Inhibition of Nitric Oxide Synthesis Is Detrimental During Endotoxemia

Emery A. Minnard, MD; Jian Shou, MD; Hassan Naama, FRCSI; Alex Cech, MD; Hubert Gallagher, FRCSI; John M. Daly, MD
Arch Surg. 1994;129(2):142-148. doi:10.1001/archsurg.1994.01420260038004.
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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 μg/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 μmol/L to 7 and 11 μmol/L (P<.05) and reduced mean plasma nitrite concentrations from 100 and 118 μmol/L to 46 and 108 μmol/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).

Conclusion:  Inhibition of nitric oxide production is detrimental in this murine model of endotoxemia.(Arch Surg. 1994;129:142-148)


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