Role of oxidant stress in endothelial dysfunction produced by experimental hyperhomocyst(e)inemia in humans
Role of oxidant stress in endothelial dysfunction produced by experimental hyperhomocyst(e)inemia in humans
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DOI：
10.1161/01.cir.100.11.1161
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发表时间：
1999-09-14
期刊：
影响因子：
37.8
通讯作者：
Haynes, WG
中科院分区：
文献类型：
--
作者：
Kanani, PM;Sinkey, CA;Haynes, WG
背景-血浆同型半胱氨酸浓度的适度升高与动脉粥样硬化和高血压有关。我们验证了实验中同型半胱氨酸水平的扰动会产生抵抗和管道血管内皮细胞功能障碍的假说，这是通过增加氧化应激而发生的。方法和结果-口服L蛋氨酸(100 mg/kg)在健康受试者中诱导中度高同型(E)血症(约25mU/L)。血管内皮依赖性扩张剂乙酰胆碱对前臂阻力血管的内皮功能评价采用前臂血管扩张法，管道血管内皮功能的评价采用血流介导的臂动脉扩张法。对乙酰胆碱的前臂阻力血管扩张在蛋氨酸作用7h后显著减弱(蛋氨酸，477+/-82%；安慰剂，673+/-10%；P=0.016)，蛋氨酸不改变对硝普钠和维拉帕米的血管扩张。与安慰剂(8.2+/-1.6%，P=0.01)相比，蛋氨酸负荷后8小时血流介导的血管扩张功能显著减弱(0.3+/-2.7%，P=0.01)，口服抗坏血酸(2g)可预防蛋氨酸引起的管道和阻力血管内皮功能障碍(P=0.03)。结论：通过蛋氨酸负荷增加血浆同型半胱氨酸(E)浓度可迅速损害健康人管道和阻力血管的内皮功能。管道和阻力血管的内皮功能障碍可能是已报道的同型半胱氨酸与动脉粥样硬化和高血压之间的联系的基础。氧化应激增加似乎在同型半胱氨酸的有害内皮效应中发挥了病理生理作用。
Background-Moderate elevations in plasma homocyst(e)ine concentrations are associated with atherosclerosis and hypertension. We tested the hypothesis that experimental perturbation of homocysteine levels produces resistance and conduit vessel endothelial dysfunction and that this occurs through increased oxidant stress.Methods and Results-Oral administration of L-methionine (100 mg/kg) was used to induce moderate hyperhomocyst(e)inemia (approximate to 25 mu mol/L) in healthy human subjects. Endothelial function of forearm resistance vessels was assessed by use of forearm vasodilatation to brachial artery administration of the endothelium-dependent dilator acetylcholine, Conduit vessel endothelial function was assessed with flow-mediated dilatation of the brachial artery. Forearm resistance vessel dilatation to acetylcholine was significantly impaired 7 hours after methionine (methionine,477 +/- 82%; placebo, 673 +/- I 10%; P=0.016), Methionine did not alter vasodilatation to nitroprusside and verapamil. Flow-mediated dilatation was significantly impaired 8 hours after methionine loading (0.3 +/- 2.7%) compared with placebo (8.2 +/-1.6%, P=0.01), Oral administration of the antioxidant ascorbic acid (2 g) prevented methionine-induced endothelial dysfunction in both conduit and resistance vessels (P=0.03).Conclusion-Experimentally increasing plasma homocyst(e)ine concentrations by methionine loading rapidly impairs both conduit and resistance vessel endothelial function in healthy humans. Endothelial dysfunction in conduit and resistance vessels may underlie the reported associations between homocysteine and atherosclerosis and hypertension. increased oxidant stress appears to play a pathophysiological role in the deleterious endothelial effects of homocysteine.