Late sodium current is a novel target for amiodarone: Studies in failing human myocardium
Late sodium current is a novel target for amiodarone: Studies in failing human myocardium
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DOI：
10.1006/jmcc.2001.1355
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发表时间：
2001-05-01
影响因子：
5
通讯作者：
Undrovinas, AI
中科院分区：
文献类型：
--
作者：
Maltsev, VA;Sabbah, HN;Undrovinas, AI
作者最近报道了一种新的晚Na+电流（I-Nal）的存在下，心室心肌细胞（VC）从正常和失败的人心脏分离。在失败的人类和犬VC中，I-Nal的部分阻断使动作电位（AP）持续时间正常化，并消除早期后除极（埃兹）。最新的计算机模拟研究表明，持续的Na+电流的一个显着的贡献，进入离子电流平衡的平台上的VC Ar以及其重要的rt，le在跨心室壁的Ar持续时间的分散。因此，这些数据表明I-Nal有可能成为新的治疗靶点。本研究验证了I-Nal可能是胺碘酮（AR;IIO）的新靶点的假设。采用全细胞钳夹技术，测定了正常人左心室中层VC的含量。在治疗浓度下，AMIO可有效地阻断I-Nal。IC 50为6.7 ± 1.1 μ M（平均值± S.E.M.，n = 16个细胞）。同时还研究与讨论AMIO（5 μ M）对瞬时Na+电流几乎没有影响（IC 50 = 87 +/- 28 μ M，n = 8）。AMIO非常重要。使I-Nal的稳态失活（SSI）卷曲向更负的电位移动，并以剂量依赖性方式加速衰减时间过程。在5 μ M时，AMIO使SSI偏移21 +/- 3 mV（n = 7），并使衰减时间常数从0.67 +/- 0.05 s降至0.37 +/- 0.04 s（n = 5，P
The authors recently reported the existence of a novel late Na+ current (I-Nal) in ventricular cardiomyocytes (VC) isolated from both normal and failing human hearts. Both in failing human and canine VC, partial block of I-Nal normalized action potential (AP) duration and abolished early after depolarizations (EADs). The most recent computer simulation studies indicate a significant contribution of the persistent Na+ current into the ion current balance on the plateau of VC Ar as well as its important rt,le in the dispersion of Ar duration across the ventricular wall. The data thus indicate a possibility for I-Nal to be a new therapeutic target. The present study tested a hypothesis that I-Nal could be a novel target fur amiodarone (AR;IIO). Midmyocardial VC isolated from left ventricle of explanted failing human hearts were measured by a whole-cell clamp. I-Nal was effectively blocked by AMIO in therapeutic concentrations. with IC50 being 6.7 +/- 1.1 muM (mean +/- S.E.M., n = 16 cells). At the same time. AMIO (5 muM) produced almost no effect on the transient Na+ current (IC50 = 87 +/- 28 muM, n = 8). AMIO significantly. shifted the steady-state inactivation (SSI) curl e of I-Nal towards more negative potentials and accelerated decay time course in a dose-dependent manner. At 5 muM AMIO shifted SSI by 21 +/- 3 mV (n = 7) and decreased the decay time constant from 0.67 +/- 0.05 s to 0.37 +/- 0.04 s (n = 5, P