Both flunarizine and verapamil completely suppressed and prevented dofetilide-induced Torsade de Pointes and reversed short-term variability of repolarization to baseline values.
Do flunarizine and verapamil prevent or suppress dofetilide-induced Torsade de Pointes in preclinical models?
Flunarizine and verapamil demonstrate robust anti-arrhythmic efficacy against dofetilide-induced TdP in preclinical models through divergent electrophysiological mechanisms.
BACKGROUND AND PURPOSE: The high predisposition to Torsade de Pointes (TdP) in dogs with chronic AV-block (CAVB) is well documented. The anti-arrhythmic efficacy and mode of action of Ca(2+) channel antagonists, flunarizine and verapamil against TdP were investigated. EXPERIMENTAL APPROACH: Mongrel dogs with CAVB were selected based on the inducibility of TdP with dofetilide. The effects of flunarizine and verapamil were assessed after TdP and in different experiments to prevent dofetilide-induced TdP. Electrocardiogram and ventricular monophasic action potentials were recorded. Electrophysiological parameters and short-term variability of repolarization (STV) were determined. In vitro, flunarizine and verapamil were added to determine their effect on (i) dofetilide-induced early after depolarizations (EADs) in canine ventricular myocytes (VM); (ii) diastolic Ca(2+) sparks in RyR2(R4496+/+) mouse myocytes; and (iii) peak and late I(Na) in SCN5A-HEK 293 cells. KEY RESULTS: Dofetilide increased STV prior to TdP and in VM prior to EADs. Both flunarizine and verapamil completely suppressed TdP and reversed STV to baseline values. Complete prevention of TdP was achieved with both drugs, accompanied by the prevention of an increase in STV. Suppression of EADs was confirmed after flunarizine. Only flunarizine blocked late I(Na). Ca(2+) sparks were reduced with verapamil. CONCLUSIONS AND IMPLICATIONS: Robust anti-arrhythmic efficacy was seen with both Ca(2+) channel antagonists. Their divergent electrophysiological actions may be related to different additional effects of the two drugs.
Oros et al. (2010) studied Dofetilide-induced Torsade de Pointes (TdP). Flunarizine and verapamil vs. Baseline / dofetilide alone was evaluated on Suppression and prevention of TdP and short-term variability of repolarization (STV). Both flunarizine and verapamil completely suppressed and prevented dofetilide-induced Torsade de Pointes and reversed short-term variability of repolarization to baseline values.