Unremodelled and Bradycardic Heart of the Anaesthetized Rabbit Is Applicable for Detection of Drug-induced Torsades de Pointes Arrhythmias

Background and purpose Several rabbit proarrhythmia models have been recently developed by genetic or pharmacological methods to suppress the slow component of delayed rectifier K+ currents in the ventricle, leading to reduction of the repolarization reserve. The present study was designed to characterize a novel rabbit in vivo proarrhythmia model with severe bradycardia caused by acute atrioventricular block (AVB). Experimental approach Bradycardia was induced in isoflurane-anaesthetized rabbits by creation of AVB using catheter ablation, and the ventricle was electrically driven at 60 beats min-1 throughout the experiment except when extrasystole appeared. We assessed effects of 2 antiarrhythmics, 2 quinolone antibiotics and 1 antipsychotic drug, which were chosen as positive drugs (dofetilide, sparfloxacin and haloperidol) and negative drugs (amiodarone and moxifloxacin) for induction of Torsades de Pointes arrhythmias. Key results Torsades de Pointes arrhythmias appeared with high reproducibility after the intravenous administration of dofetilide (10-100 μg kg-1) in 5 out of 6 rabbits, sparfloxacin (30 mg kg-1) in 3 out of 6 rabbits and haloperidol (0.3-3 mg kg-1) in 2 out of 6 rabbits. The lethal arrhythmias repeatedly appeared, and were accompanied with the QT interval prolongation and early afterdepolarization-like phenomena. On the other hand, neither amiodarone (0.3-10 mg kg-1, n=6) nor moxifloxacin (3-30 mg kg-1, n=6) induced such arrhythmias even in the condition of prolonged QT interval. Conclusions and implications These results suggest that the unremodelled and bradycardic heart of the anaesthetized rabbit is applicable for detection of drug-induced Torsades de Pointes arrhythmias.