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

Abstract

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). Ranolazine inhibits the late Na(+) current (I(NaL)) and is effective against arrhythmias in long QT3 syndromes despite its blocking properties of the rapid component of delayed rectifying potassium current. 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 I(NaL), action potential duration, and dofetilide-induced BVR and early afterdepolarizations. 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 micromol/l, in 75% at 10 micromol/l, and in 100% at 15 micromol/l. At 5 micromol/l, ranolazine blocked 26 +/- 3% of tetrodotoxin-sensitive I(NaL), and 49 +/- 3% at 15 micromol/l. Despite a 54% reduction of I(NaL) amplitude in cAVB compared with control cells, I(NaL) inhibition by 5 micromol/l tetrodotoxin equally shortened relative action potential duration and completely abolished dofetilide-induced early afterdepolarizations. Despite down-regulation of I(NaL) in remodeled cAVB hearts, ranolazine is antiarrhythmic against drug-induced TdP. The antiarrhythmic effects are reflected in concomitant changes of BVR.