AUTHOR=Loose Simone , Mueller Judith , Wettwer Erich , Knaut Michael , Ford John , Milnes James , Ravens Ursula 

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

JOURNAL=Frontiers in Pharmacology

VOLUME=5

YEAR=2014

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2014.00026

DOI=10.3389/fphar.2014.00026

ISSN=1663-9812

ABSTRACT=<p>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 (<italic>N</italic>-{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 (&gt;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 (APD<sub>90</sub>) and effective refractory period (ERP), but in permanent AF preparations, MK-0448 <italic>prolonged</italic> APD<sub>90</sub> and ERP. The effects of MK-0448 in intermittent AF resembled those in SR preparations. Block of I<sub>Ks</sub> is probably more prominent in AF because of reduced repolarization reserve due to AF-induced remodeling.</p>