Webb D J, Monge J C, Rabelink T J, Yanagisawa M
Department of Medicine, University of Edinburgh, Western General Hospital, UK.
Trends Pharmacol Sci. 1998 Jan;19(1):5-8. doi: 10.1016/s0165-6147(97)01144-9.
This fifth international conference on ET serves to underline the rapid pace of development of our understanding of the very versatile ET system. On the one hand, the body uses ETs at several stages in embryonic development, in normal postnatal growth, and in cardiovascular homeostasis under healthy conditions. On the other hand, overwhelming evidence now exists that ET-1 plays important pathophysiological roles in conditions of decompensated vascular homeostasis. Indeed, in CHF this evidence is sufficient to justify the large-scale studies of morbidity and mortality needed to market ET antagonists as medicines. Other potentially important cardiovascular indications for ET antagonists are still emerging--including hypertension, stroke, subarachnoid haemorrhage and renal failure--and all are likely to be the subject of clinical trials over the next few years. As yet, there has been little work outside the cardiovascular and renal fields, but other areas, such as cancer treatment, may also prove promising. New molecules with increasing selectivity (ETA and ETB) continue to emerge and may be valuable. Inhibition of ECE-1 remains as an alternative approach and nonpeptide ECE inhibitors now exist. There appears to be a consensus that ETA blockade is beneficial in cardiovascular and renal disease. However, several strands of work presented at the meeting--the hypertensive salt-sensitive phenotype of rescued ETB knockout mice, the sustained and progressive hypertensive effects of ETB-selective antagonism in rats, ETB-mediated vasodilatation and natriuresis in dogs, and nitric oxide-dependent ETB-mediated vasodilatation in humans--all suggest that ETB-mediated vascular and renal responses may be protective. The development of selective ETA antagonists, therefore, now seems fully justified. In the future, direct comparisons in animal models, and patients, of ETA and ETA/B antagonists will be important in determining the value of additional ETB receptor blockade in individual diseases.
本次第五届国际内皮素会议旨在强调，我们对极为多样的内皮素系统的认识正迅速发展。一方面，机体在胚胎发育的多个阶段、出生后的正常生长过程以及健康状态下的心血管稳态维持中都会用到内皮素。另一方面，现在有大量证据表明，内皮素 -1 在血管稳态失代偿的情况下发挥着重要的病理生理作用。事实上，在慢性心力衰竭中，这一证据足以支持开展将内皮素拮抗剂作为药物推向市场所需的大规模发病率和死亡率研究。内皮素拮抗剂其他潜在的重要心血管适应症仍在不断涌现，包括高血压、中风、蛛网膜下腔出血和肾衰竭，而且所有这些都可能成为未来几年临床试验的对象。到目前为止，心血管和肾脏领域之外的研究工作还很少，但其他领域，如癌症治疗，也可能前景广阔。具有越来越高选择性（ETA 和 ETB）的新分子不断出现，可能具有重要价值。抑制内皮素转换酶 -1 仍是一种替代方法，目前已有非肽类内皮素转换酶抑制剂。似乎已形成一种共识，即阻断 ETA 在心血管和肾脏疾病中有益。然而，会议上展示的几项研究结果——获救的 ETB 基因敲除小鼠的高血压盐敏感表型、ETB 选择性拮抗在大鼠中产生的持续和进行性高血压效应、ETB 介导的犬血管舒张和利钠作用，以及人类中一氧化氮依赖的 ETB 介导的血管舒张——都表明，ETB 介导的血管和肾脏反应可能具有保护作用。因此，开发选择性 ETA 拮抗剂现在看来是完全合理的。未来，在动物模型和患者中对 ETA 拮抗剂与 ETA/B 拮抗剂进行直接比较，对于确定在个别疾病中额外阻断 ETB 受体的价值将具有重要意义。
