Febuxostat, a novel xanthine oxidoreductase inhibitor, improves hypertension and endothelial dysfunction in spontaneously hypertensive rats
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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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The involvement of l-arginine in different metabolic pathways makes the use of l-arginine levels as a biomarker a poor indicator of outcomes.
“It seems that the involvement of l-arginine in different metabolic pathways makes the use of l-arginine levels as a biomarker a poor indicator of outcomes (668, 857, 1029).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [857]
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- Authors
- Shirakura, T., Nomura, J., Matsui, C., Kobayashi, T., Tamura, M., & Masuzaki, H.
- Affiliations
- Teijin Pharma Limited (Japan) (JP)
- University of the Ryukyus (JP)
- Corresponding author
- Shirakura, Takashi
- Venue
- Naunyn-Schmiedeberg's Archives of Pharmacology
- Published
- 2016-05-20
- Volume
- 389
- Issue
- 8
- Pages
- 831-838
- ISSN
- 0028-1298 (ISSN-L)
- 1432-1912
- PMC
- PMC4939152
- OpenAlex
- W2400185022
- Cited by
- 36
- References
- 62
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 2 · 2023: 2 · 2022: 4 · 2021: 5 · 2020: 5 · 2019: 2 · 2018: 5 · 2017: 4 · 2016: 2
- FWCI
- 4.35
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Naunyn-Schmiedeberg s Archives of Pharmacology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Teijin pharma limited
- Topics
- Health Sciences › Medicine › Nephrology › Gout, Hyperuricemia, Uric Acid
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Eicosanoids and Hypertension Pharmacology
- Keywords
- febuxostat, xanthine oxidase inhibition, hypertension, endothelial dysfunction, oxidative stress, nitrotyrosine, spontaneously hypertensive rats, uric acid, acetylcholine-induced relaxation, vascular dysfunction, hyperuricemia
- MeSH terms
- Febuxostat, Animals, Antihypertensive Agents, Blood Pressure, Disease Models, Animal, Endothelium, Vascular, Enzyme Inhibitors, Hypertension, Male, Rats, Inbred SHR, Rats, Inbred WKY, Time Factors, Tyrosine, Vasodilation, Vasodilator Agents, Xanthine Oxidase, Biomarkers, Oxidative Stress
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