Gilligan D M, Sack M N, Guetta V, Casino P R, Quyyumi A A, Rader D J, Panza J A, Cannon R O
Cardiology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892.
J Am Coll Cardiol. 1994 Dec;24(7):1611-7. doi: 10.1016/0735-1097(94)90164-3.
The aims of this study were to determine whether antioxidant vitamins could reduce the susceptibility of low density lipoprotein (LDL) to oxidation and improve endothelium-dependent vasodilator responsiveness in patients with hypercholesterolemia.
Animals and humans with hypercholesterolemia have exhibited impaired endothelium-dependent vasodilation. In vitro studies suggest that oxidatively modified LDL can impair nitric oxide production.
Forearm blood flow was measured with strain gauge plethysmography and brachial artery drug infusions in 19 patients, aged 52 +/- 9 years, with hypercholesterolemia (mean +/- SD total cholesterol 283 +/- 22 mg/dl, LDL 197 +/- 31 mg/dl) and in 14 subjects, aged 48 +/- 8 years, with normal cholesterol levels (total cholesterol 169 +/- 20 mg/dl, LDL 102 +/- 25 mg/dl). Acetylcholine (7.5, 15 and 30 micrograms/min) was utilized as an endothelium-dependent vasodilator, and sodium nitroprusside (0.8, 1.6 and 3.2 micrograms/min) was used to test endothelium-independent vasodilation. Oxidative susceptibility of LDL was measured by a spectrophotometric assay of conjugated diene production after the addition of copper chloride. Hypercholesterolemic patients then received daily antioxidant vitamin supplements (beta-carotene [30 mg], ascorbic acid [vitamin C] [1,000 mg], vitamin E [800 IU]) for 1 month, with repeat measurement of both forearm blood flow responsiveness to the same agonists and LDL oxidizability.
The maximal flow in response to acetylcholine was impaired in patients compared with that in normal subjects (9.8 +/- 7.8 vs. 15.9 +/- 8.1 ml/min per 100 ml, p = 0.03), with similar maximal flow responses to sodium nitroprusside (9.5 +/- 4.2 vs. 9.0 +/- 2.8 ml/min per 100 ml, p = 0.72). After 1 month of vitamin therapy, the onset of LDL oxidation was prolonged over baseline measurements by 71 +/- 67%, and the maximal rate of oxidation was decreased by 26 +/- 25% (both p < 0.001). However, the maximal forearm blood flow response to acetylcholine remained unchanged from baseline values (maximal flow after acetylcholine 9.0 +/- 6.2 vs. 9.8 +/- 7.8 ml/min per 100 ml, p = 0.57). This study had 80% power (alpha = 0.05) to exclude a 45% increase over baseline value in acetylcholine-stimulated flow during vitamin therapy.
Although 1 month of administration of antioxidant vitamin supplements in hypercholesterolemic patients reduced the susceptibility of LDL to oxidation, impairment in endothelial function remained unaltered. The use of nonvitamin antioxidants or concomitant reduction in LDL levels, as well as more sensitive techniques for measuring vascular responsiveness, may be required to show a beneficial effect on endothelial vasodilator function.
本研究旨在确定抗氧化维生素是否可降低高胆固醇血症患者低密度脂蛋白（LDL）的氧化易感性，并改善内皮依赖性血管舒张反应性。
高胆固醇血症的动物和人类表现出内皮依赖性血管舒张受损。体外研究表明，氧化修饰的LDL可损害一氧化氮的产生。
采用应变片体积描记法和肱动脉药物输注法测量19例年龄为52±9岁的高胆固醇血症患者（平均±标准差，总胆固醇283±22mg/dl，LDL 197±31mg/dl）和14例年龄为48±8岁、胆固醇水平正常（总胆固醇169±20mg/dl，LDL 102±25mg/dl）的受试者的前臂血流量。使用乙酰胆碱（7.5、15和30微克/分钟）作为内皮依赖性血管舒张剂，硝普钠（0.8、1.6和3.2微克/分钟）用于测试非内皮依赖性血管舒张。通过加入氯化铜后共轭二烯生成的分光光度法测定LDL的氧化易感性。高胆固醇血症患者随后每日接受抗氧化维生素补充剂（β-胡萝卜素[30mg]、抗坏血酸[维生素C][1000mg]、维生素E[800IU]），持续1个月，再次测量前臂对相同激动剂的血流量反应和LDL氧化能力。
与正常受试者相比，患者对乙酰胆碱的最大血流量受损（每100ml分别为9.8±7.8与15.9±8.1ml/分钟，p=0.03），对硝普钠的最大血流量反应相似（每100ml分别为9.5±4.2与9.0±2.8ml/分钟，p=0.72）。维生素治疗1个月后，LDL氧化的起始时间比基线测量延长了71±67%，最大氧化速率降低了26±25%（均p<0.001）。然而，对乙酰胆碱的最大前臂血流量反应与基线值相比保持不变（乙酰胆碱后最大血流量为每100ml 9.0±6.2与9.8±7.8ml/分钟，p=0.57）。本研究有80%的检验效能（α=0.05）排除维生素治疗期间乙酰胆碱刺激的血流量比基线值增加45%的情况。
尽管高胆固醇血症患者服用抗氧化维生素补充剂1个月可降低LDL的氧化易感性，但内皮功能障碍仍未改变。可能需要使用非维生素抗氧化剂或同时降低LDL水平，以及更敏感的测量血管反应性的技术，以显示对内皮血管舒张功能的有益作用。
