Hyperuricemia induces endothelial dysfunction.

Uday M Khosla; Sergey Zharikov; Jennifer L Finch; Takahiko Nakagawa; Carlos Roncal; Wei Mu; Karina Krotova; Edward R Block; Sharma Prabhakar; Richard J Johnson

doi:10.1111/j.1523-1755.2005.00273.x

PubMed · 15840020

Hyperuricemia induces endothelial dysfunction.

Uday M Khosla·Sergey Zharikov·Jennifer L Finch·Takahiko Nakagawa·Carlos Roncal·Wei Mu·Karina Krotova·Edward R Block·Sharma Prabhakar·Richard J Johnson

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Abstract

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.

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Animals Cattle Cells, Cultured Endothelium, Vascular Humans Hyperuricemia In Vitro Techniques Male Nitric Oxide Rats Rats, Sprague-Dawley Journal Article Research Support, N.I.H., Extramural Research Support, U.S. Gov't, P.H.S.

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Uday M Khosla, Sergey Zharikov, Jennifer L Finch, Takahiko Nakagawa, Carlos Roncal, Wei Mu, Karina Krotova, Edward R Block, Sharma Prabhakar, Richard J Johnson. 2005. Hyperuricemia induces endothelial dysfunction.. https://doi.org/10.1111/j.1523-1755.2005.00273.x

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