Abstract
The role of inducible nitric-oxide synthase (iNOS) in lipopolysaccharide (LPS)-induced hepatic oxidant stress was evaluated using the iNOS inhibitor l-iminoethyl-lysine (l-NIL). Male rats were divided into three groups. One group received LPS (Salmonella minnesota) 2 mg/kg i.v. A second group received 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, blood and liver tissue were collected. Serum nitrate/nitrite (metabolic products of nitric oxide) levels were increased from 5.4 ± 1.5 nmol/ml in the saline 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 malondialdehyde levels were increased from 0.20 ± 0.02 nmol/mg (n = 4) in the saline group to 0.41 ± 0.03 nmol/mg (n = 4) in the LPS group.l-NIL significantly 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 LPS treatment as compared with saline. l-NIL significantly reversed the levels 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 group to 7.04 ± 0.46 nmol/mg (n = 7). These data indicate that LPS-induced nitric oxide generation can result in oxidant stress in the liver, and that inhibitors of iNOS may offer some protection in LPS-induced hepatic toxicity.
Footnotes
-
Send reprint requests to: Philip R. Mayeux, Ph.D., Dept. of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, 4301 W. Markham St., Slot 611, Little Rock, AR 72205. E-mail:mayeuxphilipr{at}exchange.uams.edu
-
↵1 This work was supported by National Institutes of Health Grants DK44716 to P.R.M. and GM58884 to J.A.H.
- Abbreviations:
- LPS
- lipopolysaccharide
- NO
- nitric oxide
- iNOS
- inducible NO synthase
- ONOO−
- peroxynitrite
- l-NIL
- l-iminoethyl-lysine
- TBARS
- thiobarbituric acid-reactive substances
- PAGE
- polyacrylamide gel electrophoresis
- ALT
- alanine aminotransferase
- Received December 7, 1999.
- Accepted February 17, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|