Late Na+ Current Inhibition by Ranolazine Reduces Torsades de Pointes in the Chronic Atrioventricular Block Dog Model

Objectives: This study investigated whether ranolazine reduces dofetilide-induced torsades de pointes (TdP) in a model of long QT syndrome with down-regulated K+ currents due to hypertrophic remodeling in the dog with chronic atrioventricular block (cAVB). Background: Ranolazine inhibits the late Na+ current (INaL) and is effective against arrhythmias in long QT3 syndromes despite its blocking properties of the rapid component of delayed rectifying potassium current. Methods: Ranolazine was administered to cAVB dogs before or after TdP induction with dofetilide and electrophysiological parameters were determined including beat-to-beat variability of repolarization (BVR). In single ventricular myocytes, effects of ranolazine were studied on INaL, action potential duration, and dofetilide-induced BVR and early afterdepolarizations. Results: After dofetilide, ranolazine reduced the number of TdP episodes from 10 ± 3 to 3 ± 1 (p < 0.05) and partially reversed the increase of BVR with no abbreviation of the dofetilide-induced QT prolongation. Likewise, pre-treatment with ranolazine, or using lidocaine as a specific Na+ channel blocker, attenuated TdP, but failed to prevent dofetilide-induced increases in QT, BVR, and ectopic activity. In cAVB myocytes, ranolazine suppressed dofetilide-induced early afterdepolarizations in 25% of cells at 5 μmol/l, in 75% at 10 μmol/l, and in 100% at 15 μmol/l. At 5 μmol/l, ranolazine blocked 26 ± 3% of tetrodotoxin-sensitive INaL, and 49 ± 3% at 15 μmol/l. Despite a 54% reduction of INaL amplitude in cAVB compared with control cells, INaL inhibition by 5 μmol/l tetrodotoxin equally shortened relative action potential duration and completely abolished dofetilide-induced early afterdepolarizations. Conclusions: Despite down-regulation of INaL in remodeled cAVB hearts, ranolazine is antiarrhythmic against drug-induced TdP. The antiarrhythmic effects are reflected in concomitant changes of BVR. [Copyright &y& Elsevier]