Donckier J E
Department of Internal Medicine and Endocrinology, Université Catholique de Louvain, University Hospital of Mont-Godinne, B-5530 YVOIR, Belgium.
Heart Fail Rev. 2001 Dec;6(4):253-64. doi: 10.1023/a:1011419223152.
Since its discovery in 1988, there has been increasing evidence that endothelin-1 (ET-1) plays an important role in the pathophysiology of hypertension and its related end-organ damages. First studies, using ET-1 administration in animals or in humans suspected this role by demonstrating the hypertensive properties of ET-1. The latter, due to stimulation of ET(A) receptors inducing sustained vasoconstriction have been reported to follow transient vasodilation linked with activation of an endothelial ET(B) receptor releasing nitric oxide (NO). In certain instances, ET(B) smooth-muscle receptors might also induce contraction. Cloning of these receptors helped to develop ET-1 receptor antagonists. As soon as one of them became available, bosentan, a dual (ET(A) and ET(B)) ET-1 receptor antagonist, we tested its effects in the canine model of perinephritic hypertension. Bosentan was found to exert striking hypotensive effects, due to peripheral vasodilation but without affecting cardiac function. In further experiments, we observed that effects of bosentan were additional to those of ACE inhibitors or angiotensin II antagonists. This opened new therapeutic perspectives and also suggested a proper role of ET-1 in hypertension, independent of the renin-angiotensin system. To explain this role, we demonstrated a real imbalance characterized by an impairment of the NO system in favor of the ET-1 pathway. Recent studies suggest that such an imbalance may also occur in human hypertension. Furthermore, the contribution of ET-1 to human hypertension appears more convincing since bosentan was shown to decrease blood pressure in hypertensive subjects. Finally, ET-1 receptor antagonists might be of therapeutic interest to prevent hypertension induced end-organ damages. Whether or not these compounds are able to prevent or to reverse target organ injuries in man remains to be investigated.
自1988年内皮素-1（ET-1）被发现以来，越来越多的证据表明，ET-1在高血压及其相关靶器官损害的病理生理学中发挥重要作用。最初，通过在动物或疑似患有高血压的人类中给予ET-1进行的研究，发现ET-1具有升压特性，从而怀疑其具有这一作用。据报道，ET-1由于刺激ET(A)受体诱导持续血管收缩，在与释放一氧化氮（NO）的内皮ET(B)受体激活相关的短暂血管舒张之后出现。在某些情况下，ET(B)平滑肌受体也可能诱导收缩。这些受体的克隆有助于开发ET-1受体拮抗剂。当其中一种拮抗剂波生坦（一种双重（ET(A)和ET(B)）ET-1受体拮抗剂）可用时，我们在犬类肾周围性高血压模型中测试了其效果。结果发现，波生坦由于外周血管舒张而发挥显著的降压作用，但不影响心脏功能。在进一步的实验中，我们观察到波生坦的作用是在血管紧张素转换酶（ACE）抑制剂或血管紧张素II拮抗剂的作用之外的。这开辟了新的治疗前景，也表明ET-1在高血压中具有独立于肾素-血管紧张素系统的适当作用。为了解释这一作用，我们证明了一种以NO系统受损而有利于ET-1途径为特征的实际失衡。最近的研究表明，这种失衡也可能发生在人类高血压中。此外，ET-1对人类高血压的作用似乎更有说服力，因为波生坦已被证明可降低高血压患者的血压。最后，ET-1受体拮抗剂可能对预防高血压引起的靶器官损害具有治疗意义。这些化合物是否能够预防或逆转人类的靶器官损伤仍有待研究。
