Xanthine oxidase and its products,
uric acid and ROS, have been implicated in the pathogenesis of
cardiovascular disease, such as
hypertension. We have previously reported that
allopurinol inhibition of XO does not alter the progression of
deoxycorticosterone acetate (
DOCA)-
salt hypertension in rats. However other researchers have observed a reduction in blood pressure after
allopurinol treatment in the same model. To resolve this controversy, in this study we used the newer and more effective XO inhibitor
febuxostat, and hypothesized that a more complete XO blockade might impair
hypertension development and its end-organ consequences. We used
DOCA-
salt hypertensive rats and administered vehicle (
salt water) or
febuxostat (orally, 5 mg/kg/day in
salt water) in a short-term "reversal" experiment (2 weeks of treatment 3 weeks after
DOCA-
salt beginning) and a long-term "prevention" experiment (treatment throughout 4 weeks of
DOCA-
salt). We confirmed XO inhibition by
febuxostat by measuring circulating and tissue levels of XO metabolites. We found an overall increase in
hypoxanthine (XO substrate) and decrease in
uric acid (XO product) levels following
febuxostat treatment. However, despite a trend for reduced blood pressure in the last week of long-term
febuxostat treatment, no statistically significant difference in hemodynamic parameters was observed in either study. Additionally, no change was observed in relative heart and kidney weight. Aortic media/lumen ratio was minimally improved by long-term
febuxostat treatment. Additionally,
febuxostat incubation in vitro did not modify contraction of aorta or vena cava to
norepinephrine,
angiotensin II or
endothelin-1. We conclude that XO inhibition is insufficient to attenuate
hypertension in the rat
DOCA-
salt model, although beneficial vascular effects are possible.