Nathan Davies, Gabrie Ten Have, Vikram Sharma, Lars Ytrebø, Sambit Sen, Christopher Rose, Arthur Revhaug, R. P. Mookerjee, Rajiv Jalan, Nicholaas Deutz.
Background: In acute liver failure (ALF) arginine concentrations are believed to be decreased, potentially limiting substrate for nitric oxide production. However, our prior observations in a porcine hepatic devascularisation model showed no significant change in systemic haemodynamics. To further characterize the metabolic fate of arginine in ALF, we systematically assessed de-novo arginine generation, inter-organ flux of arginine, and its metabolism by the arginase pathway. Methods: Female adult pigs (30−35Kg) were randomized into either Sham (N = 8) or ALF groups (N = 8). ALF was induced by hepatic devascularisation, and the animals sampled over 6 hours. Measurements: Plasma arginine, citrulline, ornithine levels (HPLC); arginase activity (colourimetric assay); nitric oxide (stable isotope labelled citrulline generation-HPLC). Whole body metabolic rates and inter organ flux were calculated after stable isotope-labelled amino-acid infusions and calculation of arterio venous concentration differences across each organ. Results: Plasma arginine levels decreased by 50% of the basal level at T=6 hrs (p < 0.001), whereas plasma citrulline and ornithine levels progressively increased in the ALF group compared to Sham (p < 0.001 and p < 0.001, respectively). Calculation of the whole body rate of appearance of Arginine and nitric oxide showed no difference between the two groups. However, there was an increase in the rate of de novo arginine synthesis in ALF pigs. Inter-organ flux data showed citrulline is predominantly produced in the small intestine and consumed in the kidney. Arginine and Ornithine were both primarily produced in the kidney. Plasma arginase activity (liberating ornithine) significantly increased in the ALF group over 6 hrs, whereas no change was observed in Sham animals. Conclusions: In this model of ALF, we demonstrated that although de novo production of arginine is increased, whole body level of arginine and consequent nitric oxide production remains unchanged. This we show to be due to the significantly increased arginase activity manifest by the greater levels of ornithine in the ALF group. The effect of arginase in reducing plasma arginine and thereby, the substrate for NO synthesis, may result in the impaired organ perfusion typically observed in ALF, and contribute to multiple organ dysfunction. This work was partly supported by The Norwegian MRC.
