Skibsbye Lasse, Bengaard Anne K, Uldum-Nielsen A M, Boddum Kim, Christ Torsten, Jespersen Thomas
Cardiac Physiology Laboratory, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, DZHK: German Centre for Cardiovascular Research, Hamburg, Germany.
Front Physiol. 2018 Jun 5;9:510. doi: 10.3389/fphys.2018.00510. eCollection 2018.
Sympathetic and vagal activation is linked to atrial arrhythmogenesis. Here we investigated the small conductance Ca-activated K (SK)-channel pore-blocker -(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 APD (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 APD 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 APD and ERP prolongation and shorter AF durations. Fleca treatment in CCh-stimulated atria prolonged APD 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.
交感神经和迷走神经激活与心房心律失常的发生有关。在此，我们研究了小电导钙激活钾（SK）通道孔阻滞剂 -（吡啶-2-基）-4-（吡啶-2-基）噻唑-2-胺（ICA）对离体大鼠心房在β-肾上腺素能[异丙肾上腺素（ISO）]和毒蕈碱M2[卡巴胆碱（CCh）]激活期间的动作电位（AP）和心房颤动（AF）参数的影响。此外，将ICA的抗心律失常疗效与IC类抗心律失常药物氟卡尼（Fleca）进行了对比。ISO增加了自发搏动频率，但不影响其他AP参数。正如预期的那样，CCh使静息膜电位超极化（-6.2±0.9 mV），缩短了动作电位时程（APD；24.2±1.6对17.7±1.1 ms）和有效不应期（ERP；20.0±1.3对15.8±1.3 ms）。与对照心房相比，在存在CCh的情况下，猝发起搏触发AF的持续时间未改变（12.8±5.3对11.2±3.6 s），而β-肾上腺素能激活导致AF持续时间缩短（3.3±1.7 s）且AF频率低于CCh。在ISO刺激的心房中用ICA（10 μM）处理可延长APD和ERP，同时AF负荷降低（7.1±5.5对0.1±0.1 s）。在CCh刺激的心房中，ICA处理也导致APD和ERP延长以及AF持续时间缩短。在CCh刺激的心房中，Fleca处理延长了APD和ERP，并将AF持续时间缩短至与ICA相似的程度。毒蕈碱激活的心房比β-肾上腺素能受体激活的心房构成更易致心律失常的底物。ICA对SK通道的药理抑制在两种情况下均有效，且与Fleca同样有效。
