Hyndman, Kelly A
Kohan, Donald E
Pollock, Jennifer S
Pollock, David M
Webb, David J
American Society for Pharmacology and Experimental Therapeutics
MetadataShow full item record
Davenport, A., Hyndman, K. A., Dhaun, N., Southan, C., Kohan, D. E., Pollock, J. S., Pollock, D. M., et al. (2016). Endothelin. Pharmacological Reviews, 68 357-418. https://doi.org/10.1124/pr.115.011833
The endothelins comprise three structurally similar twenty-one amino acids peptides. Endothelin-1 and 2 activate two G-protein coupled receptors, ET_A and ET_B, with equal affinity whereas endothelin-3 has a lower affinity for the ET_A 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 ET_A and ET_B antagonists and ET_B agonists together with radiolabeled analogues have accurately delineated endothelin pharmacology in humans and animal models, although surprisingly no ET_A 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 ET_B 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 ET_B monoclonal antibodies and the potential of signaling pathway biased agonists and antagonists.
We (APD, JJM) thank the British Heart Foundation (PS/02/001, PG/05/127/19872, FS/12/64/130001), Wellcome Trust Programme in Metabolic and Cardiovascular Disease 096822/Z/11/Z NIHR Cambridge Biomedical Research Centre and the Pulmonary Hypertension Association UK; Wellcome Biomedical Resources Grant 099156/Z/12/Z for support for IUPHAR/BPS Guide to PHARMACOLOGY (CS). We acknowledge National Heart, Lung, and Blood Institute Grants P01 HL95499 (D.E.K., K.A.H., D.M.P., J.S.P.), P01 HL69999 (D.M.P., J.S.P.), U01HL117684 (D.M.P.).
Wellcome Trust (096822/Z/11/Z)
Embargo Lift Date
External DOI: https://doi.org/10.1124/pr.115.011833
This record's URL: https://www.repository.cam.ac.uk/handle/1810/253028