title: 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.
authors.affiliation: Department of Pharmacology and Toxicology, Medical Faculty Carl Gustav Carus, Dresden University of Technology Dresden, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Loose
authors.affiliation: Department of Pharmacology and Toxicology, Medical Faculty Carl Gustav Carus, Dresden University of Technology Dresden, Germany.
authors.forename: Judith
authors.initials: J
authors.lastname: Mueller
authors.affiliation: Department of Pharmacology and Toxicology, Medical Faculty Carl Gustav Carus, Dresden University of Technology Dresden, Germany.
authors.forename: Erich
authors.initials: E
authors.lastname: Wettwer
authors.affiliation: Clinic for Cardiac Surgery, Heart Center Dresden Dresden, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Knaut
authors.affiliation: Xention Ltd. Cambridge, UK.
authors.forename: John
authors.initials: J
authors.lastname: Ford
authors.affiliation: Xention Ltd. Cambridge, UK.
authors.forename: James
authors.initials: J
authors.lastname: Milnes
authors.affiliation: Department of Pharmacology and Toxicology, Medical Faculty Carl Gustav Carus, Dresden University of Technology Dresden, Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Ravens
keywords: IKur blocker; Kv1.5; MK-0448; atrial fibrillation; human right atrial action potentials