title: Febuxostat, a novel xanthine oxidoreductase inhibitor, improves hypertension and endothelial dysfunction in spontaneously hypertensive rats.
abstract: 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.
authors.affiliation: Pharmaceutical Development Research Laboratories, Teijin Institute for Bio-Medical Research, Teijin Pharma Ltd., 4-3-2, Asahigaoka, Hino, 191-852, Tokyo, Japan. t.shirakura@teijin.co.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Shirakura
authors.affiliation: Pharmaceutical Development Research Laboratories, Teijin Institute for Bio-Medical Research, Teijin Pharma Ltd., 4-3-2, Asahigaoka, Hino, 191-852, Tokyo, Japan.
authors.forename: Johji
authors.initials: J
authors.lastname: Nomura
authors.affiliation: Pharmaceutical Development Research Laboratories, Teijin Institute for Bio-Medical Research, Teijin Pharma Ltd., 4-3-2, Asahigaoka, Hino, 191-852, Tokyo, Japan.
authors.forename: Chieko
authors.initials: C
authors.lastname: Matsui
authors.affiliation: Pharmaceutical Development Research Laboratories, Teijin Institute for Bio-Medical Research, Teijin Pharma Ltd., 4-3-2, Asahigaoka, Hino, 191-852, Tokyo, Japan.
authors.forename: Tsunefumi
authors.initials: T
authors.lastname: Kobayashi
authors.affiliation: Pharmaceutical Development Research Laboratories, Teijin Institute for Bio-Medical Research, Teijin Pharma Ltd., 4-3-2, Asahigaoka, Hino, 191-852, Tokyo, Japan.
authors.forename: Mizuho
authors.initials: M
authors.lastname: Tamura
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Hematology, Rheumatology (Second Department of Internal Medicine), Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Masuzaki
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D015415:Biomarkers / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D000069465:Febuxostat / Q000494:pharmacology*; D006973:Hypertension / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013997:Time Factors; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000959:Antihypertensive Agents; D015415:Biomarkers; D004791:Enzyme Inhibitors; D014665:Vasodilator Agents; D000069465:Febuxostat; C002744:3-nitrotyrosine; D014443:Tyrosine; D014969:Xanthine Oxidase
keywords: Endothelial dysfunction; Febuxostat; Hypertension; Xanthine oxidase