title: Endothelin receptors and their antagonists.
abstract: All three members of the endothelin (ET) family of peptides, ET-1, ET-2, and ET-3, are expressed in the human kidney, with ET-1 being the predominant isoform. ET-1 and ET-2 bind to two G-protein-coupled receptors, ETA and ETB, whereas at physiological concentrations ET-3 has little affinity for the ET(A) receptor. The human kidney is unusual among the peripheral organs in expressing a high density of ET(B). The renal vascular endothelium only expresses the ET(B) subtype and ET-1 acts in an autocrine or paracrine manner to release vasodilators. Endothelial ETB in kidney, as well as liver and lungs, also has a critical role in scavenging ET-1 from the plasma. The third major function is ET-1 activation of ET(B) in in the nephron to reduce salt and water re-absorption. In contrast, ET(A) predominate on smooth muscle, causing vasoconstriction and mediating many of the pathophysiological actions of ET-1. The role of the two receptors has been delineated using highly selective ET(A) (BQ123, TAK-044) and ET(B) (BQ788) peptide antagonists. Nonpeptide antagonists, bosentan, macitentan, and ambrisentan, that are either mixed ET(A)/ET(B) antagonists or display ET(A) selectivity, have been approved for clinical use but to date are limited to pulmonary hypertension. Ambrisentan is in clinical trials in patients with type 2 diabetic nephropathy. This review summarizes ET-receptor antagonism in the human kidney, and considers the relative merits of selective versus nonselective antagonism in renal disease.
authors.affiliation: Clinical Pharmacology Unit, University of Cambridge, Addenbrooke׳s Hospital, Cambridge, United Kingdom.
authors.forename: Janet J
authors.initials: JJ
authors.lastname: Maguire
authors.affiliation: Clinical Pharmacology Unit, University of Cambridge, Addenbrooke׳s Hospital, Cambridge, United Kingdom. Electronic address: apd10@medschl.cam.ac.uk.
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Davenport
mesh_terms: D065128:Endothelin Receptor Antagonists / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000503:physiopathology*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D017466:Receptors, Endothelin / Q000378:metabolism*; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D065128:Endothelin Receptor Antagonists; D017466:Receptors, Endothelin
keywords: Ambrisentan; antagonist; bosentan; endothelin-1; macitentan; sitaxentan