The positive inotropic effect of endothelin-1 is mediated by mitochondrial reactive oxygen species

V. C. De Giusti, M. V. Correa, M. C. Villa-Abrille, C. Beltrano, A. M. Yeves, G. E.Chiappe de Cingolani, H. E. Cingolani, E. A. Aiello

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44 Scopus citations

Abstract

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 ({radical dot}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 above control, n = 6, p < 0.05). ET-1 also induced an increase in {radical dot}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.

Original languageEnglish (US)
Pages (from-to)264-271
Number of pages8
JournalLife Sciences
Volume83
Issue number7-8
DOIs
StatePublished - Aug 15 2008

Keywords

  • Cardiac myocytes
  • Endothelin-1
  • Inotropic effect
  • Reactive oxygen species
  • Sodium-hydrogen exchanger

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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