Document Detail

Effects of a Highly Selective Acetylcholine-activated K+ Channel Blocker on Experimental Atrial Fibrillation.
MedLine Citation:
PMID:  21156770     Owner:  NLM     Status:  Publisher    
BACKGROUND: -The acetylcholine-activated K(+) current (I(K,ACh)) is a novel candidate for atrial-specific antiarrhythmic therapy. This study investigates the involvement of I(K,ACh) in atrial fibrillation (AF) using NTC-801, a novel potent and selective I(K,ACh) blocker. METHODS AND 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 (II(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 (10-100 nmol/L) reversed the action potential duration (APD(90)) shortened by carbachol or adenosine in atrial cells, whereas it did not afftect APD(90) at 100 nmol/L in ventricular cells. Antiarrhythmic effects of NTC-801 were evaluated in three AF models in vivo. NTC-801 significantly prolonged atrial effective refractory period (ERP) without affecting ventricular ERP under vagal nerve stimulation (VNS). NTC-801 dose-dependently converted AF to normal sinus rhythm in both VNS (0.3-3 μg/kg/min, i.v.)- and aconitine (0.01-0.1 mg/kg, i.v.)-induced models. In a rapid atrial pacing model, NTC-801 (3 μg/kg/min, i.v.) significantly decreased AF inducibility with a prolonged atrial ERP that was frequency-independent. CONCLUSIONS: -A selective I(K,ACh) blockade induced by NTC-801 exerted anti-AF effects mediated by atrial-selective ERP prolongation. These findings suggest that I(K,ACh) may be important in the development and maintenance of atrial fibrillation.
Taiichi Machida; Norio Hashimoto; Ippei Kuwahara; Yasuhiro Ogino; Junji Matsuura; Wataru Yamamoto; Yasuhiro Itano; Akira Zamma; Ryo Matsumoto; Junji Kamon; Tsunefumi Kobayashi; Norihisa Ishiwata; Toru Yamashita; Takehiko Ogura; Haruaki Nakaya
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2010-12-14
Journal Detail:
Title:  Circulation. Arrhythmia and electrophysiology     Volume:  -     ISSN:  1941-3084     ISO Abbreviation:  -     Publication Date:  2010 Dec 
Date Detail:
Created Date:  2010-12-15     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101474365     Medline TA:  Circ Arrhythm Electrophysiol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
1 Pharmaceutical Development Res Labs, Teijin Instit for Bio-Medical Res, Teijin Pharma Ltd, Japan;
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