Abstract 11210: Effects of NTC-801, a Selective KACh Channel Blocker, on Atrial Fibrillation in A Canine Model of Rapid Atrial Pacing: A Comparison with Dofetilide and Flecainide
The acetylcholine (ACh) receptor-activated K+ current (IK,ACh) is a novel candidate for atrial-specific antiarrhythmic therapy. It is not determined whether ACh receptor-activated K+ (KACh) channel blockers would exert antiarrhythmic effects against atrial fibrillation (AF) associated with electrical remodeling in vivo. The present study was conducted to examine the effects of NTC-801, a highly-selective KACh channel blocker, on AF in a canine model with electrical remodeling.
The experimental substrate for AF was created in dogs via left atrial (LA)-tachypacing (400 bpm, 3-5 weeks). NTC-801, dofetilide and flecainide were intravenously infused for 15 min and the effects on AF inducibility, atrial effective refractory period (ERP) and atrial conduction velocity (CV) were examined. The effect of NTC-801 on AF termination was also evaluated.
After LA pacing, atrial ERP was shortened and AF inducibility was increased, suggesting the electrical remodeling occurred in this model. NTC-801 (0.3-3 µg/kg/min) inhibited AF inducibility in a dose-dependent manner. The inhibition rates of AF induction were 3.3, 15.0, 63.3, and 93.3% (p<0.001) in vehicle, NTC-801 0.3, 1 and 3 µg/kg/min groups, respectively. Dofetilide (5.3 µg/kg/min) and flecainide (0.13 mg/kg/min) did not show significant effects on AF induction with the inhibition rates of 20.0 and 68.0%, respectively. NTC-801 significantly prolonged atrial ERP in a dose-dependent manner, while dofetilide and flecainide exhibited minimal effects. In addition, the effects of NTC-801 on atrial ERP was frequency-independent at the basic cycle length of 300, 250 and 200 ms, respectively. Flecainide but not NTC-801 or dofetilide decreased atrial CV. Furthermore, NTC-801 (0.1 mg/kg, i.v. bolus) converted AF to normal sinus rhythm. While vehicle terminated none of 6 dogs, NTC-801 terminated AF in 5 of 8 dogs (p<0.05).
NTC-801 showed better antiarrhythmic efficacy than dofetilide or flecainide in this model of atrial pacing-induced AF. The antiarrhythmic activity of NTC-801 was likely due to prolongation of atrial ERP, which was independent of stimulation frequency. These results suggest that NTC-801 may have superior efficacy against AF that is associated with atrial electrical remodeling.
- © 2012 by American Heart Association, Inc.