NDT Advance Access originally published online on November 29, 2007
Nephrology Dialysis Transplantation 2008 23(4):1179-1185; doi:10.1093/ndt/gfm783
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Treatment with the xanthine oxidase inhibitor febuxostat lowers uric acid and alleviates systemic and glomerular hypertension in experimental hyperuricaemia
1 Department of Nephrology 2 Department of Pathology, Instituto Nacional de Cardiologiá Ignacio Chávez, Mexico City, Mexico 3 TAP Pharmaceutical Products Inc., Lake Forest, IL, USA 4 Department of Nephrology, Hypertension and Transplantation, University of Florida, Gainesville, FL, USA
Laura G. Sánchez-Lozada, Department of Nephrology, Instituto Nacional de Cardiologiá Ignacio Chavez, Juan Badiano 1, 14080-Mexico City, Mexico. Tel: +52-5555736902; Fax: +52-5555737716; E-mail: lgsanchezlozada{at}hotmail.com
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Abstract |
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Background. Experimentally-induced hyperuricaemia [due to inhibition of uricase with oxonic acid (OA)] in rats causes hypertension and renal alterations which can be prevented by lowering uric acid (UA) with allopurinol. Febuxostat (Fx), an investigational, nonpurine and selective xanthine oxidase inhibitor, is a more effective UA-lowering agent than allopurinol. We therefore tested the hypothesis that Fx might be useful in treating hyperuricemia-induced hypertension and renal damage.
Methods. Four groups of male rats were studied: OA (750 mg/kg by daily gavage) was given for 8 weeks and Fx (5–6 mg/kg/day in drinking water; OA+Fx: n = 10) or placebo (OA+P: n = 11) were administered for 4 weeks beginning at 4 weeks after initiation of the study. Two groups of normal (N) rats were studied as controls (N+P and N+Fx: n = 10/group). Systolic blood pressure (SBP) and fasting plasma UA were measured in all animals at baseline and at 4 and 8 weeks. Glomerular haemodynamics by micropuncture techniques were determined at 8 weeks followed by histological evaluation of glomerular and afferent arteriole morphologies.
Results. In OA-induced hyperuricaemic rats, Fx lowered UA and ameliorated systemic and glomerular hypertension as well as mesangial matrix expansion and the development of preglomerular arteriolar disease as indicated by a reduction of the arteriolar area and media-to-lumen ratio. In normal rats, Fx tended to lower UA and had no effect on blood pressure, renal hemodynamics and afferent arteriole morphology.
Conclusion. These results suggest that Fx merits further evaluation for the treatment of hypertension and renal alterations induced by hyperuricaemia.
Keywords: febuxostat; glomerular hypertension; hyperuricaemia; systemic hypertension; xanthine oxidase
Received for publication: 2. 5.07
Accepted in revised form: 8.10.07