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Cardiovasc Res. 2004 Apr 1;62(1):202-11.

Measurements of nitric oxide concentration and hyporeactivity in rat superior mesenteric artery exposed to endotoxin.

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  • 1Departament of Pharmacology, University of Aarhus, 8000 Aarhus C, Denmark.

Abstract

OBJECTIVE:

The present study was designed to relate nitric oxide (NO) concentration to changes in vascular reactivity in rat superior mesenteric arteries treated with lipopolysaccharide (LPS, 10 microg ml-1, 1-8 h).

METHODS:

In rat mesenteric arteries, isometric tension was recorded in wire myographs, protein expression was evaluated by Western blot and/or immunohistochemistry and NO concentration was measured by application of a NO specific electrode.

RESULTS:

Incubation with LPS (5 h) resulted in inducible NO synthase (iNOS) expression and enhanced superoxide dismutase (Cu/Zn-SOD and Mn-SOD) expression, but it did not modify endothelial NO synthase (eNOS) expression. Noradrenaline (0.5 microM) evoked increases in NO concentration and tension by, respectively, 5.0+/-2.0 nM and 4.4+/-0.1 N m-1 (n=6). While NO concentration was unaltered, incubation with LPS reduced noradrenaline contraction to 3.5+/-0.2 N m-1 (n=39, P<0.05). In contrast to indomethacin, 1400 W (10 microM) restored noradrenaline contraction, while the combination of noradrenaline and oxyhaemoglobin (10 microM) evoked less contraction in LPS compared to control segments. Polyethylene glycol (PEG)-catalase in combination with oxyhaemoglobin reversed noradrenaline hyporeactivity in LPS-treated segments. LPS did not increase, but reduced basal NO concentration, an effect which was reversed by 1400 W and tempol (100 microM). In LPS-treated segments contracted with noradrenaline, the NO synthase substrate, l-arginine (100 microM), relaxed and increased NO concentration with, respectively, 73+/-9% and 19.5+/-6.5 nM (n=5). 1400 W and oxyhaemoglobin reversed l-arginine relaxation and increases in NO concentration. In contrast to tempol and PEG-catalase, N-acetylcysteine (0.1-1 mM), which is able to release NO from intracellular stores, relaxed LPS-treated tissue, an effect that was abolished by long-term, but not by short-term, incubation with 1400 W.

CONCLUSIONS:

The present study provides direct evidence that exposure to LPS results in induction of iNOS and SOD associated with noradrenaline hyporeactivity, while increased NO is only measured when l-arginine is present. A catalase-sensitive mechanism and release of NO from N-acetylcysteine-sensitive stores could also contribute to the vascular hyporeactivity.

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