Detrimental effects of a nitric oxide synthase inhibitor (N-omega-nitro-L-arginine-methyl-ester) in a murine sepsis model

Abstract

Objective: To examine the effects of a nitric oxide synthase inhibitor on host elimination of bacteria, tumor necrosis factor (TNF) production, and survival in a murine sepsis model.

Design: Prospective randomized experimental trials.

Setting: Laboratory.

Materials: Female Balb/c mice.

Interventions: Balb/c mice were injected with Escherichia coli (10(8) colony-forming units per body) into the peritoneal cavity. N-omega-Nitro-L-arginine-methyl-ester (L-NAME), an inhibitor of nitric oxide synthase, was given intraperitoneally at 10 mg/kg (N10 group) or 100 mg/kg (N100 group) 1 hour before bacterial challenge.

Main outcome measures: Thirty animals were observed for survival. Samples of peritoneal lavaged fluid (PLF), blood, liver, and lungs were obtained at 4 and 6 hours after bacterial challenge (n = 60). The peritoneal exudative cells were counted. Viable bacterial counts were determined in PLF, blood, and organs. The TNF levels also were determined in plasma, PLF, and supernatant samples of cultured peritoneal exudative cells.

Results: Survival times after E coli challenge were significantly reduced by pretreatment with L-NAME (100 mg/kg intraperitoneally). Numbers of viable bacteria in the peritoneal cavity and plasma TNF level 4 hours after E coli challenge were higher in both L-NAME-treated groups than in the control group. The number of bacteria in the blood and the plasma TNF level 6 hours after E coli challenge were higher in the L-NAME-treated group (N100 group) than in the control group. Conversely, the number of hepatic bacteria in the control group was significantly higher than in the L-NAME-treated groups. Plasma TNF level showed significant positive correlations with numbers of bacteria in the PLF and in the blood 4 hours after challenge. No significant differences were noted in TNF levels in PLF and peritoneal exudative cell cultured supernatants.

Conclusion: Inhibition of nitric oxide production is detrimental in this gram-negative sepsis model.