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

• Published in: Journal of the American College of Cardiology 2010-02, Vol.55 (8), p.801-809
• Main Authors: Antoons, Gudrun, PhD, Oros, Avram, MD, PhD, Beekman, Jet D.M., BSc, Engelen, Markus A., MD, Houtman, Marien J.C., BSc, Belardinelli, Luiz, MD, Stengl, Milan, PhD, Vos, Marc A., PhD
• Format: Article
• Language: English
• Subjects: Acetanilides - pharmacology; Acute coronary syndromes; Animals; Anti-Arrhythmia Agents - pharmacology; antiarrhythmic agents; arrhythmias; Atrioventricular Block - complications; Cardiac arrhythmia; Cardiology; Cardiovascular; Dogs; Experiments; Heart failure; Internal Medicine; Lidocaine - pharmacology; long QT syndromes; Models, Animal; Phenethylamines - pharmacology; Piperazines - pharmacology; Potassium Channel Blockers - pharmacology; Ranolazine; Rodents; sodium channels; Sodium Channels - drug effects; Software; Sulfonamides - pharmacology; Torsades de Pointes - chemically induced; Torsades de Pointes - drug therapy; Variance analysis
• ISSN: 0735-1097; 1558-3597
• DOI: 10.1016/j.jacc.2009.10.033

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.