Detrimental effects of a nitric oxide synthase inhibitor (N-omega-nitro-L-arginine-methyl-ester) in a murine sepsis model
K. Fukatsu, H. Saito, R. Fukushima, T. Inoue, M. T. Lin, T. Inaba and T. Muto
Department of Surgery, University of Tokyo, Japan.
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.
