title: Association between synthesis and release of cGMP and nitric oxide biosynthesis by hepatocytes.
abstract: Hepatocytes are known to synthesize nitric oxide (NO) from L-arginine via an inducible NO synthase. Studies were performed to determine the relationship between hepatocyte NO production and the stimulation of hepatocyte soluble guanylate cyclase. A combination of lipopolysaccharide (LPS), interferon-gamma, tumor necrosis factor, and interleukin-1 stimulates the biosynthesis of large quantities of nitrite and nitrate (NO2- + NO3-). Hepatocyte NO2- + NO3- production was associated with only small increases in intracellular guanosine 3',5'-cyclic monophosphate (cGMP) levels but much greater increases in extracellular cGMP release over an 18-h time period. This cGMP synthesis was dependent on the L-arginine concentration and was inhibited in a reversible manner by NG-monomethyl-L-arginine. The cytokines or LPS added alone induced small increases in nitrogen oxide production and concomitant minor elevations in cGMP release. Atrial natriuretic peptide also stimulated the release of cGMP by hepatocytes which appeared to be independent of the cytokine+LPS-induced cGMP release. The addition of probenecid reduced the cGMP release by 66%, while cell damage was excluded as a cause for the extracellular release. Addition of 3-isobutyl-1-methylxanthine, but not M&B 22948, increased hepatocyte intra- and extracellular cGMP levels after cytokine+LPS stimulation. Induction of nitrogen oxide synthesis by hepatocytes in vivo by injecting rats with killed Corynebacterium parvum resulted in increased cGMP levels in freshly isolated hepatocytes and increased cGMP release by the hepatocytes when placed in culture.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Neurobiology, University of Pittsburgh, Pennsylvania 15261.
authors.forename: T R
authors.initials: TR
authors.lastname: Billiar
authors.forename: R D
authors.initials: RD
authors.lastname: Curran
authors.forename: B G
authors.initials: BG
authors.lastname: Harbrecht
authors.forename: J
authors.initials: J
authors.lastname: Stadler
authors.forename: D L
authors.initials: DL
authors.lastname: Williams
authors.forename: J B
authors.initials: JB
authors.lastname: Ochoa
authors.forename: M
authors.initials: M
authors.lastname: Di Silvio
authors.forename: R L
authors.initials: RL
authors.lastname: Simmons
authors.forename: S A
authors.initials: SA
authors.lastname: Murray
mesh_terms: D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D009320:Atrial Natriuretic Factor / Q000494:pharmacology; D003354:Corynebacterium Infections / Q000378:metabolism / Q000473:pathology; D006152:Cyclic GMP / Q000378:metabolism*; D016207:Cytokines / Q000494:pharmacology; D008070:Lipopolysaccharides; D008099:Liver / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism*; D009609:Nitrous Oxide / Q000378:metabolism; D011425:Propionibacterium acnes; D019323:omega-N-Methylarginine
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D009320:Atrial Natriuretic Factor; D001120:Arginine; D006152:Cyclic GMP; D009609:Nitrous Oxide