Abstract
The proarrhythmic effects of class III antiarrhythmic drugs and non-cardiovascular drugs which have been shown to prolong the QT interval were assessed using the three different types of canine models. The proarrhythmic action of sematilide was assessed first using the canine isolated, blood-perfused ventricular tissue preparation. Sematilide prolonged MAP90 and ERP, in which the increase in the former was greater than the latter, indicating prolongation of relative refractory period (RRP=MAP90 -ERP). Ventricular tachyarrhythmias were induced when extrastimulus was applied within the RRP. This arrhythmic zone increased as RRP increased Next, electrophysiological effects in vivo of dofetilide, nifekalant, cisapride, sulpiride, haloperidol and sparfloxacin were assessed using halothane-anesthetized canine model. Dofetilide and nifekalant slowed heart rate and prolonged MAP90 and ERP, while no significant change was detected in other cardiovascular parameters. The other drugs also exerted similar effects to class III drugs, however they also exerted negative inotropic, dromotropic and hypotensive actions. RRP was prolonged by each drug. Finally, torsadegenic action of sematilide, nifekalant, cisapride, terfenadine, sulpiride and sparfloxacin was assessed using chronic complete atrioventricular block dogs using Holter ECG monitoring in conscious state. Oral administration of clinically relevant doses of drugs did not induce any arrhythmia, while 5-40 times higher doses induced polymorphic ventricular tachycardia. These results indicate that drug-induced prolongation and backward shift of RRP may be substrates for Torsades de Pointes.
