title: Effects of the selective KACh channel blocker NTC-801 on atrial fibrillation in a canine model of atrial tachypacing: comparison with class Ic and III drugs.
abstract: The present study examines the effects of NTC-801, a highly selective acetylcholine (ACh) receptor-activated potassium (KACh) channel blocker, on atrial fibrillation (AF) in a canine model with electrical remodeling. An experimental substrate for AF was created in dogs via left atrial (LA) tachypacing (400 bpm, 3-5 weeks). NTC-801, dofetilide, and flecainide were intravenously infused for 15 minutes, and the effects on AF inducibility, atrial effective refractory period (ERP), and atrial conduction velocity were examined. The effect of NTC-801 on AF termination was also evaluated. Atrial ERP was shortened and AF inducibility was increased after LA tachypacing. NTC-801 (0.3-3 µg·kg⁻¹·min⁻¹) prolonged atrial ERP irrespective of stimulation frequency and dose-dependently decreased AF inducibility. Dofetilide (5.3 µg·kg⁻¹·min⁻¹) and flecainide (0.13 mg·kg⁻¹·min⁻¹) did not significantly inhibit AF inducibility and minimally affected atrial ERP. Flecainide decreased atrial conduction velocity, whereas NTC-801 and dofetilide did not. NTC-801 (0.1 mg/kg) converted AF to normal sinus rhythm. In summary, NTC-801 exerted more effective antiarrhythmic effects than dofetilide and flecainide in a canine LA-tachypacing AF model. The antiarrhythmic activity of NTC-801 was probably due to prolonging atrial ERP independently of stimulation frequency. These results suggest that NTC-801 could prevent AF more effectively in the setting of atrial electrical remodeling.
authors.affiliation: *Pharmaceutical Development Research Laboratories, Teijin Institute for Bio-Medical Research, Teijin Pharma Limited, Tokyo, Japan; †Pharmaceutical Research Department, Biological Research Laboratories, Nissan Chemical Industries, Ltd, Saitama, Japan; ‡Department of Cardiology, Keio University School of Medicine, Tokyo, Japan; §Department of Pharmacology, Chiba University Graduate School of Medicine, Chiba, Japan; and ¶Mita Hospital, International University of Health and Welfare, Tokyo, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Yamamoto
authors.forename: Norio
authors.initials: N
authors.lastname: Hashimoto
authors.forename: Junji
authors.initials: J
authors.lastname: Matsuura
authors.forename: Taiichi
authors.initials: T
authors.lastname: Machida
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Ogino
authors.forename: Tsunefumi
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Yamanaka
authors.forename: Norihisa
authors.initials: N
authors.lastname: Ishiwata
authors.forename: Toru
authors.initials: T
authors.lastname: Yamashita
authors.forename: Kojiro
authors.initials: K
authors.lastname: Tanimoto
authors.forename: Shunichiro
authors.initials: S
authors.lastname: Miyoshi
authors.forename: Keiichi
authors.initials: K
authors.lastname: Fukuda
authors.forename: Haruaki
authors.initials: H
authors.lastname: Nakaya
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ogawa
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D001281:Atrial Fibrillation / Q000188:drug therapy*; D002304:Cardiac Pacing, Artificial; D004285:Dogs; D004562:Electrocardiography / Q000187:drug effects; D005424:Flecainide / Q000627:therapeutic use; D006325:Heart Atria / Q000187:drug effects; D006329:Heart Conduction System / Q000187:drug effects; D010627:Phenethylamines / Q000627:therapeutic use; D026902:Potassium Channel Blockers / Q000627:therapeutic use*; D011950:Receptors, Cholinergic / Q000187:drug effects*; D013449:Sulfonamides / Q000627:therapeutic use; D013610:Tachycardia / Q000188:drug therapy / Q000503:physiopathology
chemical_list: D000889:Anti-Arrhythmia Agents; D010627:Phenethylamines; D026902:Potassium Channel Blockers; D011950:Receptors, Cholinergic; D013449:Sulfonamides; D005424:Flecainide; C063533:dofetilide