Blocking late sodium current reduces hydrogen peroxide-induced arrhythmogenic activity and contractile dysfunction
Blocking late sodium current reduces hydrogen peroxide-induced arrhythmogenic activity and contractile dysfunction
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DOI：
10.1124/jpet.106.101832
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发表时间：
2006-07-01
影响因子：
3.5
通讯作者：
Belardinelli, Luiz
中科院分区：
文献类型：
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作者：
Song, Yejia;Shryock, John C.;Belardinelli, Luiz
活性氧（Reactive oxygen species，ROS），包括过氧化氢（H_2O_2），可引起细胞内钙超载和缺血再灌注损伤。本研究的目的是检查的假设，H2 O2诱导的血管活性和收缩功能障碍的结果，H2 O2的影响，以增加晚钠电流（晚I-Na）的幅度。豚鼠和兔分离的心室肌细胞暴露于200 μ M H2 O2。采用全细胞膜片钳技术和视频边缘检测技术分别测量跨膜电压和电流以及收缩缩短。[Na[Ca ~（2+）]（i）和[Ca ~（2+）]（i）通过荧光测量测定。H_2O_2引起的持续性晚INa几乎完全抑制10 μ M河豚毒素（TTX）。H_2O_2使动作电位时程（APD）延长，细胞收缩的舒张速率减慢，诱发早期后除极（埃兹）和后收缩。H_2O_2也使[Na ~+]（i）和[Ca ~（2+）]（i）增加。雷诺嗪（10 μ M），一种新的抑制剂晚1钠，衰减H2 O2诱导晚I-Na 51 +/-9%。TTX（2 μ M）或10 μ M雷诺嗪衰减H2 O2诱导的APD延长和抑制埃兹。雷诺嗪可加快H2 O2诱导的收缩后收缩的舒张速率，并可消除H2 O2诱导的收缩后收缩。用雷诺嗪预处理心肌细胞延迟并减少H2 O2引起的APD、[Na+]（i）和[Ca 2 +]（i）的增加。总之，结果证实了这一假设，即在晚I-Na的增加，心室肌细胞暴露于H2 O2有助于电和收缩功能障碍，并建议，抑制晚I-Na可能提供保护，防止ROS诱导的Na+和Ca 2+超载。
Reactive oxygen species (ROS), including H2O2, cause intracellular calcium overload and ischemia-reperfusion damage. The objective of this study was to examine the hypothesis that H2O2-induced arrhythmic activity and contractile dysfunction are the results of an effect of H2O2 to increase the magnitude of the late sodium current (late I-Na). Guinea pig and rabbit isolated ventricular myocytes were exposed to 200 mu M H2O2. Transmembrane voltages and currents and twitch shortening were measured using the whole-cell patch-clamp technique and video edge detection, respectively. [Na+](i) and [Ca2+](i) were determined by fluorescence measurements. H2O2 caused a persistent late INa that was almost completely inhibited by 10 mu M tetrodotoxin (TTX). H2O2 prolonged the action potential duration (APD), slowed the relaxation rate of cell contraction, and induced early afterdepolarizations (EADs) and after contractions. H2O2 also caused increases of [Na+](i) and [Ca2+](i). Ranolazine (10 mu M), a novel inhibitor of late 1 Na, attenuated H2O2 induced late I-Na by 51 +/- 9%. TTX ( 2 mu M) or 10 mu M ranolazine attenuated H2O2-induced APD prolongation and suppressed EADs. Ranolazine accelerated the twitch relaxation rate in the presence of H2O2 and abolished H2O2-induced aftercontractions. Pretreatment of myocytes with ranolazine delayed and reduced the increases of APD, [Na+](i), and [Ca2+](i) caused by H2O2. In conclusion, the results confirm the hypothesis that an increase in late I-Na during exposure of ventricular myocytes to H2O2 contributes to electrical and contractile dysfunction and suggest that inhibition of late I-Na may offer protection against ROS-induced Na+ and Ca2+ overload.