Since its identification in 1988, 1 endothelin has attracted intensive interdisciplinary research interest because of itsunique profile as an endo-thelium-derived vasoactive factor with a powerful and characteristically long-lasting vasopressor activity. Indeed, in terms of cellular mechanisms of action, endothelin appears to be quite similar to many classic vasoconstrictor substances such as angiotensin II and norepinephrine. However, the slow time course of the regulatory mechanisms of its biosynthesis and secretion more resembles that of inflammatory cytokines, giving this family of small peptides a unique position within the realm of intercellular mediators with cardiovascular relevance.

See p 1203 The endothelins are a family of 21-residue peptides consisting of three structurally related isoforms called endothelin (ET)-1, ET-2, and ET-3.2 These mature, active forms are produced from the corresponding" 200-residue prepropolypeptides that are encoded by three separate genes. These prepropeptides are first processed by a furin-like processing protease3 into bio-logically inactive intermediates called big ET-1,-2, and-3. Big endothelins are then proteolytically activated via cleavage at the common Trp21 residue by a highly specific endopeptidase (s) called endothelin-converting enzyme (ECE). 4 The production of endothelins is tightly regulated at the level of mRNA transcription. In vascular endothelial cells, ET-1, once synthesized, is secreted via the constitutive pathway of secretion with-out further regulation at the level of exocytosis. Endothelins are expressed on proper stimulation in various cell types, although vascular endothelial cells appear to be the most abundant source of ET-1 in vivo under healthy conditions, and the endothelial cells produce only ET-1. It seems reasonable to consider that endothelins act primarily as local, paracrine/autocrine hormones, because (1) the" target" cell types that have endothelin receptors can always be found in the vicinity of the" producer" cell types withinthe same tissue;(2) circulating plasma levels of endothelinsare generally much lower than the threshold concentrations for pharmacological activities; and (3) circulating endothelins