The positive inotropic effect of endothelin-1 is mediated by mitochondrial reactive oxygen species
The positive inotropic effect of endothelin-1 is mediated by mitochondrial reactive oxygen species
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DOI：
10.1016/j.lfs.2008.06.008
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发表时间：
2008-08-15
期刊：
影响因子：
6.1
通讯作者：
Aiello, E. A.
中科院分区：
文献类型：
--
作者：
De Giusti, V. C.;Correa, M. V.;Aiello, E. A.
我们先前已经证明了活性氧（ROS）参与生理浓度的血管紧张素II（Ang II，1 nM）的正性肌力作用。本工作的目的是评估的作用和来源的活性氧产生的正性肌力作用所产生的等效浓度的内皮素-1（ET-1，0.4 nM）。用摄像机测定肌节缩短率，用化学发光法测定超氧阴离子（O-center dot（2）-），用落射荧光法测定RIDS产生量和细胞内pH（pH（i））。ET-1诱导的正性肌力作用（40.4 ± 3.1%，n = 10，p < 0.05）与ROS产生的增加有关（高于对照组105 ± 29荧光单位，n = 6，p < 0.05）。ET-1还诱导0-2产生的增加，其被NADPH氧化酶阻断剂夹竹桃苷和线粒体ATP敏感性K+通道（mK（ATP））阻断剂格列本脲和5羟基癸酸抑制。夹竹桃素可抑制ET-1的正性肌力作用（0.3 mM：6.3 +/-6.6%，n = 13），格列本脲（50 μ M; 8.8 +/-3.5%，n = 6）、5羟基癸酸（500 μ M：14.1 +/- 8.1，n = 9）和通过用MPG（2 mM：0.92 +/-5.6%，n = 8）清除ROS。ET-1可增强酸负荷后Na+/H+交换器（NHE）的质子外排（J（H）），MPG可阻断ET-1的这种作用。因此，ET诱导的正性肌力作用也受到NHE选择性阻断剂HOE 642（5 μ M; 9.37 +/-6.07%，n = 7）的抑制。数据显示，诱导收缩性增加约40%的ET-1浓度的作用完全由线粒体ROS形成和NHE刺激触发的细胞内途径介导。(C)2008年爱思唯尔公司All rights reserved.
We have previously demonstrated the participation of reactive oxygen species (ROS) in the positive inotropic effect of a physiological concentration of Angiotensin II (Ang II, 1 nM). The objective of the present work was to evaluate the role and source of ROS generation in the positive inotropic effect produced by an equipotent concentration of endothelin-1 (ET-1, 0.4 nM). Isolated cat ventricular myocytes were used to measure sarcomere shortening with a video-camera, superoxide anion (O-center dot(2)-) with chemiluminescence, and RIDS production and intracellular pH (pH(i)) with epifluorescence. The ET-1-induced positive inotropic effect (40.4 +/- 3.1%, n = 10, p < 0.05) was associated to an increase in ROS production (105 +/- 29 fluorescence units above control, n = 6, p < 0.05). ET-1 also induced an increase in 0-2 production that was inhibited by the NADPH oxiclase blocker, apocynin, and by the blockers of mitochondrial ATP-sensitive K+ channels (mK(ATP)), glibenclamide and 5 hydroxydecanoic acid. The ET-1-induced positive inotropic effect was inhibited by apocynin (0.3 mM: 6.3 +/- 6.6%, n = 13), glibenclamide (50 mu M; 8.8 +/- 3.5%, n = 6), 5 hydroxydecanoic acid (500 mu m: 14.1 +/- 8.1, n = 9), and by scavenging ROS with MPG(2 mM: 0.92 +/- 5.6%, n = 8). ET-1 enhanced proton efflux (J(H)) carried by the Na+/H+ exchanger (NHE) after an acid load, effect that was blocked by MPG. Consistently, the ET-induced positive inotropic effect was also inhibited by the NHE selective blocker HOE642 (5 mu M; 9.37 +/- 6.07%, n = 7). The data show that the effect of a concentration of ET-1 that induces an increase in contractility of about 40% is totally mediated by an intracellular pathway triggered by mitochondrial ROS formation and stimulation of the NHE. (C) 2008 Elsevier Inc. All rights reserved.