Nitric oxide and L-arginine metabolism in a devascularized porcine model of acute liver failure

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 availabili...

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Published in:American journal of physiology: Gastrointestinal and liver physiology 2012-08, Vol.303 (3), p.G435-G441
Main Authors: Sharma, Vikram, Ten Have, Gabriella A M, Ytrebo, Lars, Sen, Sambit, Rose, Christopher F, Dalton, R Neil, Turner, Charles, Revhaug, Arthur, van-Eijk, Hans M H, Deutz, Nicolaas E P, Jalan, Rajiv, Mookerjee, Rajeshwar P, Davies, Nathan A
Format: Article
Language:English
Subjects:
Amino acids
Animals
Arginase - blood
Arginine - analogs & derivatives
Arginine - blood
Arginine - metabolism
Arginine - pharmacology
Biosynthesis
Citrulline - blood
Disease Models, Animal
Female
Hepatology
Hogs
Liver - blood supply
Liver and Biliary Tract
Liver Failure, Acute - blood
Liver Failure, Acute - metabolism
Metabolism
Nitric oxide
Nitric Oxide - metabolism
Ornithine - blood
Portacaval Shunt, Surgical
Sus scrofa
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Summary: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.
ISSN:0193-1857
1522-1547
DOI:10.1152/ajpgi.00268.2011