Preclinical research
Peroxynitrite decomposition catalysts prevent myocardial dysfunction and inflammation in endotoxemic rats

https://doi.org/10.1016/j.jacc.2004.01.047Get rights and content
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Abstract

Objectives

The aim of this study was to test whether peroxynitrite neutralizers would reduce peroxynitrite accumulation and improve myocardial contractile dysfunction and inflammation in endotoxin-treated rats.

Background

Release of endogenous proinflammatory cytokines such as tumor necrosis factor (TNF)-alpha in response to endotoxin is responsible for the production of large amounts of nitric oxide (NO), which may exert detrimental effects on the myocardium in animal models, isolated hearts, and isolated cardiac myocytes. Recent studies have indicated that many of the deleterious effects of NO are mediated by peroxynitrite, a powerful oxidant generated from a fast diffusion-limited reaction of NO and superoxide anion.

Methods

We studied the effects of peroxynitrite neutralizers, such as mercaptoethylguanidine (MEG) sodium succinate (10 mg/kg) and 5,10,15,20-tetrakis(4-sulfonatophenyl)-porphyrinato iron (III) (FeTPPS) (30 mg/kg) on peroxynitrite accumulation, in vivo endothelial cell-leukocyte activation on the mesenteric venule, and myocardial contractile dysfunction and inflammation in a model of sepsis induced by injection of endotoxin (10 mg/kg) in rats.

Results

Mercaptoethylguanidine sodium succinate and FeTPPS largely prevented the accumulation of peroxynitrite as measured by plasma rhodamine fluorescence and heart nitrotyrosine staining. Interestingly, MEG sodium succinate and FeTPPS improved endotoxin-induced myocardial contractile dysfunction, which was associated with reduced degradation of nuclear factor kappa B inhibitory protein I-kappa-B, plasma TNF-alpha levels, and microvascular endothelial cell-leukocyte activation.

Conclusions

These observations suggest that the beneficial effects of MEG and FeTPPS on endotoxin-induced myocardial contractile dysfunction could be related to the unique effects of these compounds on cardiovascular inflammation processes.

Abbreviations

FeTPPS
5,10,15,20-tetrakis(4-sulfonatophenyl)-porphyrinato iron (III)
IL
interleukin
iNOS
inducible nitric oxide synthase
L-NAME
N-nitro-L-arginine methyl ester
MEG
mercaptoethylguanidine
NF
nuclear factor
NO
nitric oxide
TNF
tumor necrosis factor

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Supported by 1) ET1-306 from Fondation de l'Avenir pour la recherche médicale appliquée (2001); 2) EA 2689; Université Lille 2; and 3) ENDOTIS Pharma (Parc Eurasanté, 59260 Loos, France).