivative of amiodarone with a more favorable safety profile.…”