Abstract
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) and atrial fibrillation (AF) parameters in isolated rat atria during β-adrenergic [isoprenaline (ISO)] and muscarinic M2 [carbachol (CCh)] activation. Furthermore, antiarrhythmic efficacy of ICA was benchmarked toward the class-IC antiarrhythmic drug flecainide (Fleca). ISO increased the spontaneous beating frequency but did not affect other AP parameters. As expected, CCh hyperpolarized resting membrane potential (-6.2 ± 0.9 mV), shortened APD90 (24.2 ± 1.6 vs. 17.7 ± 1.1 ms), and effective refractory period (ERP; 20.0 ± 1.3 vs. 15.8 ± 1.3 ms). The duration of burst pacing triggered AF was unchanged in the presence of CCh compared to control atria (12.8 ± 5.3 vs. 11.2 ± 3.6 s), while β-adrenergic activation resulted in shorter AF durations (3.3 ± 1.7 s) and lower AF-frequency compared to CCh. Treatment with ICA (10 μM) in ISO -stimulated atria prolonged APD90 and ERP, while the AF burden was reduced (7.1 ± 5.5 vs. 0.1 ± 0.1 s). In CCh-stimulated atria, ICA treatment also resulted in APD90 and ERP prolongation and shorter AF durations. Fleca treatment in CCh-stimulated atria prolonged APD90 and ERP and abbreviated the AF duration to a similar extent as with ICA. Muscarinic activated atria constitutes a more arrhythmogenic substrate than β-adrenoceptor activated atria. Pharmacological inhibition of SK channels by ICA is effective under both conditions and equally efficacious to Fleca.
Highlights
Atrial fibrillation is the most prevalent cardiac arrhythmia, associated with increased cardiac morbidity and mortality (Andrade et al, 2014; Jalife and Kaur, 2015; Walfridsson et al, 2015)
A high-resistance electrode is impaled into a single cardiomyocyte in a multicellular tissue, making it possible to measure transmembrane action potential (AP) in beating isolated rat atria
The atria were stimulated at 5 Hz pacing in all experiments apart from the ISO-treated group which were stimulated at 8 Hz to overrule the increase in intrinsic beating frequency
Summary
Atrial fibrillation is the most prevalent cardiac arrhythmia, associated with increased cardiac morbidity and mortality (Andrade et al, 2014; Jalife and Kaur, 2015; Walfridsson et al, 2015). Autonomic receptors have been described as an efficacious clinical target for interventional anti-AF therapy (Linz et al, 2014). Autonomic nerves exert stimulatory or inhibitory effects via adrenergic endogenous neurotransmitter norepinephrine (NE) and muscarinic acetylcholine (ACh) receptors, respectively (Christ et al, 2014). Sympathetic nerves exert their effect through various α- and especially β-adrenergic receptor (β-AR) subtypes. Β1 receptors, activating through cAMP and phosphorylation by protein kinase A (PKA), have a profound effect on both calcium handling and electrophysiology of atrial and ventricular cardiomyocytes (Brodde et al, 2001; Volders, 2010). Activation of IK,ACh results in RMP hyperpolarization, abbreviated atrial APD, and effective refractory period (Shimizu et al, 1994; Wang et al, 2013)
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