Endothelin as a Regulator of Vascular Tone in Man: Studies in Upper Limb Resistance and Capacitance Vessels

Abstract

In their seminal paper of 1988, Yanagisawa and colleagues [1] described an endothelium-derived 21 amino acid peptide, endothelin-1, with extremely potent and uniquely sustained vasoconstrictor and pressor actions. Endothelin-1 is one of a family of three isopeptides, and is the predominant isopeptide generated by the vascular endothelium [2]. The other members of the family, endothelin-2 and endothelin-3, are more difficult to detect and are probably less important in the human cardiovasculature. Endothelin-1 is generated from a 38 amino acid precursor, big endothelin-1, through the action of a unique ‘endothelin converting enzyme’ (ECE), a membranebound phosphoramidon-sensitive, thiorphan-insensitive neutral metalloprotease [3–6] which may prove an important target for drug development. One form of this enzyme, ECE-1, has recently been cloned [7]. Endothelin-1 exerts its actions through binding to at least two receptors, both of which have been isolated by in vitro expression of cloned human cDNA [8, 9]. ETA receptors are highly expressed in vascular smooth muscle cells and appear to be the major receptor subtype causing vasoconstriction in large human arteries [10]. These receptors have an agonist potency: endothelin-1 > endothelin-2 ≫ endothelin-3. ETB receptors are present on the luminal surface of endothelial cells where they have been clearly shown to mediate release of endothelium-dependent vasodilator substances. However, receptors with the pharmacological characteristics of the ETB subtype are also present in vascular smooth muscle where they can contribute to vasoconstriction [11–13]. These receptors have an agonist potency: endothelin-1 = endothelin-2 = endothelin-3.