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Europace Advance Access published online on March 9, 2007
Europace, doi:10.1093/europace/eum018
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© The European Society of Cardiology 2007. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

NIP-141, a multiple ion channel blocker, terminates aconitine-induced atrial fibrillation and prevents the rapid pacing-induced atrial effective refractory period shortening in dogs

Norio Hashimoto*, Toru Yamashita, Naoki Fujikura and Nobutomo Tsuruzoe

Biological Research Laboratories, Nissan Chemical Industries Ltd, 1470 Shiraoka, Minamisaitama, Saitama 349-0294, Japan

Aims 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.

Methods and results 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 IKr blocker (d-sotalol; 4 mg/kg) and a Ca2+ 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 Ca2+ channel, but not to Na+ channel site 1 receptor using radioligands binding assay.

Conclusion 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 Ca2+ channels.

Key Words: Atrial fibrillation, Antiarrhythmic agents, Electrical remodelling, Na+ channel, Ca2+ channel

* Corresponding author. Tel: +81 480 92 2513; fax: +81 480 90 1014. E-mail address: hashimotot{at}nissanchem.co.jp

Manuscript submitted 20 July 2006. Accepted after revision 18 January 2007.


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