title: Antiarrhythmic effect of the Ca2+-activated K+(SK) channel inhibitor ICA combined with either amiodarone or dofetilide in an isolated heart model of atrial fibrillation.
abstract: Dose is an important parameter in terms of both efficacy and adverse effects in pharmacological treatment of atrial fibrillation (AF). Both of the class III antiarrhythmics dofetilide and amiodarone have documented anti-AF effects. While dofetilide has dose-related ventricular side effects, amiodarone primarily has adverse non-cardiac effects. Pharmacological inhibition of small conductance Ca2+-activated K+(SK) channels has recently been reported to be antiarrhythmic in a number of animal AF models. In a Langendorff model of acutely induced AF on guinea pig hearts, it was investigated whether a combination of the SK channel blocker N-(pyridin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine (ICA) together with either dofetilide or amiodarone provided a synergistic effect. The duration of AF was reduced with otherwise subefficacious concentrations of either dofetilide or amiodarone when combined with ICA, also at a subefficacious concentration. At a concentration level effective as monotherapy, dofetilide produced a marked increase in the QT interval. This QT prolonging effect was absent when combined with ICA at non-efficacious monotherapy concentrations. The results thereby reveal that combination of subefficacious concentrations of an SK channel blocker and either dofetilide or amiodarone can maintain anti-AF properties, while the risk of ventricular arrhythmias is reduced.
authors.affiliation: The Danish National Research Foundation Centre for Cardiac Arrhythmia, Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3A, 2200, Copenhagen N, Denmark.|Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jeppe Egedal
authors.initials: JE
authors.lastname: Kirchhoff
authors.affiliation: The Danish National Research Foundation Centre for Cardiac Arrhythmia, Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3A, 2200, Copenhagen N, Denmark.|Acesion Pharma, Copenhagen, Denmark.
authors.forename: Jonas Goldin
authors.initials: JG
authors.lastname: Diness
authors.affiliation: Acesion Pharma, Copenhagen, Denmark.
authors.forename: Lea
authors.initials: L
authors.lastname: Abildgaard
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Majid
authors.initials: M
authors.lastname: Sheykhzade
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.|Acesion Pharma, Copenhagen, Denmark.|Lundbeck A/S, Copenhagen, Denmark.
authors.forename: Morten
authors.initials: M
authors.lastname: Grunnet
authors.affiliation: The Danish National Research Foundation Centre for Cardiac Arrhythmia, Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3A, 2200, Copenhagen N, Denmark. thojes@sund.ku.dk.
authors.forename: Thomas
authors.initials: T
authors.lastname: Jespersen
mesh_terms: D000638:Amiodarone / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001281:Atrial Fibrillation / Q000188:drug therapy*; D004357:Drug Synergism; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate; D000067268:Isolated Heart Preparation; D010627:Phenethylamines / Q000494:pharmacology* / Q000627:therapeutic use; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D013844:Thiazoles / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000889:Anti-Arrhythmia Agents; C000597600:N-(pyridin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine; D010627:Phenethylamines; D026902:Potassium Channel Blockers; D011725:Pyridines; D051640:Small-Conductance Calcium-Activated Potassium Channels; D013449:Sulfonamides; D013844:Thiazoles; D000638:Amiodarone; C063533:dofetilide
keywords: Amiodarone; Antiarrhythmic drugs; Combination therapy; Dofetilide; QT prolongation; hERG1 and calcium-activated potassium channels