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

Tedisamil is a bradycardiac agent that prolongs the QT interval of the ECG 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 were examined in rabbit isolated hearts in which bradycardia was induced by AV ablation. The QT interval was prolonged in a reverse rate‐dependent fashion by dofetilide (3 and 30 n M ) and tedisamil (0.3 and 3 μ M ). Torsades de pointes was observed in 1/7 hearts treated with 3 n M dofetilide and 0/7 hearts treated with 0.3 μ M tedisamil. The incidence of torsades de pointes was increased to 5/7 in hearts treated with 30 n M dofetilide and to 7/7 in hearts treated with 3 μ M tedisamil (both P <0.05 vs control). The actions of 30 n M dofetilide and 3 μ M tedisamil were also examined in hearts paced at 50, 100, 200 and 50 beats min −1 successively. Both drugs caused torsades de pointes in 5/5 hearts paced at 50 beats min −1 ; however, the incidence was reduced to 0/5 during pacing at 200 beats min −1 . Thus, drug‐induced proarrhythmia was bradycardia‐dependent. 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 occurrence of torsades de pointes ( r =0.91, P <0.01). The results suggest that tedisamil, like dofetilide, presents a risk for development of torsades de pointes.British Journal of Pharmacology (2001) 132 , 1493–1500; doi: 10.1038/sj.bjp.0703967