Premium
Pterins inhibit nitric oxide synthase activity in rat alveolar macrophages
Author(s) -
Jorens Philippe G.,
Overveld Frans J.,
Bult Hidde,
Vermeire Paul A.,
Herman Arnold G.
Publication year - 1992
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1992.tb13411.x
Subject(s) - citrulline , nitric oxide , nitric oxide synthase , biosynthesis , biochemistry , biopterin , nitrite , chemistry , arginine , pterin , omega n methylarginine , lipopolysaccharide , biology , enzyme , tetrahydrobiopterin , amino acid , cofactor , endocrinology , organic chemistry , nitrate
1 The synthesis of nitrite and citrulline from l ‐arginine by immune‐stimulated rat alveolar macrophages and the modulation of this synthesis were studied. 2,4‐Diamino‐6‐hydroxypyrimidine (DAHP), 6 R ‐5,6,7,8‐tetrahydro‐ l ‐biopterin (BH 4 ) and l ‐sepiapterin were potent inhibitors of the recombinant interferon‐γ induced production of nitrogen oxides in intact cultured cells with I 50 values for BH 4 and l ‐sepiapterin of approximately 10 μ m . They were equally effective in inhibiting the induced production of citrulline. This inhibitory effect was concentration‐dependent for all three modulators investigated. 2 The inhibitory effects were not dependent on incubation times of either 24 or 48 h, on the immune‐stimulus used (lipopolysaccharide, interferon‐γ), or whether these stimuli were added during or after the induction period. 3 Pterin‐6‐carboxylic acid (PCA), which cannot be converted into BH 4 , and methotrexate (MTX), which inhibits dihydrofolatereductase but not de novo biosynthesis of BH 4 , did not change the production of nitrite. 4 The data indicate that DAHP, an inhibitor of the de novo biosynthesis of the co‐factor BH 4 , blocks the nitric oxide synthase activity in intact cells. Since the pterins BH 4 and l ‐sepiapterin blocked the l ‐arginine dependent production of nitrite and citrulline, the activity of nitric oxide synthase in phagocytic cells may be regulated by metabolic endproducts of the de novo biosynthesis of BH 4 .