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.
OBJECTIVE
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.


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 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.


CONCLUSIONS
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.
Hashimoto
Norio
N
Biological Research Laboratories, Nissan Chemical Industries Ltd, 1470 Shiraoka, Minamisaitama, Saitama 349-0294, Japan. hashimotot@nissanchem.co.jp
Yamashita
Toru
T
Fujikura
Naoki
N
Tsuruzoe
Nobutomo
N
D000818:Animals; D001281:Atrial Fibrillation / Q000139:chemically induced / Q000503:physiopathology* / Q000517:prevention & control*; D001578:Benzopyrans / Q000008:administration & dosage*; D002304:Cardiac Pacing, Artificial / Q000379:methods*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006329:Heart Conduction System / Q000187:drug effects* / Q000503:physiopathology*; D007473:Ion Channels / Q000037:antagonists & inhibitors; D012032:Refractory Period, Electrophysiological / Q000187:drug effects*; D016896:Treatment Outcome
D001578:Benzopyrans; D007473:Ion Channels; C449401:NIP 141