NONSELECTIVE VERSUS SELECTIVE-INHIBITION OF INDUCIBLE NITRIC-OXIDE SYNTHASE IN EXPERIMENTAL ENDOTOXIC-SHOCK

The effects of two nitric oxide synthase (NOS) inhibitors with differe nt isoform selectivity were compared in a murine model of endotoxemia. Mice challenged with 70 mg/kg intraperitoneal (ip) lipopolysaccharide (LPS) were treated 6 h after LPS with either N-G-gamma-L-arginine met hyl ester (L-NAME, nonselective NOS inhibitor, 10-60 mg/kg), L-canavan ine (selective inhibitor of inducible NOS, 50-300 mg/kg), or saline (0 .2 mt) given ip, In a subset of mice, plasma concentrations of nitrate (NO breakdown product), lipase (pancreas injury), lactate dehydrogena se, and transaminases (liver injury) were measured 16 h after LPS, Alt hough both inhibitors reduced plasma nitrate, they produced contrastin g effects on survival and organ injury. L-NAME enhanced liver damage a nd tended to accelerate the time of death, while L-canavanine signific antly reduced mortality and had no deleterious effects in terms of org an damage. These results indicate that nonselective NOS inhibitors are detrimental in endotoxic shock and support the potential usefulness o f selective inducible NOS inhibitors in this setting.