title: Endothelin.
abstract: 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.
authors.affiliation: Experimental Medicine and Immunotherapeutics, University of Cambridge, Cambridge, United Kingdom (A.P.D., J.J.M.); IUPHAR/BPS Guide to PHARMACOLOGY, Centre for Integrative Physiology, University of Edinburgh, Hugh Robson Building, Edinburgh, United Kingdom (C.S.); Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, Utah (D.E.K.); Cardio-Renal Physiology & Medicine, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama (K.A.H., J.S.P., D.M.P.); and Department of Renal Medicine, Royal Infirmary of Edinburgh (N.D.) and University/British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute (D.J.W.N.D.), Edinburgh, Scotland, United Kingdom apd10@medschl.cam.ac.uk.
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Davenport
authors.affiliation: Experimental Medicine and Immunotherapeutics, University of Cambridge, Cambridge, United Kingdom (A.P.D., J.J.M.); IUPHAR/BPS Guide to PHARMACOLOGY, Centre for Integrative Physiology, University of Edinburgh, Hugh Robson Building, Edinburgh, United Kingdom (C.S.); Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, Utah (D.E.K.); Cardio-Renal Physiology & Medicine, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama (K.A.H., J.S.P., D.M.P.); and Department of Renal Medicine, Royal Infirmary of Edinburgh (N.D.) and University/British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute (D.J.W.N.D.), Edinburgh, Scotland, United Kingdom.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Hyndman
authors.affiliation: Experimental Medicine and Immunotherapeutics, University of Cambridge, Cambridge, United Kingdom (A.P.D., J.J.M.); IUPHAR/BPS Guide to PHARMACOLOGY, Centre for Integrative Physiology, University of Edinburgh, Hugh Robson Building, Edinburgh, United Kingdom (C.S.); Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, Utah (D.E.K.); Cardio-Renal Physiology & Medicine, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama (K.A.H., J.S.P., D.M.P.); and Department of Renal Medicine, Royal Infirmary of Edinburgh (N.D.) and University/British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute (D.J.W.N.D.), Edinburgh, Scotland, United Kingdom.
authors.forename: Neeraj
authors.initials: N
authors.lastname: Dhaun
authors.affiliation: Experimental Medicine and Immunotherapeutics, University of Cambridge, Cambridge, United Kingdom (A.P.D., J.J.M.); IUPHAR/BPS Guide to PHARMACOLOGY, Centre for Integrative Physiology, University of Edinburgh, Hugh Robson Building, Edinburgh, United Kingdom (C.S.); Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, Utah (D.E.K.); Cardio-Renal Physiology & Medicine, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama (K.A.H., J.S.P., D.M.P.); and Department of Renal Medicine, Royal Infirmary of Edinburgh (N.D.) and University/British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute (D.J.W.N.D.), Edinburgh, Scotland, United Kingdom.
authors.forename: Christopher
authors.initials: C
authors.lastname: Southan
authors.affiliation: Experimental Medicine and Immunotherapeutics, University of Cambridge, Cambridge, United Kingdom (A.P.D., J.J.M.); IUPHAR/BPS Guide to PHARMACOLOGY, Centre for Integrative Physiology, University of Edinburgh, Hugh Robson Building, Edinburgh, United Kingdom (C.S.); Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, Utah (D.E.K.); Cardio-Renal Physiology & Medicine, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama (K.A.H., J.S.P., D.M.P.); and Department of Renal Medicine, Royal Infirmary of Edinburgh (N.D.) and University/British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute (D.J.W.N.D.), Edinburgh, Scotland, United Kingdom.
authors.forename: Donald E
authors.initials: DE
authors.lastname: Kohan
authors.affiliation: Experimental Medicine and Immunotherapeutics, University of Cambridge, Cambridge, United Kingdom (A.P.D., J.J.M.); IUPHAR/BPS Guide to PHARMACOLOGY, Centre for Integrative Physiology, University of Edinburgh, Hugh Robson Building, Edinburgh, United Kingdom (C.S.); Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, Utah (D.E.K.); Cardio-Renal Physiology & Medicine, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama (K.A.H., J.S.P., D.M.P.); and Department of Renal Medicine, Royal Infirmary of Edinburgh (N.D.) and University/British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute (D.J.W.N.D.), Edinburgh, Scotland, United Kingdom.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Pollock
authors.affiliation: Experimental Medicine and Immunotherapeutics, University of Cambridge, Cambridge, United Kingdom (A.P.D., J.J.M.); IUPHAR/BPS Guide to PHARMACOLOGY, Centre for Integrative Physiology, University of Edinburgh, Hugh Robson Building, Edinburgh, United Kingdom (C.S.); Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, Utah (D.E.K.); Cardio-Renal Physiology & Medicine, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama (K.A.H., J.S.P., D.M.P.); and Department of Renal Medicine, Royal Infirmary of Edinburgh (N.D.) and University/British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute (D.J.W.N.D.), Edinburgh, Scotland, United Kingdom.
authors.forename: David M
authors.initials: DM
authors.lastname: Pollock
authors.affiliation: Experimental Medicine and Immunotherapeutics, University of Cambridge, Cambridge, United Kingdom (A.P.D., J.J.M.); IUPHAR/BPS Guide to PHARMACOLOGY, Centre for Integrative Physiology, University of Edinburgh, Hugh Robson Building, Edinburgh, United Kingdom (C.S.); Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, Utah (D.E.K.); Cardio-Renal Physiology & Medicine, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama (K.A.H., J.S.P., D.M.P.); and Department of Renal Medicine, Royal Infirmary of Edinburgh (N.D.) and University/British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute (D.J.W.N.D.), Edinburgh, Scotland, United Kingdom.
authors.forename: David J
authors.initials: DJ
authors.lastname: Webb
authors.affiliation: Experimental Medicine and Immunotherapeutics, University of Cambridge, Cambridge, United Kingdom (A.P.D., J.J.M.); IUPHAR/BPS Guide to PHARMACOLOGY, Centre for Integrative Physiology, University of Edinburgh, Hugh Robson Building, Edinburgh, United Kingdom (C.S.); Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, Utah (D.E.K.); Cardio-Renal Physiology & Medicine, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama (K.A.H., J.S.P., D.M.P.); and Department of Renal Medicine, Royal Infirmary of Edinburgh (N.D.) and University/British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute (D.J.W.N.D.), Edinburgh, Scotland, United Kingdom.
authors.forename: Janet J
authors.initials: JJ
authors.lastname: Maguire
mesh_terms: D000818:Animals; D065128:Endothelin Receptor Antagonists / Q000145:classification / Q000494:pharmacology; D016232:Endothelins / Q000378:metabolism; D006801:Humans; D017466:Receptors, Endothelin / Q000819:agonists / Q000737:chemistry / Q000378:metabolism
chemical_list: D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D017466:Receptors, Endothelin