Tedisamil and dofetilide-induced torsades de pointes, rate and potassium dependence

1 Tedisamil is a bradycardiac agent that prolongs the QT interval of the EC G and prevents cardiac arrhythmias. Given this profile, tedisamil might be expected to have proarrhythmic actions similar to Class III antiarrhythmic drugs. To address this question, the actions of dofetilide and tedisamil we re examined in rabbit isolated hearts in which bradycardia was induced by A V ablation. 2 The QT interval was prolonged in a reverse rate-dependent fashion by dofe tilide (3 and 30 nM) and tedisamil (0.3 and 3 muM) 3 Torsades de pointes was observed in 1/7 hearts treated with 3 nhl dofetil ide and 0/7 hearts treated with 0.3 muM tedisamil. The incidence of torsade s de pointes was increased to 5/7 in hearts treated with 30 nM dofetilide a nd to 7/7 in hearts treated with 3 muM tedisamil (both P<0.05 vs control). 4 The actions of 30 nM dofetilide and 3 <mu>M tedisamil were also examined in hearts paced at 50, 100, 200 and 50 beats min(-1) successively. Both dru gs caused torsades de pointes in 5/5 hearts paced at 50 beats min(-1); howe ver, the incidence was reduced to 0/5 during pacing at 200 beats min(-1). T hus, drug-induced proarrhythmia was bradycardia-dependent. 5 Drug-induced prolongation of the interval between the peak and end of the T-wave (QTa-e) was reverse rate-dependent and was associated with the occu rrence of torsades de pointes (r=0.91, P<0.01). 6 The results suggest that tedisamil, like dofetilide, presents a risk for development of torsades de pointes.