Xanthine oxidase inhibition attenuates endothelial dysfunction caused by chronic intermittent hypoxia in rats.

BACKGROUND: Xanthine oxidase is a major source of superoxide in the vascular endothelium. Previous work in humans demonstrated improved conduit artery function following xanthine oxidase inhibition in patients with obstructive sleep apnea.
OBJECTIVES: To determine whether impairments in endothelium-dependent vasodilation produced by exposure to chronic intermittent hypoxia are prevented by in vivo treatment with allopurinol, a xanthine oxidase inhibitor.
METHODS: Sprague-Dawley rats received allopurinol (65 mg/kg/day) or vehicle via oral gavage. Half of each group was exposed to intermittent hypoxia (FIO(2) = 0.10 for 1 min, 15×/h, 12 h/day) and the other half to normoxia. After 14 days, gracilis arteries were isolated, cannulated with micropipettes, and perfused and superfused with physiological salt solution. Diameters were measured before and after exposure to acetylcholine (10(-6)M) and nitroprusside (10(-4)M).
RESULTS: In vehicle-treated rats, intermittent hypoxia impaired acetylcholine-induced vasodilation compared to normoxia (+4 ± 4 vs. +21 ± 6 μm, p = 0.01). Allopurinol attenuated this impairment (+26 ± 6 vs. +34 ± 9 μm for intermittent hypoxia and normoxia groups treated with allopurinol, p = 0.55). In contrast, nitroprusside-induced vasodilation was similar in all rats (p = 0.43). Neither allopurinol nor intermittent hypoxia affected vessel morphometry or systemic markers of oxidative stress. Urinary uric acid concentrations were reduced in allopurinol- versus vehicle-treated rats (p = 0.02).
CONCLUSIONS: These data confirm previous findings that exposure to intermittent hypoxia impairs endothelium-dependent vasodilation in skeletal muscle resistance arteries and extend them by demonstrating that this impairment can be prevented with allopurinol. Thus, xanthine oxidase appears to play a key role in mediating intermittent hypoxia-induced vascular dysfunction.