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Peroxynitrite decomposition catalysts prevent myocardial dysfunction and inflammation in endotoxemic rats

Steve Lancel, PhD^*, Stéphanie Tissier, MD^*, Serge Mordon, PhD^*, Xavier Marechal, PhD^*, Florence Depontieu, PhD, Arnaud Scherpereel, MD, PhD, Claude Chopin, MD^* and Remi Neviere, MD, PhD^*,*

^* EA 2689, Université de Lille 2, Faculté de Médecine, Lille, France
Département de Physiologie, Faculté de Médecine, Lille, France
INSERM U416, Institut Pasteur de Lille, Lille, France

Manuscript received September 22, 2003; revised manuscript received January 8, 2004, accepted January 12, 2004.

^* Reprint requests and correspondence: Dr. Remi Neviere, Département de Physiologie, Faculté de Médecine, 1, place de Verdun, Lille Cedex 59045, France.
rneviere{at}univ-lille2.fr

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 and Acronyms   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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