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, N-G-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 mu M in control-treated animals to 282 mu M in L-NMMA-treated animals (P < .001). This compared to a level of 103 mu M 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.