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.
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.
Authors: Stephen Ph Alexander; Anthony P Davenport; Eamonn Kelly; Neil Marrion; John A Peters; Helen E Benson; Elena Faccenda; Adam J Pawson; Joanna L Sharman; Christopher Southan; Jamie A Davies Journal: Br J Pharmacol Date: 2015-12 Impact factor: 8.739
Authors: P G Volders; K R Sipido; M A Vos; R L Spätjens; J D Leunissen; E Carmeliet; H J Wellens Journal: Circulation Date: 1999-12-14 Impact factor: 29.690
Authors: Rosanne Varkevisser; Marc A Vos; Jet D Beekman; Ralph G Tieland; Marcel A Van Der Heyden Journal: J Cardiovasc Electrophysiol Date: 2014-09-19
Authors: Milan Stengl; Paul G A Volders; Morten B Thomsen; Roel L H M G Spätjens; Karin R Sipido; Marc A Vos Journal: J Physiol Date: 2003-06-20 Impact factor: 5.182