title: Selective targeting of nitric oxide synthase inhibitors to system y+ in activated macrophages.
abstract: Amino acid transport systems mediating uptake of nitric oxide (NO) synthase inhibitors were characterized in the murine macrophage cell line J774. Treatment of J774 cells with bacterial endotoxin (LPS, 1 microgram ml-1, 24 h) selectively increased the transport capacity for NG-monomethyl-L-[14C]arginine (L-NMMA), whereas transport of NG-nitro-L-[3H]arginine (L-NNA) was unaffected. Inhibition studies established that the cationic transport system y+ mediates uptake of L-arginine, L-NMMA and NG-iminoethyl-L-ornithine (L-NIO). A neutral transporter, with low substrate specificity and insensitive to LPS, mediates uptake of L-citrulline, L-NNA and its methyl ester L-NAME. We conclude that enhanced expression of the y+ transporter in LPS-stimulated macrophages may facilitate the targeting of selective inhibitors of inducible NO synthase to activated cells generating NO in endotoxin shock.
authors.affiliation: Vascular Biology Research Centre, King's College London, UK.
authors.forename: A R
authors.initials: AR
authors.lastname: Baydoun
authors.forename: G E
authors.initials: GE
authors.lastname: Mann
mesh_terms: D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors*; D026905:Amino Acid Transport Systems; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D001693:Biological Transport, Active / Q000187:drug effects; D002172:Canavanine / Q000493:pharmacokinetics / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D002956:Citrulline / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008562:Membrane Glycoproteins; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D019331:NG-Nitroarginine Methyl Ester; D019001:Nitric Oxide Synthase; D019335:Nitroarginine; D009952:Ornithine / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D011991:Receptors, Virus; D019323:omega-N-Methylarginine
chemical_list: D026905:Amino Acid Transport Systems; D002352:Carrier Proteins; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D011991:Receptors, Virus; C070506:ecotropic murine leukemia virus receptor; D019335:Nitroarginine; D019323:omega-N-Methylarginine; D002956:Citrulline; C065027:N(G)-iminoethylornithine; D002172:Canavanine; D001120:Arginine; D009952:Ornithine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D019331:NG-Nitroarginine Methyl Ester