Lakenau Institute for Medical Research, Wynnewood, PA.
Sideny Kimmel College of Medicine, Thomas Jefferson University, Philadelphia, PA.
J Cardiovasc Pharmacol. 2020 Aug;76(2):164-172. doi: 10.1097/FJC.0000000000000855.
The mechanisms underlying atrial-selective prolongation of effective refractory period (ERP) and suppression of atrial fibrillation (AF) by NS8593 and UCL1684, small conductance calcium-activated potassium (SK) channel blockers, are poorly defined. The purpose of the study was to confirm the effectiveness of these agents to suppress AF and to probe the underlying mechanisms. Transmembrane action potentials and pseudoelectrocardiograms were recorded from canine isolated coronary-perfused canine atrial and ventricular wedge preparations. Patch clamp techniques were used to record sodium channel current (INa) in atrial and ventricular myocytes and human embryonic kidney cells. In both atria and ventricles, NS8593 (3-10 µM) and UCL1684 (0.5 µM) did not significantly alter action potential duration, suggesting little to no SK channel inhibition. Both agents caused atrial-selective: (1) prolongation of ERP secondary to development of postrepolarization refractoriness, (2) reduction of Vmax, and (3) increase of diastolic threshold of excitation (all are sodium-mediated parameters). NS8593 and UCL1684 significantly reduced INa density in human embryonic kidney cells as well as in atrial but not in ventricular myocytes at physiologically relevant holding potentials. NS8593 caused a shift of steady-state inactivation to negative potentials in atrial but not ventricular cells. NS8593 and UCL1684 prevented induction of acetylcholine-mediated AF in 6/6 and 8/8 preparations, respectively. This anti-AF effect was associated with strong rate-dependent depression of excitability. The SK channel blockers, NS8593 and UCL1684, are effective in preventing the development of AF due to potent atrial-selective inhibition of INa, causing atrial-selective prolongation of ERP secondary to induction of postrepolarization refractoriness.
SK 钙激活钾通道阻滞剂 NS8593 和 UCL1684 致心房 ERP 延长及房颤（AF）抑制的作用机制尚不完全清楚。本研究旨在证实这两种药物抑制 AF 的有效性，并探究其潜在的作用机制。采用膜片钳技术，从犬冠状血管灌流的心房和心室楔形标本中记录跨膜动作电位和伪心电图。采用膜片钳技术记录心房和心室肌细胞及人胚肾细胞的钠通道电流（INa）。在心房和心室中，NS8593（3-10 μM）和 UCL1684（0.5 μM）均未显著改变动作电位时程，提示 SK 通道抑制作用较小或无。这两种药物均导致：（1）复极化后不应期延长，ERP 延长，（2）Vmax 降低，（3）舒张期阈电位上移（均为钠介导参数），从而引起心房选择性改变。NS8593 和 UCL1684 显著降低了人胚肾细胞及心房而非心室肌细胞的 INa 密度，在生理相关的保持电位下。NS8593 导致心房而非心室细胞的稳态失活向负电位移动。NS8593 和 UCL1684 分别使 6/6 和 8/8 标本中乙酰胆碱诱导的 AF 发生率降低。这种抗 AF 作用与兴奋的强频率依赖性抑制有关。SK 钙激活钾通道阻滞剂 NS8593 和 UCL1684 通过对 INa 的有效心房选择性抑制，可预防 AF 的发生，导致复极化后不应期延长，从而延长心房 ERP，这是预防 AF 的有效方法。
