Gilligan D M, Guetta V, Panza J A, García C E, Quyyumi A A, Cannon R O
Cardiology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md 20892.
Circulation. 1994 Jul;90(1):35-41. doi: 10.1161/01.cir.90.1.35.
Endothelial dysfunction is increasingly recognized as an early and important feature of vascular disease. Endothelium-dependent vasodilation is impaired in humans with hypercholesterolemia, although it is unknown whether this defect is selective for some pathways of nitric oxide production or indicates a more generalized abnormality of endothelial function. The aim of this study was to further elucidate the nature of endothelial dysfunction in human hypercholesterolemia by comparing vascular responses of agonists that use different signal transduction pathways to activate production of nitric oxide.
Forearm flow was measured in 12 hypercholesterolemic patients (total cholesterol, 286 +/- 35 mg/dL [mean +/- SD]) aged 50 +/- 11 years and in 12 healthy subjects (total cholesterol, 173 +/- 27 mg/dL) aged 48 +/- 7 years using strain-gauge plethysmography and brachial artery drug infusions. The endothelium-dependent vasodilators used were acetylcholine (7.5, 15, and 30 micrograms/min), which uses a pertussis toxin-sensitive signal transduction pathway, and bradykinin (100, 200, and 400 ng/min), which uses a pertussis toxin-insensitive signal transduction pathway to activate nitric oxide production. Sodium nitroprusside (0.8, 1.6, and 3.2 micrograms/min) was used to test endothelium-independent vasodilation. The maximum flow in response to acetylcholine was markedly impaired in patients compared with healthy subjects (8.0 +/- 5.1 versus 17.5 +/- 7.7 mL.min-1. 100 mL-1, P = .002). However, the maximum forearm flow in response to bradykinin was similar in the two groups (13.0 +/- 4.5 versus 16.2 +/- 5.5 mL.min-1 x 100 mL-, P = .14), as was the maximum flow in response to sodium nitroprusside (7.0 +/- 2.8 versus 8.4 +/- 2.2 mL.min-1 x 100 mL-1, P = .13). NG-Monomethyl-L-arginine, an inhibitor of nitric oxide synthesis, reduced the maximum forearm vasodilation induced by bradykinin to the same extent in patients and in healthy subjects (-29 +/- 8% versus -32 +/- 6% reduction in peak flow, P = .80), with similar maximum flows in response to bradykinin (9.2 +/- 4.0 versus 10.4 +/- 2.6 mL.min-1 x 100 mL-1, P = .35).
Hypercholesterolemic patients are capable of normal nitric oxide bioavailability in response to bradykinin. Impairment of microvascular endothelial vasodilator function in human hypercholesterolemia is selective, and the defect occurs at the level of the acetylcholine receptor or its signal transduction pathway.
内皮功能障碍日益被认为是血管疾病的早期重要特征。高胆固醇血症患者的内皮依赖性血管舒张功能受损，尽管尚不清楚这种缺陷是对某些一氧化氮产生途径具有选择性，还是表明内皮功能存在更普遍的异常。本研究的目的是通过比较使用不同信号转导途径激活一氧化氮产生的激动剂的血管反应，进一步阐明人类高胆固醇血症中内皮功能障碍的本质。
使用应变片体积描记法和肱动脉药物输注，测量了12名年龄50±11岁的高胆固醇血症患者（总胆固醇，286±35mg/dL[平均值±标准差]）和12名年龄48±7岁的健康受试者（总胆固醇，173±27mg/dL）的前臂血流量。所使用的内皮依赖性血管舒张剂为乙酰胆碱（7.5、15和30μg/min），其使用百日咳毒素敏感的信号转导途径，以及缓激肽（100、200和400ng/min），其使用百日咳毒素不敏感的信号转导途径来激活一氧化氮产生。硝普钠（0.8、1.6和3.2μg/min）用于测试非内皮依赖性血管舒张。与健康受试者相比，患者对乙酰胆碱的最大血流量明显受损（8.０±5.1对17.5±7.7mL·min-1·100mL-1，P = 0.002）。然而，两组对缓激肽的最大前臂血流量相似（13.0±4.5对16.2±5.5mL·min-1×100mL-，P = 0.14），对硝普钠的最大血流量也相似（7.0±2.8对8.4±2.2mL·min-1×100mL-1，P = 0.13）。一氧化氮合成抑制剂NG-单甲基-L-精氨酸在患者和健康受试者中使缓激肽诱导的最大前臂血管舒张降低到相同程度（峰值血流量降低-29±8%对-32±6%，P = 0.80），对缓激肽的最大血流量相似（9.2±4.0对10.4±2.6mL·min-1×100mL-1，P = 0.35）。
高胆固醇血症患者对缓激肽有正常的一氧化氮生物利用度。人类高胆固醇血症中微血管内皮血管舒张功能障碍具有选择性，缺陷发生在乙酰胆碱受体或其信号转导途径水平。
