Document Detail

Interactions of peroxynitrite with uric acid in the presence of ascorbate and thiols: implications for uncoupling endothelial nitric oxide synthase.
MedLine Citation:
PMID:  15963955     Owner:  NLM     Status:  MEDLINE    
It has been suggested that uric acid acts as a peroxynitrite scavenger although it may also stimulate lipid peroxidation. To gain insight into how uric acid may act as an antioxidant, we used electron spin resonance to study the reaction of uric acid and plasma antioxidants with ONOO-. Peroxynitrite reacted with typical plasma concentrations of urate 16-fold faster than with ascorbate and 3-fold faster than cysteine. Xanthine but not other purine-analogs also reacted with peroxynitrite. The reaction between ONOO- and urate produced a carbon-centered free radical, which was inhibited by either ascorbate or cysteine. Moreover, scavenging of ONOO- by urate was significantly increased in the presence of ascorbate and cysteine. An important effect of ONOO- is oxidation of tetrahydrobiopterin, leading to uncoupling of nitric oxide synthase. The protection of eNOS function by urate, ascorbate and thiols in ONOO(-)-treated bovine aortic endothelial cells (BAECs) was, therefore, investigated by measuring superoxide and NO using the spin probe 1-hydroxy-3-methoxycarbonyl-2,2,5,5-tetramethyl-pyrrolidine (CMH) and the NO-spin trap Fe[DETC]2. Peroxynitrite increased superoxide and decreased NO production by eNOS indicating eNOS uncoupling. Urate partially prevented this effect of ONOO- while treatment of BAECs with the combination of either urate with ascorbate or urate with cysteine completely prevented eNOS uncoupling caused by ONOO-. We conclude that the reducing and acidic properties of urate are important in effective scavenging of peroxynitrite and that cysteine and ascorbate markedly augment urate's antioxidant effect by reducing urate-derived radicals.
Nermin Kuzkaya; Norbert Weissmann; David G Harrison; Sergey Dikalov
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Biochemical pharmacology     Volume:  70     ISSN:  0006-2952     ISO Abbreviation:  Biochem. Pharmacol.     Publication Date:  2005 Aug 
Date Detail:
Created Date:  2005-07-04     Completed Date:  2005-08-18     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0101032     Medline TA:  Biochem Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  343-54     Citation Subset:  IM    
Department of Internal Medicine, Justus-Liebig University School of Medicine, Giessen, Germany.
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MeSH Terms
Ascorbic Acid / metabolism*
Cells, Cultured
Drug Interactions
Endothelium, Vascular / enzymology
Nitric Oxide Synthase / antagonists & inhibitors*,  metabolism
Nitric Oxide Synthase Type III
Peroxynitrous Acid / chemistry,  metabolism*
Sulfhydryl Compounds / chemistry,  metabolism*
Uncoupling Agents / chemistry,  metabolism*
Uric Acid / chemistry,  metabolism*
Grant Support
P0-1 HL058000-05/HL/NHLBI NIH HHS; R0-1 HL39006/HL/NHLBI NIH HHS
Reg. No./Substance:
0/Sulfhydryl Compounds; 0/Uncoupling Agents; 14691-52-2/Peroxynitrous Acid; 50-81-7/Ascorbic Acid; 69-93-2/Uric Acid; EC Oxide Synthase; EC Oxide Synthase Type III

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