Selective targeting of nitric oxide synthase inhibitors to system y+ in activated macrophages.
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.
Baydoun
A R
AR
Vascular Biology Research Centre, King's College London, UK.
Mann
G E
GE
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
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