Key result
NIP-151 potently blocked IKACh (IC50 1.6 nM) and dose-dependently terminated atrial fibrillation in canine models with an atrial-specific ERP-prolonging profile, unlike dofetilide.
Why the study?
Does NIP-151 terminate atrial fibrillation and affect electrophysiological parameters differently than dofetilide in canine models?
Does NIP-151 terminate atrial fibrillation and affect electrophysiological parameters differently than dofetilide in canine models?
NIP-151, a novel IKACh blocker, effectively terminates atrial fibrillation in canine models with an atrial-specific profile, suggesting a lower risk of proarrhythmia compared to IKr blockers like dofetilide.
May advance atrial-selective IKACh blockade for AF; leaves open human translation and proarrhythmia risk reduction.
We investigated the electrophysiological and antiarrhythmic effects of a novel antiarrhythmic agent, NIP-151, and compared these effects with those of an IKr-blocker dofetilide. NIP-151 potently inhibited acetylcholine-activated K current (IKACh) with an IC50, with 1.6 nM in HEK293 cells expressing the GIRK1/4 channel, but it had little effect on IKr (IC50 = 57.6 microM). NIP-151 dose-dependently terminated AF both in vagal nerve stimulation-induced AF (at 5 and 15 microg/kg per minute) and aconitine-induced AF (at 30 and 100 microg/kg) models. This compound significantly prolonged the atrial effective refractory period (ERP), but it had no significant effects on ventricular ERP. There were no significant changes on electrocardiographic variables with NIP-151 (up to 1,000 microg/kg per minute) administration. In contrast, dofetilide had little effect in either AF model, even though this compound potently prolonged atrial ERP. Dofetilide also significantly prolonged ventricular ERP and the QT interval in anesthetized dogs, which are related to proarrhythmic risk. In conclusion, a novel antiarrhythmic agent NIP-151, which potently blocked IKACh, was highly effective in the two types of canine AF models with an atrial-specific ERP-prolonging profile. Therefore, NIP-151 might be useful for the treatment of AF with lower risk of proarrhythmia, compared with IKr blockers.
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Hashimoto et al. (2008) studied Atrial fibrillation (experimental models). NIP-151 vs. Dofetilide was evaluated on Inhibition of IKACh and termination of AF. NIP-151 potently blocked IKACh (IC50 1.6 nM) and dose-dependently terminated atrial fibrillation in canine models with an atrial-specific ERP-prolonging profile, unlike dofetilide.
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