Peroxynitrite decomposition catalysts prevent myocardial dysfunction and inflammation in endotoxemic rats.
OBJECTIVE
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.
Lancel
Steve
S
EA 2689, Université de Lille 2, Faculté de Médecine, Lille, France.
Tissier
Stéphanie
S
Mordon
Serge
S
Marechal
Xavier
X
Depontieu
Florence
F
Scherpereel
Arnaud
A
Chopin
Claude
C
Neviere
Remi
R
D000818:Animals; D015415:Biomarkers / Q000097:blood; D002384:Catalysis; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D019446:Endotoxemia / Q000150:complications* / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005456:Fluorescent Dyes; D006146:Guanidines / Q000494:pharmacology; D020672:I-kappa B Proteins / Q000187:drug effects / Q000378:metabolism; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D008665:Metalloporphyrins / Q000378:metabolism / Q000494:pharmacology; D008955:Models, Cardiovascular; D009205:Myocarditis / Q000378:metabolism / Q000503:physiopathology* / Q000517:prevention & control*; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000187:drug effects / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D030421:Peroxynitrous Acid / Q000378:metabolism* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000187:drug effects / Q000378:metabolism; D014966:Xanthenes
C466420:5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrinato iron(III) chloride; C473808:9-(o-carboxyphenyl)-2-chloro-6-(bis(2-pyridylmethyl)amino)-3-xanthanone; D015415:Biomarkers; D004791:Enzyme Inhibitors; D005456:Fluorescent Dyes; D006146:Guanidines; D020672:I-kappa B Proteins; D008665:Metalloporphyrins; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D014966:Xanthenes; D030421:Peroxynitrous Acid; C002744:3-nitrotyrosine; D014443:Tyrosine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; C100078:2-mercaptoethylguanidine; D019331:NG-Nitroarginine Methyl Ester