title: Inhibition of tetrahydrobiopterin synthesis reduces nitric oxide production by isolated glomeruli in immune complex glomerulonephritis.
abstract: We studied the effect of modulators of tetrahydrobiopterin (BH4) synthesis on the production of nitrite by glomeruli from rats with immune complex-mediated glomerular inflammation. Glomeruli were isolated 24 h after induction of accelerated nephrotoxic nephritis and cultured at 2,000/ml for 48 h. Lipopolysaccharide dose dependently increased ex vivo nitrite production. 2,4-Diamino-6-hydroxypyrimidine (DAHP), an inhibitor of the de novo synthetic pathway of BH4, inhibited nitrite production by up to 50% and this effect was reversed by sepiapterin, a substrate for the salvage pathway of BH4 synthesis. Sepiapterin alone increased nitrite generation indicating that BH4 is rate limiting. Inhibition of both pathways with DAHP and methotrexate led to 80% inhibition of nitrite. Pharmacological inhibition of BH4 synthesis may be a useful mechanism to reduce nitric oxide synthesis in immune complex inflammation.
authors.affiliation: Department of Histopathology, Imperial College of Science, Technology and Medicine, London, UK.
authors.forename: A J
authors.initials: AJ
authors.lastname: Bune
authors.forename: H T
authors.initials: HT
authors.lastname: Cook
mesh_terms: D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001708:Biopterins / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005921:Glomerulonephritis / Q000276:immunology*; D007042:Hypoxanthines / Q000494:pharmacology; D007105:Immune Complex Diseases; D007678:Kidney Glomerulus / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008727:Methotrexate / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D011621:Pteridines / Q000494:pharmacology; D011622:Pterins; D051381:Rats
chemical_list: D004791:Enzyme Inhibitors; D007042:Hypoxanthines; D008070:Lipopolysaccharides; D011621:Pteridines; D011622:Pterins; D001708:Biopterins; D009569:Nitric Oxide; D001120:Arginine; C016727:sepiapterin; D019001:Nitric Oxide Synthase; C017202:2,4-diaminohypoxanthine; C003402:sapropterin; D019331:NG-Nitroarginine Methyl Ester; D008727:Methotrexate