Characterization of endothelin synthetic pathways and receptor subtypes: physiological and pathophysiological implications.

The endothelins are a family of three widely expressed 21 amino acid peptides. Apart from the ability to constrict vascular smooth muscle, they have numerous other potent effects, from enhancing mitogenesis to influencing nervous function. The pathway of their production involves the initial synthesis of a predominantly inactive 38 to 41 amino acid precursor, big endothelin, which is cleaved to the active form by an as yet unidentified, but widely distributed, endothelin-converting enzyme. This enzyme has been partially characterized and appears to be a metalloprotease, active at neutral pH, which is inhibited by phosphoramidon. However, other enzymes, including those contained in inflammatory cells, can also convert big endothelin to its active form. Research in the past 2 to 3 years has revealed at least two endothelin receptors. These are widely distributed throughout the body and are present, for instance, on vascular and non-vascular smooth muscle, nervous tissue, and endothelial and epithelial cells. There is also a fairly large degree of heterogeneity between species in the distribution of these endothelin receptors. The endothelins have been widely implicated in a number of disease states and the recent development of selective and non-selective antagonists of these receptors, such as BQ-123, PD 142893, and Ro 46-2005 is finally making available the tools required to elucidate their true roles.