Effects of IKur blocker MK-0448 on human right atrial action potentials from patients in sinus rhythm and in permanent atrial fibrillation

Abstract

Selective blockers of the Kv1.5 channel have been developed for the treatment of atrial fibrillation (AF), but little is known how these atrial-selective drugs affect human action potentials (APs). Therefore we have investigated the Kv1.5 blocker MK-0448 (N-{6-[(1S)-1-(4-fluorophenyl)-2,2-di(pyridin-3-yl)ethyl]pyridin-2-yl}methanesulfon- amide) in right atrial trabeculae from patients in sinus rhythm (SR), permanent AF (>6 months), and intermittent AF. MK-0448 blocked Kv1.5 current in an expression system and concentration-dependently elevated the plateau phase of atrial APs. In SR preparations stimulated at 1 Hz, MK-0448 (3 μM) shortened action potential duration at 90% of repolarization (APD90) and effective refractory period (ERP), but in permanent AF preparations, MK-0448 prolonged APD90 and ERP. The effects of MK-0448 in intermittent AF resembled those in SR preparations. Block of IKs is probably more prominent in AF because of reduced repolarization reserve due to AF-induced remodeling. © 2014 Loose, Mueller, Wettwer, Knaut, Ford, Milnes and Ravens.