Hagiwara Mihoko, Shibuta Seiji, Takada Kazuhiro, Kambayashi Ryuichi, Nakajo Misako, Aimoto Megumi, Nagasawa Yoshinobu, Takahara Akira
Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Toho University, Chiba, Japan.
Br J Pharmacol. 2017 Aug;174(15):2591-2605. doi: 10.1111/bph.13870. Epub 2017 Jul 5.
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).
Bradycardia was induced in isoflurane-anaesthetized rabbits by inducing AVB with catheter ablation, and the ventricle was electrically driven at 60 beats min 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).
In our model, TdP arrhythmias appeared with high reproducibility after i.v. dofetilide (10-100 μg·kg ) in five out of six rabbits, sparfloxacin (30 mg·kg ) in three out of six rabbits and haloperidol (0.3-3 mg·kg ) 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 , n = 6) nor moxifloxacin (3-30 mg·kg , n = 6) induced such arrhythmias, even when QT intervals were prolonged.
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.
已经开发了几种兔心律失常模型，采用遗传或药理学方法抑制心室延迟整流钾电流的缓慢成分，导致复极储备减少。在此，我们描述了一种由急性房室传导阻滞（AVB）引起严重心动过缓的新型兔体内心律失常模型。
在异氟烷麻醉的兔中，通过导管消融诱导AVB来诱发心动过缓，并且在整个实验过程中，除了出现期外收缩时，以每分钟60次的频率对心室进行电驱动。我们评估了两种抗心律失常药、两种喹诺酮类抗生素和一种抗精神病药物的作用，这些药物被选为诱发尖端扭转型室性心动过速（TdP）的阳性药物（多非利特、司帕沙星和氟哌啶醇）和阴性药物（胺碘酮和莫西沙星）。
在我们的模型中，静脉注射多非利特（10 - 100μg·kg）后，六只兔中有五只出现TdP心律失常，且重现性高；静脉注射司帕沙星（30mg·kg）后，六只兔中有三只出现；静脉注射氟哌啶醇（0.3 - 3mg·kg）后，六只兔中有两只出现。致死性心律失常反复出现，并伴有QT间期延长和早期后去极化样现象。即使QT间期延长，胺碘酮（0.3 - 10mg·kg，n = 6）和莫西沙星（3 - 30mg·kg，n = 6）也未诱发此类心律失常。
这些结果表明，我们的麻醉兔未重构和心动过缓心脏模型是检测药物诱发TdP心律失常的有用测试系统。
