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

Autor: Thomas Jespersen, Morten Grunnet, Majid Sheykhzade, Jeppe Egedal Kirchhoff, Lea Abildgaard, Jonas Goldin Diness
Jazyk: angličtina
Rok vydání: 2016
Předmět:
0301 basic medicine
medicine.medical_specialty
Combination therapy
Physiology
Pyridines
Small-Conductance Calcium-Activated Potassium Channels
Dofetilide
Clinical Biochemistry
Guinea Pigs
Amiodarone
QT prolongation
030204 cardiovascular system & hematology
Pharmacology
QT interval
SK channel
03 medical and health sciences
0302 clinical medicine
Heart Rate
Physiology (medical)
Internal medicine
Atrial Fibrillation
Phenethylamines
medicine
Potassium Channel Blockers
Animals
Adverse effect
Sulfonamides
business.industry
Atrial fibrillation
Drug Synergism
Heart
Isolated Heart Preparation
medicine.disease
Antiarrhythmic drugs
Thiazoles
030104 developmental biology
Cardiology
cardiovascular system
Antiarrhythmic effect
hERG1 and calcium-activated potassium channels
business
Anti-Arrhythmia Agents
Ion Channels
Receptors and Transporters
medicine.drug
Zdroj: Pflugers Archiv
Kirchhoff, J E, Diness, J G, Abildgaard, L, Sheykhzade, M, Grunnet, M & Jespersen, T 2016, ' Antiarrhythmic effect of the Ca(2+)-activated K(+) (SK) channel inhibitor ICA combined with either amiodarone or dofetilide in an isolated heart model of atrial fibrillation ', Pfluegers Archiv, vol. 468, no. 11, pp. 1853–1863 . https://doi.org/10.1007/s00424-016-1883-9
ISSN: 1432-2013
0031-6768
Popis: 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 Ca(2+)-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.
Databáze: OpenAIRE
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