Inhibition of tetrahydrobiopterin synthesis reduces nitric oxide production by isolated glomeruli in immune complex glomerulonephritis.
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.
Bune
A J
AJ
Department of Histopathology, Imperial College of Science, Technology and Medicine, London, UK.
Cook
H T
HT
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
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