Endothelins as Cardiovascular Peptides

Abstract

The normal functional state of the vasculature and the events leading to the development of significant arterial disease involve the interaction of important vasoactive substances, which play important modulating or initiating roles in the development of hypertension and arteriosclerosis. Three endothelins have now been identified, of which ET-1 is the best characterized. ET-1 is produced by epithelial, mesangial, neuronal and glial, and liver cells, and is the most potent vasoconstrictor yet found. Each endothelin is derived from a different gene on separate chromosomes, and each binds to at least 2 types of receptor. The plasma half-life of ET-1 is about 7 min, and this provides a rapid mechanism for adjusting vascular resistance or blood pressure. The actions of endothelin are mediated through several pathways of postreceptor signaling, including activation of the mitogen-activated protein kinase cascade, which give rise to its growth-stimulating properties. Secretion of ET-1 from cultured endothelial cells is stimulated by a wide range of substances, and is inhibited by some prostaglandins. Endothelin in turn stimulates secretion of nitric oxide, arginine vasopressin and atrial natriuretic peptide, and participates in the hormonal control of salt and water balance. Hypoxia and ischemia augment ET-1 secretion, as does insulin, and this could play a role in the accelerated vascular disease of diabetes. ET-1 also causes bronchoconstriction and has been implicated in the development of acute asthma, primary pulmonary hypertension and pulmonary fibrosis. Its role in hypertension is still debatable, though most of the manifestations of congestive heart failure can theoretically be explained by the actions of ET-1. Endothelin also has extensive renovascular and parenchymal effects in the kidney. It is hoped that a fuller understanding of the role of endothelins in normal or pathologic vasculature will lead to effective therapy based on antagonism or augmentation of specific functions.

Endothelin Limits Insulin Action in Obese/Insulin-Resistant Humans

“…This system appears to function with NO and ET-1 as mutual antagonists (50). Under conditions of health, this can produce a tightly regulated balance between these major determinants of vascular tone (8,51,52), and we have recently reported that endothelin antagonism can augment bioavailable NO in obesity (8).…”

Endothelin receptor blockade prevents augmented extracellular matrix component mRNA expression and capillary basement membrane thickening in the retina of diabetic and galactose-fed rats.

“…Endothelins (ETs) are a family of 21 amino acid peptides with diverse functions, including vasoactivity and mitogenesis (13,14). ETs consist of peptides that include ET-1, ET-2, and E T-3 (15).…”

“…Receptors for these peptides have been well class i fied and include ET A , ET B , and ET C (16,17). Originally discovered as endothelial products, the ETs have since been found in various cell types and tissues, including ocular and neuronal tissues (14,18). In addition to being potent vasoactive molecules, ETs also possess mitogenic properties (19).…”

Genetics of hypertension: from experimental models to clinical applications

“…The vascular ET system is represented mainly by ET-1 produced in endothelial cells and is cleaved from a larger precursor, 38 amino acids in length, by the endothelin converting enzyme (ECE). 145 It binds to the ET A receptor on the vascular smooth muscle and provokes vasoconstriction. Studies with endothelin receptor antagonists have indicated that endothelin-1 probably has complex opposing vascular effects mediated through vascular smooth muscle and endothelial ET(A) and ET(B) receptors.…”

“…146 At the same time, endogenous endothelin-1 acts through endothelial ET(B) receptors to stimulate formation of nitric oxide tonically and to oppose vasoconstriction. 145 In addition to its direct vascular effects, endothelin-1 has inotropic and mitogenic properties, influences homeostasis of salt and water, alters central and peripheral sympathetic activity and stimulates the renin-angiotensin-aldosterone system. In view of the multiple cardiovascular actions of endothelin-1, there has been much interest in its contribution to the pathophysiology of hypertension.…”