Effects of the New Arginase Inhibitor Nω-Hydroxy-nor-l-Arginine on NO Synthase Activity in Murine Macrophages

摘要: In stimulated murine macrophage, arginase and nitric oxide synthase (NOS) compete for their common substrate, l-arginine. The objectives of this study were (i) to test the new alpha-amino acid N(omega)-hydroxy-nor-l-arginine (nor-NOHA) as a selective inhibitor (ii) elucidate effects inhibition on l-arginine utilization by an inducible NOS. Nor-NOHA is about 40-fold more potent than N(omega)-hydroxy-l-arginine (NOHA), intermediate in l-arginine/NO pathway, inhibit hydrolysis l-ornithine catalyzed unstimulated macrophages (IC(50) values 12 +/- 5 400 50 microM, respectively). Stimulation with interferon-gamma lipopolysaccharide (IFN-gamma + LPS) results clear expression NOS (iNOS) increase activity. also IFN-gamma LPS-stimulated macrophage value 10 3 microM). contrast NOHA, nor-NOHA neither substrate nor iNOS it appears useful tool interplays between Inhibition increases nitrite l-citrulline accumulation incubation times higher h, under our conditions. Our allow determination kinetic parameters two competitive pathways proposal simple model which readily explains differences observed experiments. This accounts should be predict consequences presence active availability.