Hashimoto Norio, Yamashita Toru, Fujikura Naoki, Tsuruzoe Nobutomo
Biological Research Laboratories, Nissan Chemical Industries Ltd, 1470 Shiraoka, Minamisaitama, Saitama 349-0294, Japan.
Europace. 2007 Apr;9(4):246-51. doi: 10.1093/europace/eum018. Epub 2007 Mar 9.
NIP-141 is a novel multiple ion channel blocker with atrial selective effects. In this study, we examined the effects of NIP-141 on aconitine-induced atrial fibrillation (AF) and rapid atrial pacing-induced atrial effective refractory period (ERP) shortening in dogs.
Aconitine AF was induced by the application of aconitine on the right appendage. NIP-141 (10 mg/kg) converted AF to sinus rhythm in 5 of 6 dogs. The Na(+) channel blockers disopyramide (1 mg/kg) and phenytoin (10 mg/kg) also terminated AF, but the I(Kr) blocker (d-sotalol; 4 mg/kg) and a Ca(2+) channel blocker (verapamil; 0.3 mg/kg) did not terminate AF in this model. To clarify the mechanism of AF termination, we examined the effects on ERP and conduction time, but NIP-141 (10 mg/kg) had no significant effects. In a short-term rapid atrial pacing model, NIP-141 (2.5 mg/kg/10 min, followed by 0.033 mg/kg/min) prevented atrial ERP shortening. We also found NIP-141 bound to Na(+) channel site 2 receptor and L-type Ca(2+) channel, but not to Na(+) channel site 1 receptor using radioligands binding assay.
NIP-141 terminated AF in aconitine-induced AF and prevented the atrial remodelling by short-term rapid pacing in dogs, possibly via the blocking of Na(+) and Ca(2+) channels.
NIP - 141是一种具有心房选择性作用的新型多离子通道阻滞剂。在本研究中，我们检测了NIP - 141对乌头碱诱导的犬心房颤动（AF）以及快速心房起搏诱导的犬心房有效不应期（ERP）缩短的影响。
通过在右心耳应用乌头碱诱导乌头碱型AF。NIP - 141（10 mg/kg）使6只犬中的5只AF转为窦性心律。钠通道阻滞剂丙吡胺（1 mg/kg）和苯妥英（10 mg/kg）也能终止AF，但在此模型中，I(Kr)阻滞剂（d - 索他洛尔；4 mg/kg）和钙通道阻滞剂（维拉帕米；0.3 mg/kg）不能终止AF。为阐明AF终止的机制，我们检测了其对ERP和传导时间的影响，但NIP - 141（10 mg/kg）无显著作用。在短期快速心房起搏模型中，NIP - 141（2.5 mg/kg/10分钟，随后0.033 mg/kg/分钟）可防止心房ERP缩短。我们还通过放射性配体结合试验发现NIP - 141与钠通道位点2受体和L型钙通道结合，但不与钠通道位点1受体结合。
NIP - 141可终止乌头碱诱导的AF，并通过短期快速起搏防止犬心房重构，可能是通过阻断钠通道和钙通道实现的。
