Inhibition of nitric oxide synthase in experimental gram-negative sepsis.
Nitric oxide (NO) has been proposed as a mediator of hypotension in septic shock. The aim of this study was to determine whether an inhibitor of NO production, NG-monomethyl-L-arginine (L-NMMA), was able to protect against death in two murine models of experimental gram-negative sepsis. L-NMMA (3-300 mg kg-1) did not improve survival in intravenous or intraperitoneal models of sepsis. Seven h after intravenous infection, L-NMMA (100 mg/kg-1) reduced serum nitrite plus nitrate levels (NO breakdown products) from 774 microM in control-treated animals to 282 microM in L-NMMA-treated animals (P < .001). This compared to a level of 103 microM in uninfected mice. L-NMMA produced little change in bacterial load following infection and did not increase hepatic damage, as measured by serum levels of ornithine carbamoyltransferase. Thus, while L-NMMA may reverse the hyporesponsiveness of peripheral circulation in sepsis, it was unable to prevent death in these models of gram-negative septic shock.
Evans
T
T
Department of Infectious Diseases and Bacteriology, Royal Postgraduate Medical School, London, United Kingdom.
Carpenter
A
A
Silva
A
A
Cohen
J
J
D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D004926:Escherichia coli / Q000472:pathogenicity; D004927:Escherichia coli Infections / Q000201:enzymology*; D008099:Liver / Q000502:physiology; D051379:Mice; D009566:Nitrates / Q000097:blood; D019001:Nitric Oxide Synthase; D009573:Nitrites / Q000097:blood; D012772:Shock, Septic / Q000097:blood / Q000201:enzymology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019323:omega-N-Methylarginine
D009566:Nitrates; D009573:Nitrites; D014409:Tumor Necrosis Factor-alpha; D019323:omega-N-Methylarginine; D001120:Arginine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases