Abstract
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.
Highlights
Xanthine oxidase (XO) is a ubiquitous enzyme essential in the last steps of purine catabolism, the end-product of which, uric acid, has been independently associated with risk for cardiovascular and kidney disease [1,2]
No statistically significant difference was observed in Mean Arterial Pressure (MAP) (Fig. 1A), heart rate (Fig. 1B), systolic or diastolic pressures between the control and febuxostat-treated groups
We have shown in this study that efficient inhibition of xanthine oxidase activity and decreases in tissue and circulating levels of uric acid by febuxostat (5 mg/kg/day) do not lower blood pressure in established hypertension or attenuate hypertension development in the rat deoxycorticosterone acetate (DOCA)-salt model
Summary
Xanthine oxidase (XO) is a ubiquitous enzyme essential in the last steps of purine catabolism, the end-product of which, uric acid, has been independently associated with risk for cardiovascular and kidney disease [1,2]. Increased ROS levels are a well known pathogenetic factor in hypertension, be it experimentally induced in animals or essential/secondary hypertension in humans [3]. Excessive amounts of ROS in tissues can cause injury, and studies aimed at understanding hypertension-related tissue damage have shown increases in XO expression or activity in animal models of hypertension such as DOCA-salt and the spontaneously hypertensive rat [4,5,6]. Hyperuricemia is associated with endothelial dysfunction in humans [10] and experimentally increasing uric acid levels has lead to hypertension and renal damage in rats [11,12]
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