Pharmacy Practice Division, School of Pharmacy, University of Wisconsin, Madison 53705, USA.
Respiration. 2011;82(5):458-67. doi: 10.1159/000329341. Epub 2011 Aug 12.
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.
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.
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).
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).
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.
黄嘌呤氧化酶是血管内皮中超氧阴离子的主要来源。先前在阻塞性睡眠呼吸暂停患者中的研究表明，黄嘌呤氧化酶抑制剂可改善其主要大血管的功能。
通过给予黄嘌呤氧化酶抑制剂别嘌呤醇，确定慢性间歇性低氧暴露引起的内皮依赖性血管舒张功能障碍是否可被体内治疗所预防。
Sprague-Dawley 大鼠经口灌胃给予别嘌呤醇（65mg/kg/天）或载体。每组的一半暴露于间歇性低氧（FIO2=0.10 持续 1 分钟，15 次/小时，每天 12 小时），另一半暴露于常氧。14 天后，分离比目鱼肌动脉，用微管插管，并用生理盐溶液灌流和超灌。在暴露于乙酰胆碱（10(-6)M）和硝普钠（10(-4)M）前后测量直径。
在载体处理的大鼠中，与常氧相比，间歇性低氧可损害乙酰胆碱诱导的血管舒张（+4±4μm 对+21±6μm，p=0.01）。别嘌呤醇可减弱这种损害（间歇性低氧和常氧组用别嘌呤醇处理后分别为+26±6μm 和+34±9μm，p=0.55）。相反，硝普钠诱导的血管舒张在所有大鼠中相似（p=0.43）。别嘌呤醇和间歇性低氧均不影响血管形态计量或全身氧化应激标志物。与载体处理的大鼠相比，别嘌呤醇处理的大鼠的尿尿酸浓度降低（p=0.02）。
这些数据证实了先前的发现，即间歇性低氧暴露可损害骨骼肌阻力动脉中的内皮依赖性血管舒张，并通过证明这种损害可被别嘌呤醇预防而扩展了这些发现。因此，黄嘌呤氧化酶似乎在介导间歇性低氧诱导的血管功能障碍中发挥关键作用。
