| dc.description.abstract | Endothelins are a family of three peptides of 21 amino acids, which cause a long lasting vasoconstriction preceded by an initial depressor response, when injected intravenously to rats. The three peptides (ET-1, ET-2 and ET-3) are encoded by three different genes and are derived from precursors (''big endothelins''), which are cleaved by a novel metalloprotease sensitive to phosphoramidon (endothelin-converting enzymes 1, 2 or 3). ET-1 is a more potent vasoconstrictor than ET-3, while ET-1 and ET-3 are equipotent in inducing the depressor response, suggesting the existence of different ET rcceptors. Indeed, two ET receptors have been cloned, the ET(A) receptor which binds ET-1 with a higher affinity than ET-3 and mediates vasoconstriction, and the ET(B) receptor which binds the endothelins with similar, high affinity and mediates vasodilatation. Also, recent data indicate that a subtype of ET(B) receptors would mediate some vasoconstrictor effects of endothelins and there are some evidences for the existence of a third class of ET receptor (ET(C)). The wide distribution of ET receptors, together with the presence of ET-1 mRNA in different tissues, suggest that ET may act as local hormones. Accordingly, in addition to their role in vascular tissues, endothelins have been shown to cause non vascular effects in heart, kidney, adrenal glands, liver, and to act as neuropeptides and growth factors. Endothelins exert their effects by increasing cytosolic free calcium consecutively to stimulation of phospholipase C and calcium channels, and inhibition of the plasma membrane calcium pump. Endothelins also activate protein kinase C, raise or decrease cAMP levels, stimulate phosphatidylcholine hydrolysis, phospholipase A2, Na+/H+ exchange, modulate ionic channels and phosphorylate cytosolic proteins on tyrosine residues. The role of these peptides in pathophysiology is emerging, and should be resolved with the development of receptor antagonists and ECE inhibitors. | fr |
