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Febuxostat inhibition of xanthine oxidase does not impact blood pressure in the established DOCA‐salt hypertension
Author(s) -
Szasz Theodora,
Davis Robert Patrick,
Garver Hannah S,
Burnett Robert J,
Fink Gregory D,
Watts Stephanie W
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.872.33
Subject(s) - febuxostat , medicine , xanthine oxidase , blood pressure , endocrinology , uric acid , hypoxanthine , xanthine oxidase inhibitor , kidney , pharmacology , chemistry , hyperuricemia , enzyme , biochemistry
Xanthine oxidase (XO) has been implicated in cardiovascular disease such as hypertension. We have previously shown that allopurinol inhibition of XO does not attenuate hypertension in the rat DOCA‐salt model. However, this treatment raised questions of efficacy and specificity. We now hypothesized that febuxostat (FBX), a newer and more specific XO inhibitor, would decrease blood pressure (BP) of DOCA‐salt hypertensive rats through a vascular mechanism. FBX (5 mg/kg/day) or vehicle was administered orally for 2 weeks to male DOCA rats after 3 weeks of DOCA‐salt treatment. BP was measured via radiotelemetry. XO inhibition was assessed by HPLC measurement of XO product UA and substrates hypoxanthine and xanthine in serum, urine and tissues. End‐organ damage was grossly evaluated by measuring heart and kidney weight, as well as aorta wall/lumen ratio. FBX administration resulted in significantly reduced product and increased substrate levels in serum and tissues (serum UA ug/mg protein: vehicle=3.43±0.68, FBX=0.63±0.13). However, this treatment did not alter BP of DOCA rats or improve end‐organ damage. Additionally, contractile responses to norepinephrine, endothelin‐1 and angiotensin II of aorta and vena cava were unmodified by FBX incubation. We conclude that XO inhibition does not impact established hypertension in the DOCA‐salt rat model. Support provided by Takeda Pharmaceuticals North America, Inc.