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.
Highlights
In search of safer antiarrhythmic drugs for the treatment of atrial fibrillation (AF), selective inhibitors of IKur have been designed as atrial-selective class III antiarrhythmic agents with therapeutic potential increase atrial refractoriness (in AF)
We have previously investigated the electrophysiological effects of several IKur inhibitors, including 4-aminopyridine, AVE0118, XEN-D0101, all of which elevated the plateau phase of human right atrial action potentials (APs) recorded in trabeculae of atrial appendage obtained from patients in sinus rhythm (SR) or AF (Wettwer et al, 2004; Christ et al, 2008; Ford et al, 2013)
Since nothing is known about the effects of MK-0448 in ex-vivo human atrial tissue, we investigated its effects on the shapes of atrial APs and effective refractory period (ERP) with standard microelectrode techniques in trabeculae isolated from right atrial appendages of patients in SR and AF, who had to undergo open heart surgery
Summary
In search of safer antiarrhythmic drugs for the treatment of atrial fibrillation (AF), selective inhibitors of IKur have been designed as atrial-selective class III antiarrhythmic agents with therapeutic potential in AF. Since they target the Kv1.5 channels which are functional only in atria (Mays et al, 1995), these agents are considered to be devoid of proarrhythmic effects in ventricles and have received a lot of interest in the scientific community (for review see Ford and Milnes, 2008; Tamargo et al, 2009; Ravens, 2010; Ravens and Wettwer, 2011). We confirm that MK-0448 effectively blocks Kv1.5 current in mouse fibroblasts stably expressing the hKCNA5 gene
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