Benigni A, Remuzzi G
Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
Lancet. 1999 Jan 9;353(9147):133-8. doi: 10.1016/S0140-6736(98)09423-9.
The very potent endogenous vasoconstrictor endothelin was discovered in 1988. We know now that there are three isoforms (1, 2, and 3) and two receptor subtypes (A and B). A whole range of peptide and non-peptide antagonists has been developed, some selective for A or B receptors and others with non-selective A/B antagonistic activity. So far the main application of these agents has been experimental--ie, endothelin blockers are used to throw light on disease mechanisms, most notably cardiovascular and renal. However, the non-selective antagonist bosentan and a few other agents have been studied clinically. Evidence so far from preclinical studies and healthy volunteers and from the limited number of investigations in patients permits a listing of the potential areas of clinical interest. These are mainly cardiovascular (eg, hypertension, cerebrovascular damage, and possibly heart failure) and renal. Clouds on the horizon are the need to show that these new agents are better than existing drugs; the possibility of conflicting actions if mixed A/B antagonists are used; and animal evidence hinting that endothelin blockade during development could be dangerous.
强效内源性血管收缩剂内皮素于1988年被发现。我们现在知道有三种异构体（1、2和3）和两种受体亚型（A和B）。已经开发出一系列肽类和非肽类拮抗剂，有些对A或B受体具有选择性，有些具有非选择性A/B拮抗活性。到目前为止，这些药物的主要应用一直是实验性的——也就是说，内皮素阻滞剂用于阐明疾病机制，最显著的是心血管和肾脏方面的机制。然而，非选择性拮抗剂波生坦和其他一些药物已经进行了临床研究。到目前为止，来自临床前研究、健康志愿者以及对患者进行的有限数量研究的证据，使得列出潜在的临床关注领域成为可能。这些主要是心血管方面（如高血压、脑血管损伤，可能还有心力衰竭）和肾脏方面。未来的问题包括需要证明这些新药比现有药物更好；如果使用混合A/B拮抗剂可能存在相互冲突作用的可能性；以及动物证据表明在发育过程中阻断内皮素可能是危险的。
