Inhibition of IK,ACh current may contribute to clinical efficacy of class I and class III antiarrhythmic drugs

Dr. Voigt, Niels1, Rozmaritsa, Nadiia1, Trausch, Anne1, Zimniak, Thomasz1, Dr. Christ, Torsten1, Prof. Dr. Wettwer, Erich1, Dr. Matschke, Klaus2, Prof. Dr. Ravens, Ursula1, Prof. Dr. Dobrev, Dobromir1. 1Dresden University of Technology Department of Pharmacology and Toxicology, Fetscherstr. 74, 01307 Dresden, Germany ; 2Cardiovascular Center, Dresden University of Technology Department of Cardiosurgery, Fetscherstr. 76, 01307 Dresden, Germany.

strong>Introduction: IK1 and ACh-activated IK,ACh are implicated in atrial fibrillation (AF). In AF IK,ACh develops a receptor-independent constitutively active component that together with the increased IK1 likely supports the maintenance of AF. Here we tested whether class I (flecainide and propafenone) and class III (dofetilide and AVE0118) antiarrhythmic drugs inhibit atrial IK1 and IK,ACh in patients with and without AF.

Methods: Currents were measured with whole-cell voltage-clamp technique in atrial myocytes from 24 AF and 69 sinus rhythm (SR) patients. Carbachol (CCh, 2 µM) was employed to activate IK,ACh.

Results: Basal current in SR was not affected by either drug indicating no effect on IK1. In contrast, flecainide, propafenone, dofetilide and AVE0118 inhibited CCh-activated IK,ACh. The IC50 values were (in µM) 17.4, 0.5, 8.3 and 6.5, respectively. Basal current was larger in AF than in SR (at -80 mV: -14.0±2.2 pA/pF vs -7.2±0.6 pA/pF), whereas CCh-activated IK,ACh was smaller (-7.0±1.4 pA/pF vs -11.6±0.8 pA/pF). Only in AF the selective IK,ACh-channel blocker tertiapin reduced basal current, confirming contribution of receptor-independent constitutive IK,ACh to AF-associated increased ”IK1“. Flecainide (10 µM) and AVE0118 (10 µM), but not propafenone (10 µM) or dofetilide (30 µM), reduced basal current in AF by 3.7±1.1 pA/pF and 5.5±1.0 pA/pF, respectively, likely due to inhibition of constitutively active IK,ACh channels. In AF flecainide (10 µM), propafenone (10 µM), dofetilide (30 µM) and AVE0118 (10 µM) reduced CCh-activated IK,ACh.

Conclusions: Flecainide and AVE0118, but not propafenone and dofetilide, reduced receptor-independent constitutively-active IK,ACh suggesting that flecainide and AVE0118 may block IK,ACh channels, whereas propafenone and dofetilide likely inhibit M-receptors. Since flecainide effectively terminates AF, its efficacy to terminate AF may in part result from blockade of IK,ACh.