Article date: August 2017
By: Mihoko Hagiwara, Seiji Shibuta, Kazuhiro Takada, Ryuichi Kambayashi, Misako Nakajo, Megumi Aimoto, Yoshinobu Nagasawa, Akira Takahara in Volume 174, Issue 15, pages 2591-2605
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.
DOI: 10.1111/bph.13870
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