Molecular Pharmacology and Pathophysiological Significance of Endothelin

Abstract

ABSTRACT-Since the discovery of the most potent vasoconstrictor peptide, endothelin, in 1988, explosive investigations have rapidly clarified much of the basic pharmacological, biochemical and molecular biological features of endothelin, including the presence and structure of isopeptides and their genes (endothelin-1, -2 and -3), regulation of gene expression, intracellular processing, specific endothelia converting enzyme (ECE), receptor subtypes (ETA and ETB), intracellular signal transduction following receptor activation, etc. ECE was recently cloned, and its structure was shown to be a single transmembrane protein with a short intracellular N-terminal and a long extracellular C-terminal that contains the catalytic domain and numerous N-glycosylation sites. In addition to acute contractile or secretory actions, endothelin has been shown to exert long-term proliferative actions on many cell types. In this case, intracellular signal transduction appears to converge to activation of mitogen-activated protein kinase. As a recent dramatic advance, a number of non-peptide and orally active receptor antagonists have been developed. They, as well as current peptide antagonists, markedly accelerated the pace of investigations into the true pathophysiological roles of endogenous endothelin-1 in mature animals; e.g., hypertension, pulmonary hypertension, acute renal failure, cerebral vasospasm, vascular thickening, cardiac hypertrophy, chronic heart failure, etc. Thus, the interference with the endothelin pathway by either ECE-inhibition or receptor blockade may

Possible modulation by endothelin-1, nitric oxide, prostaglandin I 2 and thromboxane A 2 of vasoconstriction induced by an α-agonist in mesenteric arterial bed from diabetic rats

“…ET-1, a vasoconstrictor peptide secreted from endothelial cells, is thought to have a role in a number of vascular diseases [35]. ET-1 constricts smooth muscle by activating ET A receptors [36] and also leads to the release of endothelium-derived relaxing factor by way of the ET B receptors located on the endothelium [37].…”

The PI3-K/Akt pathway: roles related to alterations in vasomotor responses in diabetic models

“…Some reports suggest that a high vascular activity of angiotensin converting enzyme may promote a progressive deterioration of the cardiovascular system in STZ-induced diabetic rats (Piper et al, 2000;Crespo et al, 2003). In addition, ET-1 (a vasoconstrictor peptide secreted from endothelial cell) is thought to play a pathological role in a number of vascular diseases (Goto et al, 1996). Interestingly, it was recently reported that ET-1 can activate PI3-K in several cells (Ishibashi et al, 2000;Kawanabe et al, 2003) and that ET-1 activates NAD(P)H oxidase and induces superoxide production in cultured endothelial and smooth muscle cells (Duerrschmidt et al, 2000;Wedgwood et al, NAD(P)H oxidase is increased in STZ-induced diabetic aortae (Kanie and Kamata, 2002) and that this increase is normalized by the endothelin antagonist, J-104132, suggesting that ET-1 is involved in the increased formation of superoxide anions.…”

Effects of chronic administration of the novel endothelin antagonist J‐104132 on endothelial dysfunction in streptozotocin‐induced diabetic rat

“…Endothelin-1 (ET-1), a vasoconstrictor peptide secreted from endothelial cells, is thought to play a pathological role in a number of vascular diseases (Goto et al, 1996). Plasma ET-1 levels are increased in the diabetic state (Takahashi et al, 1990;Makino & Kamata, 1998;Makino et al, 2001) and the plasma concentration of big endothelin-1, the precursor of ET-1, is elevated in patients with diabetes mellitus (Tsunoda et al, 1991).…”