title: Nitric oxide and L-arginine metabolism in a devascularized porcine model of acute liver failure.
abstract: In acute liver failure (ALF), the hyperdynamic circulation is believed to be the result of overproduction of nitric oxide (NO) in the splanchnic circulation. However, it has been suggested that arginine concentrations (the substrate for NO) are believed to be decreased, limiting substrate availability for NO production. To characterize the metabolic fate of arginine in early-phase ALF, we systematically assessed its interorgan transport and metabolism and measured the endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA) in a porcine model of ALF. Female adult pigs (23-30 kg) were randomized to sham (N = 8) or hepatic devascularization ALF (N = 8) procedure for 6 h. We measured plasma arginine, citrulline, ornithine levels; arginase activity, NO, and ADMA. Whole body metabolic rates and interorgan flux measurements were calculated using stable isotope-labeled amino acids. Plasma arginine decreased >85% of the basal level at t = 6 h (P < 0.001), whereas citrulline and ornithine progressively increased in ALF (P < 0.001 and P < 0.001, vs. sham respectively). No difference was found between the groups in the whole body rate of appearance of arginine or NO. However, ALF showed a significant increase in de novo arginine synthesis (P < 0.05). Interorgan data showed citrulline net intestinal production and renal consumption that was related to net renal production of arginine and ornithine. Both plasma arginase activity and plasma ADMA levels significantly increased in ALF (P < 0.001). In this model of early-phase ALF, arginine deficiency or higher ADMA levels do not limit whole body NO production. Arginine deficiency is caused by arginase-related arginine clearance in which arginine production is stimulated de novo.
authors.affiliation: UCL Institute of Hepatology, Royal Free Campus, University College London, London, UK.
authors.forename: Vikram
authors.initials: V
authors.lastname: Sharma
authors.forename: Gabriella A M
authors.initials: GA
authors.lastname: Ten Have
authors.forename: Lars
authors.initials: L
authors.lastname: Ytrebo
authors.forename: Sambit
authors.initials: S
authors.lastname: Sen
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Rose
authors.forename: R Neil
authors.initials: RN
authors.lastname: Dalton
authors.forename: Charles
authors.initials: C
authors.lastname: Turner
authors.forename: Arthur
authors.initials: A
authors.lastname: Revhaug
authors.forename: Hans M H
authors.initials: HM
authors.lastname: van-Eijk
authors.forename: Nicolaas E P
authors.initials: NE
authors.lastname: Deutz
authors.forename: Rajiv
authors.initials: R
authors.lastname: Jalan
authors.forename: Rajeshwar P
authors.initials: RP
authors.lastname: Mookerjee
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Davies
mesh_terms: D000818:Animals; D001119:Arginase / Q000097:blood; D001120:Arginine / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D002956:Citrulline / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D008099:Liver / Q000098:blood supply; D017114:Liver Failure, Acute / Q000097:blood / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D009952:Ornithine / Q000097:blood; D011167:Portacaval Shunt, Surgical; D034421:Sus scrofa
chemical_list: D002956:Citrulline; D009569:Nitric Oxide; C018524:N,N-dimethylarginine; D001120:Arginine; D009952:Ornithine; D001119:Arginase