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2016 ; 68
(2
): 357-418
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Endothelin
#MMPMID26956245
Davenport AP
; Hyndman KA
; Dhaun N
; Southan C
; Kohan DE
; Pollock JS
; Pollock DM
; Webb DJ
; Maguire JJ
Pharmacol Rev
2016[Apr]; 68
(2
): 357-418
PMID26956245
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The endothelins comprise three structurally similar 21-amino acid peptides.
Endothelin-1 and -2 activate two G-protein coupled receptors, ETA and ETB, with
equal affinity, whereas endothelin-3 has a lower affinity for the ETA subtype.
Genes encoding the peptides are present only among vertebrates. The
ligand-receptor signaling pathway is a vertebrate innovation and may reflect the
evolution of endothelin-1 as the most potent vasoconstrictor in the human
cardiovascular system with remarkably long lasting action. Highly selective
peptide ETA and ETB antagonists and ETB agonists together with radiolabeled
analogs have accurately delineated endothelin pharmacology in humans and animal
models, although surprisingly no ETA agonist has been discovered. ET antagonists
(bosentan, ambrisentan) have revolutionized the treatment of pulmonary arterial
hypertension, with the next generation of antagonists exhibiting improved
efficacy (macitentan). Clinical trials continue to explore new applications,
particularly in renal failure and for reducing proteinuria in diabetic
nephropathy. Translational studies suggest a potential benefit of ETB agonists in
chemotherapy and neuroprotection. However, demonstrating clinical efficacy of
combined inhibitors of the endothelin converting enzyme and neutral endopeptidase
has proved elusive. Over 28 genetic modifications have been made to the ET system
in mice through global or cell-specific knockouts, knock ins, or alterations in
gene expression of endothelin ligands or their target receptors. These studies
have identified key roles for the endothelin isoforms and new therapeutic targets
in development, fluid-electrolyte homeostasis, and cardiovascular and neuronal
function. For the future, novel pharmacological strategies are emerging via small
molecule epigenetic modulators, biologicals such as ETB monoclonal antibodies and
the potential of signaling pathway biased agonists and antagonists.
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