Wongcharoen Wanwarang, Chen Yao-Chang, Chen Yi-Jen, Chang Che-Ming, Yeh Hung-I, Lin Cheng-I, Chen Shih-Ann
National Yang-Ming University, School of Medicine, Division of Cardiology, Veterans General Hospital-Taipei, Taiwan.
Cardiovasc Res. 2006 Jun 1;70(3):497-508. doi: 10.1016/j.cardiores.2006.02.026. Epub 2006 Mar 3.
Pulmonary veins (PVs) are the most important focus for generation of atrial fibrillation. The Na(+)/Ca(2+) exchange (NCX) current is important in PV electrical activity and cardiac glycosides-induced arrhythmias. The purpose of this study was to investigate whether KB-R7943, a NCX current blocker with preferential inhibition of the Ca(2+) influx, may alter PV electrophysiological characteristics and reduce glycoside-induced arrhythmogenicity.
Conventional microelectrodes were used to record the effects of KB-R7943 on action potentials and contractility in isolated rabbit PV tissue specimens with and without administration of ouabain. The ionic currents and intracellular calcium were studied in isolated single cardiomyocytes before and after KB-R7943 by the whole-cell patch clamp and indo-1 fluorimetric ratio techniques.
KB-R7943 (0, 3, 10, 30 microM) concentration-dependently prolonged APD(50) and APD(90) and decreased the PV firing rates (2.3 +/- 1.2 Hz, 2.1 +/- 1.2 Hz, 1.9 +/- 0.9 Hz, 1.7 +/- 1.1 Hz, n = 7, p < 0.05) and incidences of delayed afterdepolarizations (DADs). KB-R7943 (3, 30 microM) decreased transient inward currents, Ca(2+) transient and sarcoplasmic reticulum Ca(2+) content. Ouabain (0, 0.1, 1 microM) concentration-dependently increased the PV firing rates and DADs in PVs with spontaneous activity (n = 7) and induced nonsustained spontaneous activity (1 microM) in the PVs without spontaneous activity (n = 14). However, in the presence of KB-R7943 (30 microM), ouabain (1 microM) did not increase the PV firing rates or induce spontaneous activity in the PVs without spontaneous activity (n = 7).
KB-R7943 reduces the PV arrhythmogenic activity and prevents the ouabain-induced arrhythmogenicity. Our findings support the role of the NCX current in the PV electrical activity.
肺静脉（PVs）是房颤发生的最重要病灶。钠钙交换（NCX）电流在肺静脉电活动及强心苷诱发的心律失常中起重要作用。本研究旨在探讨KB-R7943，一种优先抑制钙离子内流的NCX电流阻滞剂，是否会改变肺静脉电生理特性并降低强心苷诱发的致心律失常性。
使用传统微电极记录KB-R7943对给予和未给予哇巴因的离体兔肺静脉组织标本动作电位和收缩性的影响。采用全细胞膜片钳和indo-1荧光比率技术研究KB-R7943处理前后离体单个心肌细胞的离子电流和细胞内钙。
KB-R7943（0、3、10、30微摩尔）浓度依赖性地延长动作电位时程（APD）50和APD90，并降低肺静脉发放频率（2.3±1.2次/秒、2.1±1.2次/秒、1.9±0.9次/秒、1.7±1.1次/秒，n = 7，p < 0.05）以及延迟后去极化（DADs）的发生率。KB-R7943（3、30微摩尔）降低瞬时内向电流、钙瞬变和肌浆网钙含量。哇巴因（0、0.1、1微摩尔）浓度依赖性地增加有自发活动的肺静脉发放频率和DADs（n = 7），并在无自发活动的肺静脉中诱发非持续性自发活动（1微摩尔，n = 14）。然而，在存在KB-R7943（30微摩尔）时，哇巴因（1微摩尔）未增加无自发活动的肺静脉发放频率或诱发自发活动（n = 7）。
KB-R7943降低肺静脉致心律失常活性并预防哇巴因诱发的致心律失常性。我们的数据支持NCX电流在肺静脉电活动中的作用。
