N-acetylcysteine inhibits in vivo nitric oxide production by inducible nitric oxide synthase

This in vivo study evaluates the effect of N-acetylcysteine (NAC) administr ation on nitric oxide (NO) production by the inducible form of nitric oxide synthase (iNOS). NO production was induced in the rat by the ip administra tion of 2 mg/100 g lipopolysaccharide (LPS). This treatment caused: (1) a d ecrease in body temperature within 90 min, followed by a slow return to nor mal levels; (2) an increase in plasma levels of urea, nitrite/nitrate, and citrulline; (3) the appearance in blood of nitrosyl-hemoglobin (NO-Hb) and in liver of dinitrosyl-iron-dithiolate complexes (DNIC); and (4) increased expression of iNOS mRNA in peripheral blood mononuclear cells (PBMC). Rat t reatment with 15 mg/100 g NAC ip, 30 min before LPS, resulted in a signific ant decrease in blood NO-Hb levels, plasma nitrite/nitrate and citrulline c oncentrations, and liver DNIC complexes. PBMC also showed a decreased expre ssion of iNOS mRNA. NAC pretreatment did not modify the increased levels of plasma urea or the hypothermic effect induced by the endotoxin. The admini stration of NAC following LPS intoxication (15 min prior to sacrifice) did not affect NO-Hb levels. These results demonstrate that NAC administration can modulate the massive NO production induced by LPS. This can be attribut ed mostly to the inhibitory effect of NAC on one of the events leading to i NOS protein expression. This hypothesis is also supported by the lack of ef fect of late NAC administration. (C) 2001 Academic Press.