Effects of a Highly Selective Acetylcholine-Activated K+ Channel Blocker on Experimental Atrial Fibrillation

BACKGROUND—The acetylcholine-activated K current (IK,ACh) is a novel candidate for atrial-specific antiarrhythmic therapy. The present study investigates the involvement of IK,ACh in atrial fibrillation (AF) using NTC-801, a novel potent and selective IK,ACh blocker. METHODS AND RESULTS—The effects of NTC-801, substituted 4-(aralkylamino)-2,2-dimethyl-3,4-dihydro-2H-benzopyran-3-ol, on IK,ACh and other cardiac ionic currents (INa, ICaL, Ito, IKur, IKr, IKs, IKl, IKATP, and If) and on atrial and ventricular action potentials were examined in vitro. NTC-801 potently inhibited carbachol-induced IK,ACh in guinea pig atrial cells and the GIRK1/4 current in Xenopus oocytes with IC50 values of 5.7 and 0.70 nmol/L, respectively. NTC-801 selectively inhibited IK,ACh >1000-fold over other cardiac ionic currents. NTC-801 (10 to 100 nmol/L) reversed the action potential duration (APD90) shortened by carbachol or adenosine in atrial cells, whereas it did not affect APD90 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 · min IV) and aconitine-induced (0.01 to 0.1 mg/kg IV) models. In a rapid atrial pacing model, NTC-801 (3 μg · kg · min IV) significantly decreased AF inducibility with a prolonged atrial effective refractory period that was frequency-independent. CONCLUSIONS—A selective IK,ACh blockade induced by NTC-801 exerted anti-AF effects mediated by atrial-selective effective refractory period prolongation. These findings suggest that IK,ACh may be important in the development and maintenance of AF.