Treatment with the xanthine oxidase inhibitor febuxostat lowers uric acid and alleviates systemic and glomerular hypertension in experimental hyperuricaemia.
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.


CONCLUSIONS
These results suggest that Fx merits further evaluation for the treatment of hypertension and renal alterations induced by hyperuricaemia.
Department of Nephrology, Instituto Nacional de Cardiologiá Ignacio Chavez, Juan Badiano 1, 14080-Mexico City, Mexico. lgsanchezlozada@hotmail.com
Laura G
LG
Sánchez-Lozada
Edilia
E
Tapia
Virgilia
V
Soto
Carmen
C
Avila-Casado
Martha
M
Franco
Lin
L
Zhao
Richard J
RJ
Johnson
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D000069465:Febuxostat; D005500:Follow-Up Studies; D006074:Gout Suppressants / Q000627:therapeutic use*; D006977:Hypertension, Renal / Q000097:blood / Q000188:drug therapy* / Q000209:etiology; D033461:Hyperuricemia / Q000097:blood / Q000139:chemically induced / Q000150:complications*; D007678:Kidney Glomerulus / Q000473:pathology; D008297:Male; D010094:Oxonic Acid / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation / Q000187:drug effects; D013844:Thiazoles / Q000627:therapeutic use*; D014527:Uric Acid; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors*
D006074:Gout Suppressants; D013844:Thiazoles; D000069465:Febuxostat; D014527:Uric Acid; D010094:Oxonic Acid; D014969:Xanthine Oxidase