Endothelin System: The Double-Edged Sword in Health and Disease

Abstract

The endothelin system consists of two G-protein-coupled receptors, three peptide ligands, and two activating peptidases. Its pharmacological complexity is reflected by the diverse expression pattern of endothelin system components, which have a variety of physiological and pathophysiological roles. In the vessels, the endothelin system has a basal vasoconstricting role and participates in the development of diseases such as hypertension, atherosclerosis, and vasospasm after subarachnoid hemorrhage. In the heart, the endothelin system affects inotropy and chronotropy, and it mediates cardiac hypertrophy and remodeling in congestive heart failure. In the lungs, the endothelin system regulates the tone of airways and blood vessels, and it is involved in the development of pulmonary hypertension. In the kidney, it controls water and sodium excretion and acid-base balance, and it participates in acute and chronic renal failure. In the brain, the endothelin system modulates cardiorespiratory centers and the release of hormones. More advanced functional analysis of the endothelin system awaits not only additional pharmacological studies using highly specific endothelin antagonists but also the generation of genetically altered rodent models with conditional loss-of-function and gain-of-function manipulations.

Intracrine endothelin signaling evokes IP3-dependent increases in nucleoplasmic Ca2+ in adult cardiac myocytes

“…In endothelial cells, ET-1 production is regulated at the level of transcription, mRNA stability, and maturation of the ET precursor protein, preproendothelin. Whereas extracellular ET-1 reduces the cellular content of ET-1 mRNA in endothelial cells [74], Ang II, oxidized LDL, insulin, isoproterenol, thrombin, TGFβ, TNFα, verotoxin, and VEGF increase ET-1 mRNA abundance [75][76][77]. The best characterized intracrine signalling system is that of peptidergic agonist, Ang II.…”

Endothelial cell functions

“…The endothelin family, since identified, consists of three structurally related peptides, ET-1, ET-2, and ET-3 (Kedzierski and Yanagisawa, 2001). In the vasculature, the proendothelin may be released from the non-luminal surface of the endothelial cells and converted to mature endothelin extracellularly by membrane-bound ''endothelin-converting enzymes,'' which are neutral metalloproteinases.…”

“…In contrast, the endothelin B (ET B ) receptor is situated on the endothelial cells and has a similar affinity for the three endothelin isoforms. Binding to ET A receptor stimulated phospholipase C initiating in turn events leading eventually to smooth muscle cell contraction (Kedzierski and Yanagisawa, 2001). The result of ET binding to ET B receptor on endothelial cells is the release of EDRF/ PGI 2 , which opposes the vasoconstricting action of ET.…”

Assessment of endothelial function in the patient with erectile dysfunction: an opportunity for the urologist

“…Endothelin-1 (ET-1) is a potent vasoconstrictor and proinflammatory peptide 30,31 normally secreted in a paracrine fashion from endothelial cells, 32 but can also be synthesized by macrophages. 33 In an excellent review, Boehm and Pernow 34 enumerate dozens of studies in which ET-1 is associated with endothelial dysfunction, inflammation and vasoconstriction, whereas blockade of ET-1 receptors leads to improved endothelial function with increased availability of NO.…”