HEPATOCYTE NITRIC-OXIDE BIOSYNTHESIS INHIBITS GLUCOSE OUTPUT AND COMPETES WITH UREA SYNTHESIS FOR L-ARGININE

Inflammatory stimulation of the liver is known to induce nitric oxide (NO) biosynthesis. NO can interfere with the activity of a number of e nzymes important to cellular metabolism. This study was carried out to investigate the influence of NO on rat hepatocyte glucose output and urea production. Induction of NO synthesis by incubation with a combin ation of cytokines and lipopolysaccharide led to a 48.8 +/- 2.4% inhib ition of glucose output and to a 45.0 +/- 6.4% suppression of urea pro duction. Inhibition of NO synthesis with NG(-)monomethyl-L-arginine wa s able to totally prevent these effects. High concentrations of L-argi nine overcame the inhibition of urea production caused by endogenous N O synthesis. Exposure of HC to NO donors resulted in a concentration-d ependent inhibition of glucose output, without having any effect on ur ea production. Hepatocellular glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity was also found to be inhibited by endogenously produ ced NO (33.5 +/- 5.2%), as well as by exogenously applied NO. However, an exact correlation between GAPDH activity and glucose output could not be established. These data indicate that NO biosynthesis may contr ibute to the development of hepatic dysfunction in chronic sepsis.