In a novel rabbit model of acute atrioventricular block, Torsades de Pointes was induced by dofetilide (83.3%), sparfloxacin (50%), and haloperidol (33.3%), but not by amiodarone or moxifloxacin.
Does the anaesthetized rabbit model with acute AV block accurately detect drug-induced Torsade de Pointes?
An in vivo anaesthetized rabbit model with acute AV block successfully differentiates between drugs with high and low risk of inducing Torsades de Pointes, providing a useful test system for proarrhythmia screening.
Tasa de eventos absoluta: 83.3% vs 0%
Background and Purpose Several rabbit proarrhythmia models have been developed using genetic or pharmacological methods to suppress the slow component of delayed rectifier K + currents in the ventricle, leading to reduction of the repolarization reserve. Here we have characterized 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 inducing AVB with catheter ablation, and the ventricle was electrically driven at 60 beats min −1 throughout the experiment except when extrasystoles appeared. We assessed the effects of two antiarrhythmics, two quinolone antibiotics and one antipsychotic drug, which were chosen as positive drugs (dofetilide, sparfloxacin and haloperidol) and negative drugs (amiodarone and moxifloxacin) for induction of Torsades de Pointes (TdP). Key Results In our model, TdP arrhythmias appeared with high reproducibility after i.v. dofetilide (10–100 μg·kg −1 ) in five out of six rabbits, sparfloxacin (30 mg·kg −1 ) in three out of six rabbits and haloperidol (0.3–3 mg·kg −1 ) in two out of six rabbits. The lethal arrhythmias repeatedly appeared and were accompanied with prolongation of the QT interval and early afterdepolarization‐like phenomena. Neither amiodarone (0.3–10 mg·kg −1 , n = 6) nor moxifloxacin (3–30 mg·kg −1 , n = 6) induced such arrhythmias, even when QT intervals were prolonged. Conclusions and Implications These results suggest that our model of the unremodelled and bradycardic heart of the anaesthetized rabbit is a useful test system for the detection of drug‐induced TdP arrhythmias.
Hagiwara et al. (Fri,) conducted a other in Acute atrioventricular block (n=30). Proarrhythmic drugs (dofetilide, sparfloxacin, haloperidol) vs. Negative drugs (amiodarone, moxifloxacin) was evaluated on Induction of Torsades de Pointes (TdP). In a novel rabbit model of acute atrioventricular block, Torsades de Pointes was induced by dofetilide (83.3%), sparfloxacin (50%), and haloperidol (33.3%), but not by amiodarone or moxifloxacin.