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.
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 murinesepsis model. DESIGN: Sixty-eight female Swiss-Webster (ND4) mice were injected with a sublethal dose of Escherichia colilipopolysaccharide (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.
Authors: L Molina; S Studenberg; G Wolberg; W Kazmierski; J Wilson; A Tadepalli; A C Chang; S Kosanke; L Hinshaw Journal: J Clin Invest Date: 1996-07-01 Impact factor: 14.808
Authors: M Bianchi; P Ulrich; O Bloom; M Meistrell; G A Zimmerman; H Schmidtmayerova; M Bukrinsky; T Donnelley; R Bucala; B Sherry Journal: Mol Med Date: 1995-03 Impact factor: 6.354