title: Effects of K201 on repolarization and arrhythmogenesis in anesthetized chronic atrioventricular block dogs susceptible to dofetilide-induced torsade de pointes.
abstract: The novel antiarrhythmic drug K201 (4-[3-{1-(4-benzyl)piperidinyl}propionyl]-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine monohydrochloride) is currently in development for treatment of atrial fibrillation. K201 not only controls intracellular calcium release by the ryanodine receptors, but also possesses a ventricular action that might predispose to torsade de pointes arrhythmias. The anti- and proarrhythmic effects of K201 were investigated in the anesthetized canine chronic atrioventricular block model. Two doses of K201 (0.1 and 0.3mg/kg/2 min followed by 0.01 and 0.03 mg/kg/30 min i.v.) were tested in 4 serial experiments in dogs with normally conducted sinus rhythm (n=10) and in torsade de pointes-susceptible dogs with chronic atrioventricular block. Susceptibility was assessed with dofetilide (0.025 mg/kg/5 min i.v.). Beat-to-beat variability of repolarization was quantified as short-term variability of left ventricular monophasic action potential duration. In dogs with normally conducted sinus rhythm, both doses of K201 prolonged ventricular repolarization whereas only the higher dose prolonged atrial repolarization. At chronic atrioventricular block, dofetilide induced torsade de pointes in 9 of 10 dogs. K201 did neither suppress nor prevent dofetilide-induced torsade de pointes. K201 dose-dependently prolonged ventricular repolarization. In contrary to the lower dose, the higher dose did increase beat-to-beat variability of repolarization (from 1.2 ± 0.3 to 2.9 ± 0.8 ms, P<0.05) and resulted in spontaneous, repetitive torsade de pointes arrhythmias in 1 of 7 dogs; Programmed electrical stimulation resulted in torsade de pointes in 2 more dogs. In conclusion, both doses of K201 showed a class III effect. No relevant antiarrhythmic effects against dofetilide-induced torsade de pointes were seen. Only at the higher dose a proarrhythmic signal was observed.
authors: Department of Medical Physiology, Division Heart and Lungs, University Medical Center Utrecht, Yalelaan 50, 3584 CM Utrecht, The Netherlands. t.r.g.stams@umcutrecht.nl
authors: Thom R G
authors: TR
authors: Stams
authors: Avram
authors: A
authors: Oros
authors: Roel van
authors: Rv
authors: der Nagel
authors: Jet D M
authors: JD
authors: Beekman
authors: Paul
authors: P
authors: Chamberlin
authors: Howard C
authors: HC
authors: Dittrich
authors: Marc A
authors: MA
authors: Vos
mesh_terms: D000758:Anesthesia; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D054537:Atrioventricular Block / Q000473:pathology* / Q000503:physiopathology; D002908:Chronic Disease; D004198:Disease Susceptibility; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects*; D010627:Phenethylamines / Q000009:adverse effects*; D013449:Sulfonamides / Q000009:adverse effects*; D013841:Thiazepines / Q000494:pharmacology*; D013997:Time Factors; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control
chemical_list: D000889:Anti-Arrhythmia Agents; D010627:Phenethylamines; D013449:Sulfonamides; D013841:Thiazepines; C109183:K201 compound; C063533:dofetilide