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Febuxostat, a novel xanthine oxidoreductase inhibitor, improves hypertension and endothelial dysfunction in spontaneously hypertensive rats

Xanthine oxidase (XO) is an enzyme responsible for the production of uric acid. XO produces considerable amount of oxidative stress throughout the body. To date, however, its pathophysiologic role in hypertension and endothelial dysfunction still remains controversial. To explore the possible involv...

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Autores principales: Shirakura, Takashi, Nomura, Johji, Matsui, Chieko, Kobayashi, Tsunefumi, Tamura, Mizuho, Masuzaki, Hiroaki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4939152/
https://www.ncbi.nlm.nih.gov/pubmed/27198514
http://dx.doi.org/10.1007/s00210-016-1239-1
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author Shirakura, Takashi
Nomura, Johji
Matsui, Chieko
Kobayashi, Tsunefumi
Tamura, Mizuho
Masuzaki, Hiroaki
author_facet Shirakura, Takashi
Nomura, Johji
Matsui, Chieko
Kobayashi, Tsunefumi
Tamura, Mizuho
Masuzaki, Hiroaki
author_sort Shirakura, Takashi
collection PubMed
description Xanthine oxidase (XO) is an enzyme responsible for the production of uric acid. XO produces considerable amount of oxidative stress throughout the body. To date, however, its pathophysiologic role in hypertension and endothelial dysfunction still remains controversial. To explore the possible involvement of XO-derived oxidative stress in the pathophysiology of vascular dysfunction, by use of a selective XO inhibitor, febuxostat, we investigated the impact of pharmacological inhibition of XO on hypertension and vascular endothelial dysfunction in spontaneously hypertensive rats (SHRs). Sixteen-week-old SHR and normotensive Wistar-Kyoto (WKY) rats were treated with tap water (control) or water containing febuxostat (3 mg/kg/day) for 6 weeks. Systolic blood pressure (SBP) in febuxostat-treated SHR (220 ± 3 mmHg) was significantly (P < 0.05) decreased compared with the control SHR (236 ± 4 mmHg) while SBP in febuxostat-treated WKY was constant. Acetylcholine-induced endothelium-dependent relaxation in aortas from febuxostat-treated SHR was significantly (P < 0.05) improved compared with the control SHR, whereas relaxation in response to sodium nitroprusside was not changed. Vascular XO activity and tissue nitrotyrosine level, a representative indicator of local oxidative stress, were considerably elevated in the control SHR compared with the control WKY, and this increment was abolished by febuxostat. Our results suggest that exaggerated XO activity and resultant increase in oxidative stress in this experimental model contribute to the hypertension and endothelial dysfunction, thereby supporting a notion that pharmacological inhibition of XO is valuable not only for hyperuricemia but also for treating hypertension and related endothelial dysfunction in human clinics.
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spelling pubmed-49391522016-07-21 Febuxostat, a novel xanthine oxidoreductase inhibitor, improves hypertension and endothelial dysfunction in spontaneously hypertensive rats Shirakura, Takashi Nomura, Johji Matsui, Chieko Kobayashi, Tsunefumi Tamura, Mizuho Masuzaki, Hiroaki Naunyn Schmiedebergs Arch Pharmacol Original Article Xanthine oxidase (XO) is an enzyme responsible for the production of uric acid. XO produces considerable amount of oxidative stress throughout the body. To date, however, its pathophysiologic role in hypertension and endothelial dysfunction still remains controversial. To explore the possible involvement of XO-derived oxidative stress in the pathophysiology of vascular dysfunction, by use of a selective XO inhibitor, febuxostat, we investigated the impact of pharmacological inhibition of XO on hypertension and vascular endothelial dysfunction in spontaneously hypertensive rats (SHRs). Sixteen-week-old SHR and normotensive Wistar-Kyoto (WKY) rats were treated with tap water (control) or water containing febuxostat (3 mg/kg/day) for 6 weeks. Systolic blood pressure (SBP) in febuxostat-treated SHR (220 ± 3 mmHg) was significantly (P < 0.05) decreased compared with the control SHR (236 ± 4 mmHg) while SBP in febuxostat-treated WKY was constant. Acetylcholine-induced endothelium-dependent relaxation in aortas from febuxostat-treated SHR was significantly (P < 0.05) improved compared with the control SHR, whereas relaxation in response to sodium nitroprusside was not changed. Vascular XO activity and tissue nitrotyrosine level, a representative indicator of local oxidative stress, were considerably elevated in the control SHR compared with the control WKY, and this increment was abolished by febuxostat. Our results suggest that exaggerated XO activity and resultant increase in oxidative stress in this experimental model contribute to the hypertension and endothelial dysfunction, thereby supporting a notion that pharmacological inhibition of XO is valuable not only for hyperuricemia but also for treating hypertension and related endothelial dysfunction in human clinics. Springer Berlin Heidelberg 2016-05-20 2016 /pmc/articles/PMC4939152/ /pubmed/27198514 http://dx.doi.org/10.1007/s00210-016-1239-1 Text en © The Author(s) 2016 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Original Article
Shirakura, Takashi
Nomura, Johji
Matsui, Chieko
Kobayashi, Tsunefumi
Tamura, Mizuho
Masuzaki, Hiroaki
Febuxostat, a novel xanthine oxidoreductase inhibitor, improves hypertension and endothelial dysfunction in spontaneously hypertensive rats
title Febuxostat, a novel xanthine oxidoreductase inhibitor, improves hypertension and endothelial dysfunction in spontaneously hypertensive rats
title_full Febuxostat, a novel xanthine oxidoreductase inhibitor, improves hypertension and endothelial dysfunction in spontaneously hypertensive rats
title_fullStr Febuxostat, a novel xanthine oxidoreductase inhibitor, improves hypertension and endothelial dysfunction in spontaneously hypertensive rats
title_full_unstemmed Febuxostat, a novel xanthine oxidoreductase inhibitor, improves hypertension and endothelial dysfunction in spontaneously hypertensive rats
title_short Febuxostat, a novel xanthine oxidoreductase inhibitor, improves hypertension and endothelial dysfunction in spontaneously hypertensive rats
title_sort febuxostat, a novel xanthine oxidoreductase inhibitor, improves hypertension and endothelial dysfunction in spontaneously hypertensive rats
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4939152/
https://www.ncbi.nlm.nih.gov/pubmed/27198514
http://dx.doi.org/10.1007/s00210-016-1239-1
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