Endothelin and the human kidney: a potential target for new drugs

The existence of a powerful endogenous endotheliumderived vasoconstrictor was predicted from the early 1980s, but not until 1988 did Yanagisawa and colleagues first report the identification of a 21 aminoacid peptide, endothelin (ET), from the supernatant of cultured porcine aortic endothelial cells [1]. Within a year, two further ET isoforms were described (ET-2 and ET-3), their existence having been predicted from the study of cDNA libraries isolated from several species [2], and today, no more potent vasoconstrictors have been discovered. The sarafotoxins, which are the envenoming agents of the Israeli burrowing asp, have a very high degree of sequence homology with ET, and share its effects [1]. These include, in animals, initial transient vasodilatation (via endothelial cell surface receptors and interaction with endotheliumderived relaxing factors), then intense and unusually long-lasting vasoconstriction (via receptors on smooth muscle), positive inotropy and arrhythmogenesis [3]. ET is synthesised not only by the endothelial lining of vessels in a wide variety of tissues and across many species, but also by a range of cultured cells [4], including those of epithelial, smooth muscle, mesangial, malignant and neural origin. However despite 5 years of intensive study and the publication of more than 2500 papers, a clear pathophysiological role for this family of peptides has yet to be identified.