Kanani P M, Sinkey C A, Browning R L, Allaman M, Knapp H R, Haynes W G
Departments of Pediatrics, University of Iowa College of Medicine, Iowa City, Iowa 52242, USA.
Circulation. 1999 Sep 14;100(11):1161-8. doi: 10.1161/01.cir.100.11.1161.
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.
Oral administration of L-methionine (100 mg/kg) was used to induce moderate hyperhomocyst(e)inemia ( approximately 25 micromol/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+/-110%; 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).
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.
血浆同型半胱氨酸浓度适度升高与动脉粥样硬化和高血压相关。我们检验了这样一个假设，即同型半胱氨酸水平的实验性扰动会导致阻力血管和传导血管内皮功能障碍，且这是通过增加氧化应激而发生的。
口服L-蛋氨酸（100mg/kg）用于在健康人类受试者中诱导中度高同型半胱氨酸血症（约25μmol/L）。通过测量前臂血管对肱动脉给予内皮依赖性舒张剂乙酰胆碱后的舒张反应来评估前臂阻力血管的内皮功能。通过肱动脉的血流介导的舒张来评估传导血管的内皮功能。给予蛋氨酸7小时后，前臂阻力血管对乙酰胆碱的舒张反应显著受损（蛋氨酸组，477±82%；安慰剂组，673±110%；P=0.016）。蛋氨酸未改变对硝普钠和维拉帕米的血管舒张反应。与安慰剂组（8.2±1.6%）相比，给予蛋氨酸负荷8小时后血流介导的舒张显著受损（0.3±2.7%，P=0.01）。口服抗氧化剂抗坏血酸（2g）可预防蛋氨酸诱导的传导血管和阻力血管内皮功能障碍（P=0.03）。
通过蛋氨酸负荷实验性增加血浆同型半胱氨酸浓度会迅速损害健康人的传导血管和阻力血管内皮功能。传导血管和阻力血管的内皮功能障碍可能是同型半胱氨酸与动脉粥样硬化和高血压之间已报道关联的基础。氧化应激增加似乎在同型半胱氨酸对内皮的有害作用中起病理生理作用。
