Antiarrhythmic Effects of NTC-801, a Selective Acetylcholine-Activated K⁺ Channel Blocker, on Experimental Atrial Fibrillation

Abstract

Introduction: The acetylcholine-activated K⁺ current (I_K,ACh) is a putative target for atrial-specific antiarrhythmic therapy. This study investigated the role of I_K,ACh in canine atrial fibrillation (AF) models using NTC-801, a novel potent and selective I_K,ACh blocker. Methods: Effects of NTC-801 on atrial and ventricular effective refractory period (ERP) were evaluated during vagal nerve stimulation (VNS) in dogs. Antiarrhythmic effects of NTC-801 were evaluated in canine VNS, aconitine and chronic rapid atrial pacing (RAP) AF models. Results: NTC-801 (0.3–3 µg/kg/min, i.v.) significantly prolonged atrial ERP without affecting ventricular ERP under VNS. NTC-801 (0.3–3 µg/kg/min, i.v.) dose-dependently converted AF to sinus rhythm in the VNS model. NTC-801 (0.01–0.1 mg/kg, i.v.) also dose-dependently converted AF to sinus rhythm in the aconitine model. In the chronic RAP model, NTC-801 (3 µg/kg/min, i.v.) significantly decreased AF inducibility with a frequency-independent prolongation of atrial ERP. NTC-801 (1, 3 mg/kg, p.o.) hardly affected blood pressure, heart rate and ECG parameters including QT interval in conscious dogs. Conclusions: NTC-801, a selective I_K,ACh blocker, produced anti-AF effects in various experimental AF models through atrial-selective ERP prolongation. These findings suggest that I_K,ACh plays an important role in the development and maintenance of AF and that NTC-801 may be useful for the treatment of AF.