Inhibition of nitric oxide synthesis is detrimental during endotoxemia

E. A. Minnard, J. Shou, H. Naama, A. Cech, H. Gallagher and J. M. Daly
Division of Surgical Oncology, University of Pennsylvania School of Medicine, Philadelphia.

BACKGROUND: Increased production of nitric oxide has been implicated as a mediator during septic shock and sepsis syndrome. Inhibition of nitric oxide production could be beneficial during endotoxemia to improve the individual's hemodynamic status and possibly outcome. OBJECTIVE: To evaluate the effects of nitric oxide inhibition on macrophage function and survival in a murine sepsis model. DESIGN: Sixty-eight female Swiss-Webster (ND4) mice were injected with a sublethal dose of Escherichia coli lipopolysaccharide (25 mg/kg). INTERVENTION: The treated group (n = 34) received 10 mg/kg of NG-nitro-L-arginine methyl ester at the time of lipopolysaccharide injection. MAIN OUTCOME MEASURES: Blood samples and peritoneal macrophages were obtained at baseline and at 2, 4, and 8 hours after injection. Nitrite levels were measured in 36 mice from plasma and supernatant samples of cultured peritoneal macrophages stimulated with interferon gamma (100 micrograms/mL) for 48 hours. Thirty-two animals were observed for survival. RESULTS: Administration of N-nitro-L-arginine methyl ester after lipopolysaccharide injection caused significant reductions in macrophage mean nitrite production from 13 and 15 mumol/L to 7 and 11 mumol/L (P < .05) and reduced mean plasma nitrite concentrations from 100 and 118 mumol/L to 46 and 108 mumol/L (P < .05) at 2 and 4 hours, respectively. The rate of survival was significantly decreased to 0% in the group receiving N-nitro-L-arginine methyl ester after septic challenge compared with 87.5% in controls (P < .005). CONCLUSIONS: Inhibition of nitric oxide production is detrimental in this murine model of endotoxemia.

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