Lerman A, Webster M W, Chesebro J H, Edwards W D, Wei C M, Fuster V, Burnett J C
Department of Internal Medicine, W.D.E., C.M.W., J.C.B.), Division of Cardiovascular Disease Mayo Clinic and Foundation, Rochester, Minn 55905.
Circulation. 1993 Dec;88(6):2923-8. doi: 10.1161/01.cir.88.6.2923.
Hypercholesterolemia is characterized by a coronary vasoconstrictive response to the endothelium-dependent vasodilator acetylcholine. This abnormality may be due to reduced synthesis of endothelium-derived relaxing factor and/or enhanced synthesis and release of an endothelium-derived contracting factor. Endothelin is an endothelium-derived vasoconstrictor and mitogenic peptide that is present in normal plasma, and its circulating concentrations are elevated in disease states that are characterized by abnormal endothelium-dependent relaxation to acetylcholine. The current studies were designed to test the hypotheses that experimental hypercholesterolemia results in elevation of plasma and tissue endothelin immunoreactivity and that the abnormal acetylcholine-evoked coronary vasoconstriction in the hypercholesterolemic animals is associated with further elevation of plasma endothelin.
Plasma concentrations and molecular forms of endothelin immunoreactivity were determined following 2% cholesterol diet for 4 months in pigs and during intracoronary acetylcholine administration. Second, we assessed the presence of endothelin in the coronary vascular wall by using immunohistochemistry. Hypercholesterolemia elevated plasma endothelin concentration and enhanced coronary artery tissue endothelin immunoreactivity. The endothelium-dependent vasodilator acetylcholine further increases plasma endothelin in hypercholesterolemia in association with coronary vasoconstriction. The predominant molecular form of endothelin in hypercholesterolemia is the biological active endothelin-1.
This study suggests a role for endothelin as an early participant and a marker for the endothelial dysfunction in hypercholesterolemia as well as a participant in the atherogenic process.
高胆固醇血症的特征是对内皮依赖性血管舒张剂乙酰胆碱产生冠状动脉血管收缩反应。这种异常可能是由于内皮源性舒张因子合成减少和/或内皮源性收缩因子合成与释放增加所致。内皮素是一种内皮源性血管收缩剂和促有丝分裂肽，存在于正常血浆中，在以对乙酰胆碱的内皮依赖性舒张异常为特征的疾病状态下，其循环浓度会升高。当前的研究旨在检验以下假设：实验性高胆固醇血症会导致血浆和组织内皮素免疫反应性升高，并且高胆固醇血症动物中异常的乙酰胆碱诱发的冠状动脉血管收缩与血浆内皮素的进一步升高有关。
在给猪喂食2%胆固醇饮食4个月后以及冠状动脉内注射乙酰胆碱期间，测定了内皮素免疫反应性的血浆浓度和分子形式。其次，我们通过免疫组织化学评估了冠状动脉血管壁中内皮素的存在情况。高胆固醇血症会升高血浆内皮素浓度，并增强冠状动脉组织内皮素免疫反应性。内皮依赖性血管舒张剂乙酰胆碱在高胆固醇血症中会进一步增加血浆内皮素，同时伴有冠状动脉血管收缩。高胆固醇血症中内皮素的主要分子形式是生物活性内皮素-1。
本研究表明内皮素在高胆固醇血症中作为内皮功能障碍的早期参与者和标志物以及动脉粥样硬化形成过程中的参与者发挥作用。
