Haugaard Maria Mathilde, Hesselkilde Eva Zander, Pehrson Steen, Carstensen Helena, Flethøj Mette, Præstegaard Kirstine Færgemand, Sørensen Ulrik Svane, Diness Jonas Goldin, Grunnet Morten, Buhl Rikke, Jespersen Thomas
Department of Large Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Department of Large Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Heart Rhythm. 2015 Apr;12(4):825-35. doi: 10.1016/j.hrthm.2014.12.028. Epub 2014 Dec 24.
Small-conductance calcium-activated potassium (SK) channels have been found to play an important role in atrial repolarization and atrial fibrillation (AF).
The purpose of this study was to investigate the existence and functional role of SK channels in the equine heart.
Cardiac biopsies were analyzed to investigate the expression level of the most prominent cardiac ion channels, with special focus on SK channels, in the equine heart. Subcellular distribution of SK isoform 2 (SK2) was assessed by immunohistochemistry and confocal microscopy. The electrophysiologic and anti-AF effects of the relative selective SK channel inhibitor NS8593 (5 mg/kg IV) were evaluated in anesthetized horses, focusing on the potential of NS8593 to terminate acute pacing-induced AF, drug-induced changes in atrial effective refractory period, AF duration and vulnerability, and ventricular depolarization and repolarization times.
Analysis revealed equivalent mRNA transcript levels of the 3 SK channel isoforms in atria compared to ventricles. Immunohistochemistry and confocal microscopy displayed a widespread distribution of SK2 in both atrial and ventricular cardiomyocytes. NS8593 terminated all induced AF episodes (duration ≥15 minutes), caused pronounced prolongation of atrial effective refractory period, and reduced AF duration and vulnerability. QRS duration and QTc interval were not affected by treatment.
SK channels are widely distributed in atrial and ventricular cardiomyocytes and contribute to atrial repolarization. Inhibition by NS8593 terminates pacing-induced AF of short duration and decreases AF duration and vulnerability without affecting ventricular conduction and repolarization. Thus, inhibition by NS8593 demonstrates clear atrial antiarrhythmic properties in healthy horses.
小电导钙激活钾（SK）通道已被发现对心房复极和心房颤动（AF）起重要作用。
本研究旨在调查马心脏中SK通道的存在及其功能作用。
分析心脏活检组织，以研究马心脏中最主要的心脏离子通道的表达水平，特别关注SK通道。通过免疫组织化学和共聚焦显微镜评估SK亚型2（SK2）的亚细胞分布。在麻醉的马匹中评估相对选择性SK通道抑制剂NS8593（5mg/kg静脉注射）的电生理和抗AF作用，重点关注NS8593终止急性起搏诱导的AF的潜力、药物诱导的心房有效不应期、AF持续时间和易感性变化以及心室去极化和复极化时间。
分析显示，与心室相比，心房中3种SK通道亚型的mRNA转录水平相当。免疫组织化学和共聚焦显微镜显示SK2在心房和心室心肌细胞中广泛分布。NS8593终止了所有诱导的AF发作（持续时间≥15分钟），导致心房有效不应期明显延长，并缩短了AF持续时间和易感性。QRS持续时间和QTc间期不受治疗影响。
SK通道广泛分布于心房和心室心肌细胞中，并有助于心房复极。NS8593抑制可终止短时间起搏诱导的AF，并缩短AF持续时间和易感性，而不影响心室传导和复极化。因此，NS8593抑制在健康马匹中显示出明显的心房抗心律失常特性。
