Document Detail


Hyperuricemia induces endothelial dysfunction.
MedLine Citation:
PMID:  15840020     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Hyperuricemia has been linked to cardiovascular and renal diseases, possibly through the generation of reactive oxygen species (ROS) and subsequent endothelial dysfunction. The enzymatic effect of xanthine oxidase is the production of ROS and uric acid. Studies have shown that inhibiting xanthine oxidase with allopurinol can reverse endothelial dysfunction. Furthermore, rat studies have shown that hyperuricemia-induced hypertension and vascular disease is at least partially reversed by the supplementation of the nitric oxide synthase (NOS) substrate, L-arginine. Therefore, we hypothesized that uric acid induces endothelial dysfunction by inhibiting nitric oxide production. METHODS: Hyperuricemia was induced in male Sprague-Dawley rats with an uricase inhibitor, oxonic acid, by gavage; control rats received vehicle. Allopurinol was placed in drinking water to block hyperuricemia. Rats were randomly divided into four groups: (1) control, (2) allopurinol only, (3) oxonic acid only, and (4) oxonic acid + allopurinol. Rats were sacrificed at 1 and 7 days, and their serum analyzed for serum uric acid and nitrites/nitrates concentrations. The effect of uric acid on nitric oxide production was also determined in bovine aortic endothelial cells. RESULTS: Oxonic acid induced mild hyperuricemia at both 1 and 7 days (P < 0.05). Allopurinol reversed the hyperuricemia at 7 days (P < .001). Serum nitrites and nitrates (NO(X)) were reduced in hyperuricemic rats at both 1 and 7 days (P < .001). Allopurinol slightly reversed the decrease in NO(X) at 1 day and completely at 7 days (P < .001). There was a direct linear correlation between serum uric acid and NO(X) (R(2)= 0.56) and a trend toward higher systolic blood pressure in hyperuricemic rats (P= NS). Uric acid was also found to inhibit both basal and vascular endothelial growth factor (VEGF)-induced nitric oxide production in bovine aortic endothelial cells. CONCLUSION: Hyperuricemic rats have a decrease in serum nitric oxide which is reversed by lowering uric acid levels. Soluble uric acid also impairs nitric oxide generation in cultured endothelial cells. Thus, hyperuricemia induces endothelial dysfunction; this may provide insight into a pathogenic mechanism by which uric acid may induce hypertension and vascular disease.
Authors:
Uday M Khosla; Sergey Zharikov; Jennifer L Finch; Takahiko Nakagawa; Carlos Roncal; Wei Mu; Karina Krotova; Edward R Block; Sharma Prabhakar; Richard J Johnson
Publication Detail:
Type:  In Vitro; Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Kidney international     Volume:  67     ISSN:  0085-2538     ISO Abbreviation:  Kidney Int.     Publication Date:  2005 May 
Date Detail:
Created Date:  2005-04-20     Completed Date:  2005-08-22     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0323470     Medline TA:  Kidney Int     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1739-42     Citation Subset:  IM    
Affiliation:
Baylor College of Medicine, Department of Medicine, Division of Nephrology, Houston, Texas 77030, USA. ukhosla@tmh.tmc.edu
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MeSH Terms
Descriptor/Qualifier:
Animals
Cattle
Cells, Cultured
Endothelium, Vascular / physiopathology*
Humans
Hyperuricemia / physiopathology*
Male
Nitric Oxide / biosynthesis
Rats
Rats, Sprague-Dawley
Grant Support
ID/Acronym/Agency:
DK-52121/DK/NIDDK NIH HHS; DK-64233/DK/NIDDK NIH HHS; HL-68607/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
10102-43-9/Nitric Oxide
Comments/Corrections
Comment In:
Kidney Int. 2006 May;69(9):1704   [PMID:  16652166 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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