Giannessi D, Del Ry S, Vitale R L
Laboratory of Cardiovascular Biochemistry, CNR Institute of Clinical Physiology, Pisa, Italy.
Pharmacol Res. 2001 Feb;43(2):111-26. doi: 10.1006/phrs.2000.0758.
Endothelin (ET) is a peptide composed of 21 amino acids, derived from a larger precursor, the big-endothelin, by action of the endothelin-converting enzyme (ECE) family; three isoforms of endothelin, named ET-1, ET-2 and ET-3, have been identified. Endothelin-1 is generated mainly by vascular endothelial cells and exerts various important biological actions, mediated by two receptor subtypes, ET-A and ET-B, belonging to the G protein-coupled family that have been identified in various human tissues such as the cardiac tissue. Endothelin-1 is a potent vasoconstrictive agent, has inotropic and mitogenic actions, modulates salt and water homeostasis and plays an important role in the maintenance of vascular tone and blood pressure in healthy subjects. Endothelin-1, as well as ET-A and ECE-1, also has an important role in cardiovascular development, as observed by the variety of abnormalities related to neural crest-derived tissues in mouse embryos deficient of a member of the ET-1/ECE-1/ET-A pathway. Various evidence indicates that endogenous endothelin-1 may contribute to the pathophysiology of conditions associated with sustained vasoconstriction, such as heart failure. In heart failure, elevated circulating levels of both endothelin-1 and big-endothelin-1 are observed; in failing hearts an activation of the endothelin system is found: tissue level of ET-1 is increased with respect to non-failing hearts as well as receptor density, due mainly to an upregulation of the ET-A subtype, the prevalent receptor subclass in cardiac tissue. Finally, studies in both humans and animal models of cardiovascular disease show that inhibition of the endothelin function (anti-endothelin strategy) is associated with an improvement of haemodynamic conditions; these observations indicate that endothelin receptor antagonists or endothelin-converting enzyme inhibitors may constitute a novel and potentially important class of agents for the treatment of this disease.
内皮素（ET）是一种由21个氨基酸组成的肽，它由一种更大的前体——大内皮素，通过内皮素转换酶（ECE）家族的作用产生；已鉴定出内皮素的三种异构体，即ET-1、ET-2和ET-3。内皮素-1主要由血管内皮细胞产生，并通过两种受体亚型ET-A和ET-B发挥各种重要的生物学作用，这两种受体亚型属于G蛋白偶联家族，已在多种人体组织如心脏组织中被鉴定出来。内皮素-1是一种强效的血管收缩剂，具有变力和促有丝分裂作用，调节盐和水平衡，在维持健康受试者的血管张力和血压方面发挥重要作用。内皮素-1以及ET-A和ECE-1在心血管发育中也具有重要作用，这在缺乏ET-1/ECE-1/ET-A途径成员的小鼠胚胎中与神经嵴衍生组织相关的各种异常中得到了观察。各种证据表明，内源性内皮素-1可能促成与持续性血管收缩相关病症的病理生理学，如心力衰竭。在心力衰竭中，观察到内皮素-1和大内皮素-1的循环水平升高；在衰竭心脏中发现内皮素系统被激活：与非衰竭心脏相比，ET-1的组织水平以及受体密度增加，这主要是由于ET-A亚型（心脏组织中普遍存在的受体亚类）的上调。最后，在人类和心血管疾病动物模型中的研究表明，抑制内皮素功能（抗内皮素策略）与血流动力学状况的改善相关；这些观察结果表明，内皮素受体拮抗剂或内皮素转换酶抑制剂可能构成一类新型且潜在重要的治疗该疾病的药物。
