Arginine Transport in Human Liver: Characterization and Effects of Nitric Oxide Synthase Inhibitors

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ObjectiveArginine transport was characterized and studied in human liver.Summary Background DataPlasma arginine uptake may regulate hepatocyte intracellular availability and the subsequent biosynthesis of nitric oxide (NO), but little is known about arginine transport across the human hepatocyte plasma membrane.MethodsThe authors characterized plasma membrane transport of 3[H]-L-arginine in hepatic plasma membrane vesicles (HPMVs) and in hepatocytes isolated and cultured from human liver biopsy specimens. They also studied the effects of the NO synthase inhibitors w-nitro-L-arginine methyl ester (L-NAME) and N-methylarginine (NMA) on arginine transport in HPMVs and in cultured cells.ResultsArginine transport was saturable, Na+-independent, temperature and pH sensitive, and was inhibited by the naturally occurring amino acids lysine, homoarginine, and ornithine (System y+ substrates). Arginine transport by both vesicles and cultured hepatocytes was significantly attenuated by NO synthase inhibitors, suggesting that the arginine transporter and the NO synthase enzyme may share a structurally similar arginine binding site. Dixon plot analysis showed the blockade to occur by competitive, rather than noncompetitive, inhibition. In vivo treatment of rats with lipopolysaccharide (LPS) resulted in a twofold stimulation of saturable arginine transport in the liver. This LPS-induced hepatic arginine transport activity was also inhibited by L-NAME. These data indicate that arginine transport by human hepatocytes is mediated primarily by the Na+-independent transport System y+.ConclusionsBesides inhibition of the NO synthase enzyme, the ability of arginine derivatives to block NO production may also be due to their ability to competitively inhibit arginine transport across the hepatocyte plasma membrane. The use of selective arginine derivatives that compete with arginine at the plasma membrane level may be a metabolic strategy that can be used to modulate the septic response.

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