CIC   05421
CENTRO DE INVESTIGACIONES CARDIOVASCULARES "DR. HORACIO EUGENIO CINGOLANI"
Unidad Ejecutora - UE
artículos
Título:
The positive inotropic effect of endothelin-1 is mediated by mitochondrial reactive oxygen species
Autor/es:
DE GIUSTI VC, CORREA MV, VILLA-ABRILLE MC, BELTRANO C, YEVES AM, DE CINGOLANI GE, CINGOLANI HE, AIELLO EA
Revista:
LIFE SCIENCES
Editorial:
Pergamon Press
Referencias:
Año: 2008 vol. 83 p. 264 - 271
ISSN:
0024-3205
Resumen:
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 (.O2−) with chemiluminescence, and ROS production and intracellular pH (pHi) 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 abovecontrol, n=6, p<0.05). ET-1 also induced an increase in O2 − production that was inhibited by the NADPH oxidase blocker, apocynin, and by the blockers of mitochondrial ATP-sensitive K+ channels (mKATP), 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 μM; 8.8±3.5%, n=6), 5 hydroxydecanoic acid (500 μM; 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 (JH) 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 μM; 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.