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 IC₅₀ 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 (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⁻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.