High-fat diet-induced reduction in nitric oxide-dependent arteriolar dilation in rats: role of xanthine oxidase-derived superoxide anion
High-fat diet-induced reduction in nitric oxide-dependent arteriolar dilation in rats: role of xanthine oxidase-derived superoxide anion
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DOI：
10.1152/ajpheart.00389.2006
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发表时间：
2006-11-01
影响因子：
4.8
通讯作者：
Bagi, Zsolt
中科院分区：
文献类型：
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作者：
Erdei, Nora;Toth, Attila;Bagi, Zsolt
肥胖经常导致高血压的发展。我们假设高脂肪饮食（HFD）诱导的肥胖损害了内皮依赖性的小动脉扩张。雄性Wistar大鼠喂食正常（对照）或HFD（60%饱和脂肪，10周）。在HFD大鼠中，体重、平均动脉血压、血清胰岛素、胆固醇和葡萄糖升高。大鼠对乙酰胆碱（1 μ m，最大83 +/- 3%）和组胺（10 μ m，最大16 +/- 4%）的扩张与对照反应（最大90 +/- 2%和46 +/- 4%）相比显著降低（P < 0.05）。两组一氧化氮供体硝普钠的扩张相似。n -omega-硝基- l -精氨酸甲酯对NO合成的抑制作用可减少疼痛和组胺诱导的对照小动脉扩张，但对HFD大鼠微血管无影响。模拟超氧化物歧化酶的铁或黄嘌呤氧化酶抑制剂别嘌呤醇对乙酰氨基ACh（最大值分别为90 +/- 2%和93 +/- 2%）和组胺（最大值分别为30 +/- 7%和37 +/- 8%）诱导的HFD小动脉扩张有增强作用，而NAD(P)H氧化酶抑制剂罗布麻碱对HFD小动脉扩张无显著影响。相应地，在HFD大鼠的颈动脉中，通过荧光素增强的化学发光表明，超氧化物的产生增加，与黄嘌呤氧化酶的增加有关，但与NAD(P)H氧化酶活性无关。此外，在HFD大鼠股薄动脉内皮层检测到明显的黄嘌呤氧化酶免疫染色，而在对照组则没有。这些发现表明，在肥胖大鼠中，由于黄嘌呤氧化酶衍生的超氧化物产生增强，NO介导的骨骼肌小动脉内皮依赖性扩张减少。这些改变表明，在hfd诱导的肥胖中，内皮细胞对小动脉张力的调节出现了实质性的失调，这可能导致组织血流量紊乱和外周抵抗的增加。
Obesity frequently leads to the development of hypertension. We hypothesized that high-fat diet (HFD)-induced obesity impairs the endothelium-dependent dilation of arterioles. Male Wistar rats were fed with normal (control) or HFD (60% of saturated fat, for 10 wk). In rats with HFD, body weight, mean arterial blood pressure, and serum insulin, cholesterol, and glucose were elevated. In isolated gracilis muscle arterioles (diameter: similar to 160 mu m) of HFD, rat dilations to ACh (at 1 mu M, maximum: 83 +/- 3%) and histamine (at 10 mu M, maximum: 16 +/- 4%) were significantly (P < 0.05) decreased compared with those of control responses (maximum: 90 +/- 2 and 46 +/- 4%, respectively). Dilations to the NO donor sodium nitroprusside were similar in the two groups. Inhibition of NO synthesis by N-omega-nitro-L-arginine methyl ester reduced ACh-and histamine-induced dilations in control arterioles but had no effect on microvessels of HFD rats. The superoxide dismutase mimetic Tiron or xanthine oxidase inhibitor allopurinol enhanced ACh (maximum: 90 +/- 2 and 93 +/- 2%, respectively) and histamine (maximum: 30 +/- 7 and 37 +/- 8%, respectively)-induced dilations in HFD arterioles, whereas the NAD(P)H oxidase inhibitor apocynin had no significant effect. Correspondingly, in carotid arteries of HFD rats, an enhanced superoxide production was shown by lucigenin- enhanced chemiluminescence, in association with an increased xanthine oxidase, but not NAD(P)H oxidase activity. In addition, a marked xanthine oxidase immunostaining was detected in the endothelial layer of the gracilis arterioles of HFD, but not in control rats. These findings suggest that, in obese rats, NO mediation of endothelium-dependent dilation of skeletal muscle arterioles is reduced because of an enhanced xanthine oxidase-derived superoxide production. These alterations demonstrate substantial dysregulation of arteriolar tone by the endothelium in HFD-induced obesity, which may contribute to disturbed tissue blood flow and development of increased peripheral resistance.