title: Characterization of in vivo and in vitro electrophysiological and antiarrhythmic effects of a novel IKACh blocker, NIP-151: a comparison with an IKr-blocker dofetilide.
abstract: 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.
authors.affiliation: Biological Research Laboratories, Nissan Chemical Industries, Ltd., Shiraoka, Saitama, Japan. hashimotot@nissanchem.co.jp
authors.forename: Norio
authors.initials: N
authors.lastname: Hashimoto
authors.forename: Toru
authors.initials: T
authors.lastname: Yamashita
authors.forename: Nobutomo
authors.initials: N
authors.lastname: Tsuruzoe
mesh_terms: D000157:Aconitine; D000200:Action Potentials / Q000187:drug effects; D000704:Analysis of Variance; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001281:Atrial Fibrillation / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D001578:Benzopyrans / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography; D051638:Ether-A-Go-Go Potassium Channels / Q000502:physiology; D005260:Female; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000502:physiology; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D018408:Patch-Clamp Techniques; D010627:Phenethylamines / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011817:Rabbits; D012032:Refractory Period, Electrophysiological / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology; D014630:Vagus Nerve / Q000503:physiopathology; D016278:Ventricular Function, Right
chemical_list: D000889:Anti-Arrhythmia Agents; D001578:Benzopyrans; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C529784:NIP 151; D010627:Phenethylamines; D026902:Potassium Channel Blockers; D013449:Sulfonamides; C063533:dofetilide; D000157:Aconitine