The endothelin family of peptides has long been recognized as a physiological regulator of diverse biological functions and mechanistically involved in various disease states, encompassing, among others, the cardiovascular system, the kidney, and the nervous system. Pharmacological blockade of the endothelin system, however, has encountered strong obstacles in its entry into the clinical mainstream, having obtained only a few proven indications until recently. This translational gap has been attributable predominantly to the relevant side effects associated with endothelin receptor antagonism (ERA), particularly fluid retention. Of recent, however, an expanding understanding of the pathophysiological processes involving endothelin, in conjunction with the development of new antagonists of endothelin receptors or adjustment of their doses, has driven a flourish of new clinical trials. The favorable results of some of them have extended the proven indications for ET targeting to a variety of clinical conditions, including resistant arterial hypertension and glomerulopathies. In addition, on the ground of strong preclinical evidence, other studies are ongoing to test the potential benefits of ERA in combination with other treatments, such as sodium-glucose co-transporter 2 inhibition in fluid retentive states or anti-cancer therapies in solid tumors. Furthermore, antibodies providing long-term blockade of endothelin receptors are under testing to overcome the short half-life of most small molecule endothelin antagonists. These efforts may yet bring new life to the translation of endothelin targeting strategies in clinical practice.

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