Danish National Research Foundation Centre for Cardiac Arrhythmia, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
Department of Pharmacology and Toxicology, Medical Faculty, Technical University Dresden, Dresden, Germany.
Cardiovasc Res. 2014 Jul 1;103(1):156-67. doi: 10.1093/cvr/cvu121. Epub 2014 May 9.
Small-conductance calcium-activated potassium (SK) channels are expressed in the heart of various species, including humans. The aim of the present study was to address whether SK channels play a functional role in human atria.
Quantitative real-time PCR analyses showed higher transcript levels of SK2 and SK3 than that of the SK1 subtype in human atrial tissue. SK2 and SK3 were reduced in chronic atrial fibrillation (AF) compared with sinus rhythm (SR) patients. Immunohistochemistry using confocal microscopy revealed widespread expression of SK2 in atrial myocytes. Two SK channel inhibitors (NS8593 and ICAGEN) were tested in heterologous expression systems revealing ICAGEN as being highly selective for SK channels, while NS8593 showed less selectivity for these channels. In isolated atrial myocytes from SR patients, both inhibitors decreased inwardly rectifying K(+) currents by ∼15% and prolonged action potential duration (APD), but no effect was observed in myocytes from AF patients. In trabeculae muscle strips from right atrial appendages of SR patients, both compounds increased APD and effective refractory period, and depolarized the resting membrane potential, while only NS8593 induced these effects in tissue from AF patients. SK channel inhibition did not alter any electrophysiological parameter in human interventricular septum tissue.
SK channels are present in human atria where they participate in repolarization. SK2 and SK3 were down-regulated and had reduced functional importance in chronic AF. As SK current was not found to contribute substantially to the ventricular AP, pharmacological inhibition of SK channels may be a putative atrial-selective target for future antiarrhythmic drug therapy.
小电导钙激活钾 (SK) 通道存在于多种物种的心脏中，包括人类。本研究旨在探讨 SK 通道是否在人类心房中发挥功能作用。
实时定量 PCR 分析显示，人类心房组织中 SK2 和 SK3 的转录水平高于 SK1 亚型。与窦性心律 (SR) 患者相比，慢性心房颤动 (AF) 患者的 SK2 和 SK3 减少。使用共聚焦显微镜的免疫组织化学显示 SK2 在心房肌细胞中广泛表达。在异源表达系统中测试了两种 SK 通道抑制剂 (NS8593 和 ICAGEN)，结果表明 ICAGEN 对 SK 通道具有高度选择性，而 NS8593 对这些通道的选择性较低。在来自 SR 患者的分离的心房肌细胞中，两种抑制剂均使内向整流钾 (K+) 电流减少约 15%，并延长动作电位时程 (APD)，但在来自 AF 患者的肌细胞中未观察到这种作用。在来自 SR 患者右心耳的小梁肌条中，两种化合物均增加 APD 和有效不应期，并使静息膜电位去极化，而仅 NS8593 诱导 AF 患者组织中产生这些作用。SK 通道抑制未改变人类室间隔组织中的任何电生理参数。
SK 通道存在于人类心房中，在其中参与复极。SK2 和 SK3 在慢性 AF 中下调，其功能重要性降低。由于 SK 电流对心室 AP 没有显著贡献，因此 SK 通道的药理学抑制可能成为未来抗心律失常药物治疗的潜在心房选择性靶点。
