First printed in R&D Systems' 1996 Catalog.
Endothelin-1 (ET-1), a peptide of 21 amino acid residues, is the most potent vasoconstrictor substance known. Originally isolated from porcine aortic endothelial cells1, ET-1 is now known to be one of a family of three mammalian vasoactive peptides that also includes endothelin-2 (ET-2) and endothelin-3 (ET-3).2 These related peptides differ from ET-1 at the two and six amino acid residue positions, respectively. A fourth peptide, vasoactive intestinal contractor (VIC), is sometimes classified as rat ET-2.3
All members of the endothelin family contain two essential disulfide bridges and six conserved amino acid residues at the C-terminus. In addition, all of the endothelin family members are synthesized initially as prepropolypeptides of approximately 200 amino acid residues encoded by separate genes.2 These are proteolytically cleaved4 to produce biologically-inactive propolypeptides of approximately 40 amino acid residues termed "big endothelins". Big ET-1 is cleaved by the proteolytic action of a membrane-bound metalloprotease [endothelin-converting enzyme (ECE-1)], producing the 21 amino acid residue active peptide.5 The biochemistry and biology of the endothelins have been the subject of several recent reviews.2,6,7
Two receptors for endothelins have been characterized, designated ETA and ETB. Although these receptors are structurally and functionally distinct, they share some similarities. Both are seven transmembrane domain receptors coupled through G proteins to phospholipase C.13 Both have an N-terminal signal sequence and a long N-terminal extracellular domain.13 The ETA receptor shows a higher affinity for ET-1 than for ET-2 and the lowest affinity for ET-3. The ETB receptor shows approximately equal affinity for each of the three endothelins.12,13 Both receptors are expressed in a wide variety of tissue types, in some cases with distinct expression and in some cases showing some degree of overlapping expression.6 Recent studies indicate that endothelium-dependent relaxation is mediated by the ETB receptor.6 Both the ETA and the ETB receptors play varying roles in mediation of vasopressor actions depending on the species and vasculature involved.6
The endothelins are produced by a variety of tissues in vivo, including lung and kidney7, as well as brain, pituitary, and peripheral endocrine tissues (reviewed in ref. 8) and placenta.9 ET-1, in contrast to ET-2 and ET-3, is also produced by endothelial cells; the vascular endothelium being the most abundant source of ET-1 in vivo.1,6 There are also recent reports of ET-1 production in vitro by pancreatic cancer cells10, mast cells11 and a variety of endothelial, epithelial and smooth muscle cells.12
The best-known action of ET-1 is vasoconstriction. Injection of a single dose of ET-1 produces an initial decrease in systemic blood pressure followed by a prolonged increase in blood pressure, lasting for 1 to 3 hours, the longest produced by any constrictor yet tested.13,14 The two phases of the response are probably mediated by different receptors.13 Given the slow onset and long-lasting effects of endothelins, it appears that these peptides are involved in long-term changes and not in acute responses to stimuli. In addition to their actions as vasoconstrictors, endothelins also produce a variety of other biological effects. These include stimulation of cardiac contraction, regulation of release of vasoactive substances, and stimulation of smooth muscle mitogenesis.7,12 Endothelins also stimulate contraction of most smooth muscles and stimulate secretion by tissues including kidney, liver and adrenals.7 Endothelins also act in the brain, stimulating secretion by hypothalamic and pituitary cells.8
Elevated levels of ET-1 in blood have been reported for a variety of disease conditions (reviewed in ref. 12), possibly as part of a response to stress. These conditions include: myocardial infarction15, hypertension16,17, subarachnoid hemorrhage18,19, diabetes mellitus20,21, sepsis22, HIV infection23, and some cancers.10