Received for publication May 25, 2006.
Revised June 28, 2006.
Accepted for publication June 29, 2006.

A role for nitric oxide-mediated peroxynitrite formation in a model of endotoxin induced shock

Abstract

The aim of the present study was to assess the relative contributions of peroxynitrite (ONOO-) 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, 1400W and a peroxynitrite decomposition catalyst 5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrinato iron III chloride (FeTTPs). Intravenous administration of E. coli lipopolysaccharide (LPS; 4 mg/kg) elicited a time-dependent fall in mean arterial pressure (MAP) as well as liver, renal and pancreatic tissue damage. 1400W (3-10 mg/kg i.v.) administered 30 minutes prior to 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 prior to 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.

Key words: LPS, inflammation, nitric oxide, organ failure, peroxynitrite, shock

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