期刊
LIFE SCIENCES
卷 83, 期 7-8, 页码 264-271出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.lfs.2008.06.008
关键词
endothelin-1; inotropic effect; reactive oxygen species; sodium-hydrogen exchanger; cardiac myocytes
资金
- Agencia Nacional de Promocion Cientifica y Tecnologica de Argentina [PICT 05-08512, PICT 05-12480, PICT 25495]
- Aventis Pharma (Germany) [HOE642]
- Fellows of Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET), Argentina
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.
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