Inhibition of nitric oxide synthesis is detrimental during 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 murine sepsis model.


METHODS
Sixty-eight female Swiss-Webster (ND4) mice were injected with a sublethal dose of Escherichia coli lipopolysaccharide (25 mg/kg).


METHODS
The treated group (n = 34) received 10 mg/kg of NG-nitro-L-arginine methyl ester at the time of lipopolysaccharide injection.


METHODS
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.
Minnard
E A
EA
Division of Surgical Oncology, University of Pennsylvania School of Medicine, Philadelphia.
Shou
J
J
Naama
H
H
Cech
A
A
Gallagher
H
H
Daly
J M
JM
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004731:Endotoxins / Q000009:adverse effects* / Q000097:blood; D004926:Escherichia coli; D005260:Female; D008070:Lipopolysaccharides / Q000009:adverse effects* / Q000097:blood; D008168:Lung / Q000201:enzymology / Q000473:pathology; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D009573:Nitrites / Q000097:blood; D009195:Peroxidase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D015996:Survival Rate
D004731:Endotoxins; D008070:Lipopolysaccharides; D009573:Nitrites; D013481:Superoxides; D009569:Nitric Oxide; D001120:Arginine; D009195:Peroxidase; D019331:NG-Nitroarginine Methyl Ester