NIP-141

Atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice. Rhythm control strategy for AF is limited by drug toxicity and side effects, and recent trials have shown that this strategy is not superior to a rate control one. New antiarrhythmic drugs, free of undesired effects, would enhance rhythm control, with the possibility of sinus rhythm restoration and maintenance. A promising find in the search for new antiarrhythmic therapies is atrial-tissue specific ion channels. The findings that the ultrarapid delayed rectifier (I(Kur)) and the inwardly rectifying, acetylcholine-regulated current (I(K-Ach)) exist in atrial but not ventricular tissue increase the probability that atrioselective drugs without ventricular proarrhythmic toxicity can be developed for treatment of patients with AF. There are also other potential targets for atrial-selective therapy: transient outward current (I(to)), rapidly and slowly activating delayed rectifier currents (I(Kr) and I(Ks)), atrial sodium current (I(Na)) and atrially expressed connexins. New drugs under development with promising atrial-selectivity include: tertiapin, NIP-142, NIP-141, JTV-519, AVE0118, AVE1231, DPO-1, AZD7009 and many others. Among such new agents, vernakalant hydrochloride is currently in an advanced phase of development and has already been evaluated in clinical trials. In this overview, we describe the history and current state of developmental process of the drug, as well as its mechanism of action and influence on electrophysiological parameters. Vernakalant seems to be effective in terminating recent-onset AF, but is not efficacious in long-lasting AF and atrial flutter. The drug may be relatively free of proarrhythmic effects, and exerts a protective effect on ventricular tissue and ventricular repolarization. It is expected that the intravenous formulation will soon be approved for the pharmacological termination of recent-onset AF.

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.