Oxidant stress in rat liver after lipopolysaccharide administration: Effect of inducible nitric-oxide synthase inhibition

The role of inducible nitric-oxide synthase (iNOS) in lipopolysaccharide (L PS)-induced hepatic oxidant stress was evaluated using the iNOS inhibitor L -iminoethyl-lysine (L-NIL). Male rats were divided into three groups. One g roup received LPS (Salmonella minnesota) 2 mg/kg i.v. A second group receiv ed LPS plus L-NIL (3 mg/kg i.p.) at the time of LPS administration followed by a second dose 3 h later. A third group received saline i.v. At 6 h, blo od and liver tissue were collected. Serum nitrate/nitrite (metabolic produc ts of nitric oxide) levels were increased from 5.4 +/- 1.5 nmol/ml in the s aline group to 360 +/- 48 nmol/ml in the LPS group (n = 5). Values for the LPS + L-NIL group were significantly reduced to 35 +/- 7 nmol/ml. Tissue ma londialdehyde levels were increased from 0.20 +/- 0.02 nmol/mg (n = 4) in t he saline group to 0.41 +/- 0.03 nmol/mg (n = 4) in the LPS group. L-NIL si gnificantly reduced the values in the LPS group to 0.29 +/- 0.02 nmol/mg (n = 4). 4-Hydroxynonenal-protein adducts levels were increased 3.6-fold by L PS treatment as compared with saline. L-NIL significantly reversed the leve ls to 1.6-fold (n = 4). Intracellular GSH levels were decreased from 8.49 /- 0.64 nmol/mg (n = 4) in the saline group to 5.63 +/- 0.51 nmol/mg in the LPS group (n = 7). L-NIL significantly increased the levels in the LPS gro up to 7.04 +/- 0.46 nmol/mg (n = 7). These data indicate that LPS-induced n itric oxide generation can result in oxidant stress in the liver, and that inhibitors of iNOS may offer some protection in LPS-induced hepatic toxicit y.