Inhibition of Small Conductance Calcium-Activated Potassium (SK) Channels Prevents Arrhythmias in Rat Atria During β-Adrenergic and Muscarinic Receptor Activation

• DOI: 10.3389/fphys.2018.00510
• Publication Date: 2018-06-05T00:18:51Z
• Authors: Lasse Skibsbye; Anne K. Bengaard; A. M. Uldum-Nielsen; Kim Boddum; Torsten Christ; Thomas Jespersen
• Keywords: Effective refractory period; Isoprenaline; Flecainide; SK channel

Sympathetic and vagal activation is linked to atrial arrhythmogenesis. Here we investigated the small conductance Ca2+-activated K+ (SK)-channel pore-blocker N-(pyridin-2-yl)-4-(pyridine-2-yl)thiazol-2-amine (ICA) on action potential (AP) fibrillation (AF) parameters in isolated rat atria during β-adrenergic [isoprenaline (ISO)] muscarinic M2 [carbachol (CCh)] activation. Furthermore, antiarrhythmic efficacy of ICA was benchmarked toward class-IC drug flecainide (Fleca). ISO increased spontaneous beating frequency but did not affect other AP parameters. As expected, CCh hyperpolarized resting membrane (-6.2 ± 0.9 mV), shortened APD90 (24.2 1.6 vs. 17.7 1.1 ms), effective refractory period (ERP; 20.0 1.3 15.8 ms). The duration burst pacing triggered AF unchanged presence compared control (12.8 5.3 11.2 3.6 s), while resulted shorter durations (3.3 1.7 s) lower AF-frequency CCh. Treatment with (10 μM) -stimulated prolonged ERP, burden reduced (7.1 5.5 0.1 s). In CCh-stimulated atria, treatment also ERP prolongation durations. Fleca abbreviated a similar extent as ICA. Muscarinic activated constitutes more arrhythmogenic substrate than β-adrenoceptor atria. Pharmacological inhibition SK channels by under both conditions equally efficacious Fleca.