Ferro C J, Webb D J
Clinical Pharmacology Unit and Research Centre, University Department of Medicine, Western General Hospital, Edinburgh, Scotland.
Drugs. 1996 Jan;51(1):12-27. doi: 10.2165/00003495-199651010-00003.
The endothelin family of peptides are extremely potent endogenous vasoconstrictor and pressor agents. Of the 3 isoforms, endothelin-1 is the major isoform produced by the vascular endothelium and is, therefore, likely to be of most importance for regulation of vascular function. Two endothelin receptor subtypes have so far been cloned in mammalian species; ET A, and ET B. Both receptor subtypes are found on smooth muscle cells and mediate the vasoconstrictor and pressor actions of endothelin. The ET B receptor is also found on vascular endothelial cells and mediates endothelin-dependent vasodilatation through release of nitric oxide and prostacyclin. Since their discovery in 1988, the endothelins have been the subject of intense research on their physiological function and potential pathophysiological role in cardiovascular disease. There is now good evidence that endothelin regulates vascular tone and blood pressure, and studies to support the development of endothelin receptor antagonists in conditions associated with chronic vasoconstriction, such as hypertension and heart failure, as well as in vasospastic disorders, such as subarachnoid haemorrhage and Raynaud's disease. There are now a number of selective ET A and combined ET A/B receptor antagonists available for preclinical studies. However, it is still not clear which of these will prove to be of most therapeutic value. Some of these agents are currently being assessed in early phase clinical trials. Endothelin receptor antagonists represent a novel therapeutic approach to a fundamental and newly discovered endogenous vasoconstrictor mechanism. The results of the current clinical trials are awaited with considerable interest.
内皮素肽家族是极其强效的内源性血管收缩剂和升压剂。在3种异构体中，内皮素-1是血管内皮产生的主要异构体，因此可能对血管功能调节最为重要。迄今为止，已在哺乳动物物种中克隆出两种内皮素受体亚型；ETA和ETB。两种受体亚型均存在于平滑肌细胞上，介导内皮素的血管收缩和升压作用。ETB受体也存在于血管内皮细胞上，并通过释放一氧化氮和前列环素介导内皮素依赖性血管舒张。自1988年被发现以来，内皮素一直是关于其生理功能以及在心血管疾病中潜在病理生理作用的深入研究对象。现在有充分证据表明内皮素调节血管张力和血压，并且有研究支持在与慢性血管收缩相关的病症（如高血压和心力衰竭）以及血管痉挛性疾病（如蛛网膜下腔出血和雷诺病）中开发内皮素受体拮抗剂。现在有多种选择性ETA和ETA/B联合受体拮抗剂可用于临床前研究。然而，仍不清楚其中哪种将被证明具有最大的治疗价值。其中一些药物目前正在进行早期临床试验评估。内皮素受体拮抗剂代表了一种针对一种基本且新发现的内源性血管收缩机制的新型治疗方法。人们对当前临床试验的结果怀着极大的兴趣拭目以待。
