Anthony P Davenport, Kelly A. Hyndman, Neeraj Dhaun, Christopher Southan, Donald E. Kohan, Jennifer S. Pollock, David M. Pollock, David Webb, Janet McGuire

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Abstract - The endothelins comprise three structurally similar twenty-one amino acids 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 sub-type. Genes encoding the peptides are only present 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 analogues 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 twenty eight 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, 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.
Original languageEnglish
JournalPharmacological reviews
Publication statusPublished - 1 Apr 2016


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