A role for nitric oxide-mediated peroxynitrite formation in a model of endotoxin-induced shock.
The aim of the present study was to assess the relative contributions of peroxynitrite formation following induction of nitric-oxide synthase (iNOS) in the pathophysiology of endotoxin-induced shock in the rat. To this end, we used a selective inhibitor of iNOS, N-(3-(aminomethyl)benzyl)acetamidine (1400W), and a peroxynitrite decomposition catalyst, 5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrinato iron III chloride (FeTTPs). Intravenous (i.v.) administration of Escherichia coli lipopolysaccharide (LPS; 4 mg/kg) elicited a time-dependent fall in mean arterial pressure as well as liver, renal, and pancreatic tissue damage. 1400W (3-10 mg/kg i.v.) administered 30 min before LPS delayed the development of hypotension but did not improve survival. On the other hand, FeTTPs administered (10-100 mg/kg i.v.) inhibited in a dose-dependent manner LPS-induced hypotension, tissue injury, and improved mortality rate. In separate experiments, rats were treated with LPS (4 mg/kg) or saline for control, and their aortas were isolated and placed in organ baths 2 h later. Tissues from LPS-treated rats had significant inhibition of contractile activity to phenylephrine as well as a significantly impaired relaxation response to acetylcholine. FeTPPs, when administered (100 mg/kg i.v.) 1 h before LPS, prevented the LPS-induced aortic contractile and endothelial dysfunction. These results demonstrate that nitric oxide-derived peroxynitrite formation plays an important role in this model of endotoxemia. Our results also suggest that use of an iNOS inhibitor in this setting has little beneficial effect in part because, in the presence of a failing eNOS system, some NO is needed to maintain adequate organ function.
Cuzzocrea
Salvatore
S
Department of Clinical and Experimental Medicine and Pharmacology, University of Messina, Italy.
Mazzon
Emanuela
E
Di Paola
Rosanna
R
Esposito
Emanuela
E
Macarthur
Heather
H
Matuschak
George M
GM
Salvemini
Daniela
D
D000578:Amidines / Q000627:therapeutic use; D000818:Animals; D001596:Benzylamines / Q000627:therapeutic use; D004730:Endothelium, Vascular / Q000502:physiology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology; D009102:Multiple Organ Failure / Q000188:drug therapy; D009569:Nitric Oxide / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors; D030421:Peroxynitrous Acid / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012772:Shock, Septic / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D014661:Vasoconstriction
C466420:5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrinato iron(III) chloride; D000578:Amidines; D001596:Benzylamines; D008665:Metalloporphyrins; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D052247:Nitric Oxide Synthase Type II