Effect of ranolazine on ventricular repolarization in class III antiarrhythmic drug-treated rabbits

BACKGROUND Ranolazine exhibits a synergistic effect in combination with class III drugs to suppress atrial fibrillation. OBJECTIVE To investigate whether a combination therapy affects repolarization and provokes ventricular tachyarrhythmias (VT) in a sensitive model of proarrhythmia. METHODS Thirty-seven rabbits were assigned to 3 groups and fed with amiodarone (50 mg/kg/d; n = 10) or dronedarone (50 mg/kg/d; n = 10) over a period of 6 weeks. A third group was used as control (n = 17). After obtaining baseline data in Langendorff-perfused control hearts, sotalol (100 mu M) was administered in this group. Thereafter, ranolazine (10 mu M) was additionally infused on top of amiodarone, dronedarone, or sotalol. RESULTS Chronic treatment with amiodarone or dronedarone as well as sotalol significantly increased action potential duration at 90% repolarization (APD(90)). Additional treatment with ranolazine further increased APD(90) in amiodarone- and dronedarone-pretreated hearts but not in sotalol-treated hearts. Ranolazine increased postrepolarization refractoriness as compared with amiodarone or dronedarone alone owing to a marked effect on the refractory period. In contrast to amiodarone and dronedarone, acute application of sotalol increased dispersion of repolarization (P < .05). Additional treatment with ranolazine did not further increase spatial or temporal dispersion. After lowering extracellular [K+] in bradycardic hearts, no proarrhythmia occurred in amiodarone- or dronedarone-treated hearts whereas 11 of 17 sotalol treated hearts showed early after depolarizations and subsequent polymorphic VT. Additional treatment with ranolazine reduced the number of VT episodes in sotalol-treated hearts and did not cause proarrhythmia in combination with amiodarone or dronedarone. CONCLUSIONS Application of ranolazine on top of class III drugs does not cause proarrhythmia despite a marked effect on ventricular repolarization. The effect of ranolazine on the repolarization reserve is associated with the lack of effect on early afterdepolarizations and dispersion of repolarization.