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

V. Sharma, G.A. Ten Have, L. Ytrebo, S. Sen, C. F. Rose, R. N. Dalton, C. Turner, A. Revhaug, H.M.H. van Eijk, N.E.P. Deutz, R.A. Jalan, R. P. Mookerjee, N.A. Davies

Research output: Contribution to journalArticleAcademicpeer-review

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.
Original languageEnglish
Pages (from-to)G435-G441
Number of pages7
JournalAmerican Journal of Physiology-Gastrointestinal and Liver Physiology
Volume303
Issue number3
DOIs
Publication statusPublished - Aug 2012

Keywords

  • arginine
  • asymmetric dimethylarginine
  • arginase
  • ASYMMETRIC DIMETHYLARGININE ADMA
  • FULMINANT HEPATIC-FAILURE
  • VASCULAR SMOOTH-MUSCLE
  • PORTAL-DRAINED VISCERA
  • PLASMA AMINO-ACIDS
  • INTRACRANIAL-PRESSURE
  • COLLAGEN-SYNTHESIS
  • ENDOTHELIAL-CELLS
  • GUANYLATE-CYCLASE
  • ALBUMIN DIALYSIS

Cite this

Sharma, V., Ten Have, G. A., Ytrebo, L., Sen, S., Rose, C. F., Dalton, R. N., Turner, C., Revhaug, A., van Eijk, H. M. H., Deutz, N. E. P., Jalan, R. A., Mookerjee, R. P., & Davies, N. A. (2012). Nitric oxide and L-arginine metabolism in a devascularized porcine model of acute liver failure. American Journal of Physiology-Gastrointestinal and Liver Physiology, 303(3), G435-G441. https://doi.org/10.1152/ajpgi.00268.2011