Referenced in: none

Automatically associated channels: Kir2.1 , Kir3.1

Title: Effects of a highly selective acetylcholine-activated K+ channel blocker on experimental atrial fibrillation.

Authors: 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

Journal, date & volume: Circ Arrhythm Electrophysiol, 2011 Feb , 4, 94-102

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/21156770

Abstract
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.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.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.