ARGININE TRANSPORT IN HUMAN LIVER - CHARACTERIZATION AND EFFECTS OF NITRIC-OXIDE SYNTHASE INHIBITORS

Objective Arginine transport was characterized and studied in human li ver. Summary Background Data Plasma arginine uptake may regulate hepat ocyte intracellular availability and the subsequent biosynthesis of ni tric oxide (NO), but little is known about arginine transport across t he human hepatocyte plasma membrane. Methods The authors characterized plasma membrane transport of 3[H]-L-arginine in hepatic plasma membra ne vesicles (HPMVs) and in hepatocytes isolated and cultured from huma n liver biopsy specimens. They also studied the effects of the NO synt hase inhibitors omega-nitro-L-arginine methyl ester (L-NAME) and N-met hylarginine (NMA) on arginine transport in HPMVs and in cultured cells . Results Arginine transport was saturable, Na+-independent, temperatu re and pH sensitive, and was inhibited by the naturally occurring amin o acids lysine, homoarginine, and ornithine (System y+ substrates). Ar ginine transport by both vesicles and cultured hepatocytes was signifi cantly attenuated by NO synthase inhibitors, suggesting that the argin ine transporter and the NO synthase enzyme may share a structurally si milar arginine binding site. Dixon plot analysis showed the blockade t o occur by competitive, rather than noncompetitive, inhibition. In viv o treatment of rats with lipopolysaccharide (LPS) resulted in a twofol d stimulation of saturable arginine transport in the liver, This LPS-i nduced hepatic arginine transport activity was also inhibited by L-NAM E. These data indicate that arginine transport by human hepatocytes is mediated primarily by the Na+-independent transport System y+. Conclu sions Besides inhibition of the NO synthase enzyme, the ability of arg inine derivatives to block NO production may also be due to their abil ity to competitively inhibit arginine transport across the hepatocyte plasma membrane. The use of selective arginine derivatives that compet e with arginine at the plasma membrane level may be a metabolic strate gy that can be used to modulate the septic response.