Department of Physiology, Georgia Health Sciences University, Augusta, Georgia, United States of America.
PLoS One. 2013;8(2):e56046. doi: 10.1371/journal.pone.0056046. Epub 2013 Feb 5.
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.
黄嘌呤氧化酶及其产物尿酸和 ROS 已被认为与心血管疾病（如高血压）的发病机制有关。我们之前曾报道过，别嘌醇抑制 XO 不会改变去氧皮质酮醋酸盐（DOCA-盐）高血压大鼠的进展。然而，其他研究人员在同一模型中观察到别嘌醇治疗后血压降低。为了解决这一争议，在本研究中，我们使用了更新、更有效的 XO 抑制剂非布司他，并假设更完全的 XO 阻断可能会损害高血压的发展及其终末器官的后果。我们使用 DOCA-盐性高血压大鼠，并在短期“逆转”实验（DOCA-盐开始后 2 周治疗）和长期“预防”实验（4 周 DOCA-盐治疗期间）中给予载体（盐水）或非布司他（口服，5mg/kg/天在盐水中）。我们通过测量循环和组织中 XO 代谢物的水平来证实非布司他对 XO 的抑制作用。我们发现，非布司他治疗后，黄嘌呤（XO 底物）总体水平升高，尿酸（XO 产物）水平降低。然而，尽管长期非布司他治疗的最后一周血压有下降趋势，但在两项研究中均未观察到血流动力学参数的统计学差异。此外，心脏和肾脏的相对重量没有变化。主动脉中层/腔比在长期非布司他治疗后略有改善。此外，非布司他在体外孵育不会改变去甲肾上腺素、血管紧张素 II 或内皮素-1对主动脉或腔静脉的收缩作用。我们的结论是，XO 抑制不足以减轻 DOCA-盐大鼠模型中的高血压，尽管可能存在有益的血管作用。
