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 mu g ml(-1), 24 h) selectively increased the transport capacity for N-G-monomethyl-L-[C-14]arginine (L-NMMA), whereas transport of N-g-nitro-L[H-3]arginine (L-NNA) was unaffected. Inhibition studies established that the cationic transport system y(+) mediates uptake of L-arginine, L-NMMA and N-G-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 (1) may facilitate the targeting of selective inhibitors of inducible NO synthase to activated cells generating NO in endotoxin shock. (C) 1994 Academic Press, Inc.