A class III antiarrhythmic drug nifekalant has been demonstrated to prolong the QT interval with a lower risk of torsade de pointes (TdP) than dofetilide. We pharmacologically analyzed differences of proarrhythmic mechanisms between the two drugs using a TdP model of acute atrioventricular block rabbits under the monitoring of the monophasic action potential (MAP) of the right ventricle. Intravenous administration of dofetilide (0.025 mg/kg) and nifekalant (0.3 mg/kg) prolonged the MAP duration in a similar extent, which were accompanied with an induction of early afterdepolarization (EAD) in 4 out of 5 animals and all animals, respectively. Meanwhile, TdP appeared in 4 and 1 out of 5 animals after the administration of dofetilide and nifekalant, respectively. Nifekalant-induced EAD and TdP were effectively inhibited by both pretreatment with a L-type Ca²⁺ channel inhibitor verapamil and a Na⁺/Ca²⁺ exchanger inhibitor SEA0400. On the other hand, dofetilide-induced EAD and TdP, which could be similarly suppressed by verapamil, were hardly affected by SEA0400, suggesting the less dependency of Na⁺/Ca²⁺ exchanger on induction of dofetilide-induced EAD and TdP. Thus, the results imply a significant role of L-type Ca²⁺ channels for generation of arrhythmic trigger of drug-induced long QT syndrome.