title: Effects of a highly selective acetylcholine-activated K+ channel blocker on experimental atrial fibrillation.
abstract: BACKGROUND
  The acetylcholine-activated K(+) current (I(K,ACh)) is a novel candidate for atrial-specific antiarrhythmic therapy. The present study investigates the involvement of I(K,ACh) in atrial fibrillation (AF) using NTC-801, a novel potent and selective I(K,ACh) blocker.
  
  
  RESULTS
  The effects of NTC-801, substituted 4-(aralkylamino)-2,2-dimethyl-3,4-dihydro-2H-benzopyran-3-ol, on I(K,ACh) and other cardiac ionic currents (I(Na), I(CaL), I(to), I(Kur), I(Kr), I(Ks), I(Kl), I(KATP), and I(f)) and on atrial and ventricular action potentials were examined in vitro. NTC-801 potently inhibited carbachol-induced I(K,ACh) in guinea pig atrial cells and the GIRK1/4 current in Xenopus oocytes with IC(50) values of 5.7 and 0.70 nmol/L, respectively. NTC-801 selectively inhibited I(K,ACh) >1000-fold over other cardiac ionic currents. NTC-801 (10 to 100 nmol/L) reversed the action potential duration (APD(90)) shortened by carbachol or adenosine in atrial cells, whereas it did not affect APD(90) at 100 nmol/L in ventricular cells. Antiarrhythmic effects of NTC-801 were evaluated in 3 AF models in vivo. NTC-801 significantly prolonged atrial effective refractory period without affecting ventricular effective refractory period under vagal nerve stimulation. NTC-801 dose-dependently converted AF to normal sinus rhythm in both vagal nerve stimulation-induced (0.3 to 3 μg · kg(-1) · min(-1) IV) and aconitine-induced (0.01 to 0.1 mg/kg IV) models. In a rapid atrial pacing model, NTC-801 (3 μg · kg(-1) · min(-1) IV) significantly decreased AF inducibility with a prolonged atrial effective refractory period that was frequency-independent.
  
  
  CONCLUSIONS
  A selective I(K,ACh) blockade induced by NTC-801 exerted anti-AF effects mediated by atrial-selective effective refractory period prolongation. These findings suggest that I(K,ACh) may be important in the development and maintenance of AF.
authors.affiliation: Pharmaceutical Development Research Laboratories, Teijin Institute for Bio-Medical Research, Teijin Pharma Limited, Tokyo, Japan.
authors.forename: Taiichi
authors.initials: T
authors.lastname: Machida
authors.forename: Norio
authors.initials: N
authors.lastname: Hashimoto
authors.forename: Ippei
authors.initials: I
authors.lastname: Kuwahara
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Ogino
authors.forename: Junji
authors.initials: J
authors.lastname: Matsuura
authors.forename: Wataru
authors.initials: W
authors.lastname: Yamamoto
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Itano
authors.forename: Akira
authors.initials: A
authors.lastname: Zamma
authors.forename: Ryo
authors.initials: R
authors.lastname: Matsumoto
authors.forename: Junji
authors.initials: J
authors.lastname: Kamon
authors.forename: Tsunefumi
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Norihisa
authors.initials: N
authors.lastname: Ishiwata
authors.forename: Toru
authors.initials: T
authors.lastname: Yamashita
authors.forename: Takehiko
authors.initials: T
authors.lastname: Ogura
authors.forename: Haruaki
authors.initials: H
authors.lastname: Nakaya
mesh_terms: D000109:Acetylcholine; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001281:Atrial Fibrillation / Q000188:drug therapy* / Q000503:physiopathology; D001578:Benzopyrans / Q000494:pharmacology; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D057809:HEK293 Cells; D006325:Heart Atria / Q000166:cytology / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D023421:Models, Animal; D009865:Oocytes / Q000187:drug effects; D026902:Potassium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology; D014630:Vagus Nerve / Q000187:drug effects / Q000503:physiopathology; D014981:Xenopus
chemical_list: D000889:Anti-Arrhythmia Agents; D001578:Benzopyrans; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D000109:Acetylcholine