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      Endothelin

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          Abstract

          The endothelins comprise three structurally similar 21-amino acid 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 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 ET A and ET B antagonists and ET B agonists together with radiolabeled analogs 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 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 ET B monoclonal antibodies and the potential of signaling pathway biased agonists and antagonists.

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          Most cited references 585

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          Establishment in culture of pluripotential cells from mouse embryos.

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            Normalization of hemoglobin level in patients with chronic kidney disease and anemia.

            Whether correction of anemia in patients with stage 3 or 4 chronic kidney disease improves cardiovascular outcomes is not established. We randomly assigned 603 patients with an estimated glomerular filtration rate (GFR) of 15.0 to 35.0 ml per minute per 1.73 m2 of body-surface area and mild-to-moderate anemia (hemoglobin level, 11.0 to 12.5 g per deciliter) to a target hemoglobin value in the normal range (13.0 to 15.0 g per deciliter, group 1) or the subnormal range (10.5 to 11.5 g per deciliter, group 2). Subcutaneous erythropoietin (epoetin beta) was initiated at randomization (group 1) or only after the hemoglobin level fell below 10.5 g per deciliter (group 2). The primary end point was a composite of eight cardiovascular events; secondary end points included left ventricular mass index, quality-of-life scores, and the progression of chronic kidney disease. During the 3-year study, complete correction of anemia did not affect the likelihood of a first cardiovascular event (58 events in group 1 vs. 47 events in group 2; hazard ratio, 0.78; 95% confidence interval, 0.53 to 1.14; P=0.20). Left ventricular mass index remained stable in both groups. The mean estimated GFR was 24.9 ml per minute in group 1 and 24.2 ml per minute in group 2 at baseline and decreased by 3.6 and 3.1 ml per minute per year, respectively (P=0.40). Dialysis was required in more patients in group 1 than in group 2 (127 vs. 111, P=0.03). General health and physical function improved significantly (P=0.003 and P<0.001, respectively, in group 1, as compared with group 2). There was no significant difference in the combined incidence of adverse events between the two groups, but hypertensive episodes and headaches were more prevalent in group 1. In patients with chronic kidney disease, early complete correction of anemia does not reduce the risk of cardiovascular events. (ClinicalTrials.gov number, NCT00321919 [ClinicalTrials.gov].). Copyright 2006 Massachusetts Medical Society.
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              Expression of endothelin-1 in the lungs of patients with pulmonary hypertension.

              Pulmonary hypertension is characterized by an increase in vascular tone or an abnormal proliferation of muscle cells in the walls of small pulmonary arteries. Endothelin-1 is a potent endothelium-derived vasoconstrictor peptide with important mitogenic properties. It has therefore been suggested that endothelin-1 may contribute to increases in pulmonary arterial tone or smooth-muscle proliferation in patients with pulmonary hypertension. We studied the sites and magnitude of endothelin-1 production in the lungs of patients with various causes of pulmonary hypertension. We studied the distribution of endothelin-1-like immunoreactivity (by immunocytochemical analysis) and endothelin-1 messenger RNA (by in situ hybridization) in lung specimens from 15 control subjects, 11 patients with plexogenic pulmonary arteriopathy (grades 4 through 6), and 17 patients with secondary pulmonary hypertension and pulmonary arteriopathy of grades 1 through 3. In the controls, endothelin-1-like immunoreactivity was rarely seen in vascular endothelial cells. In the patients with pulmonary hypertension, endothelin-1-like immunoreactivity was abundant, predominantly in endothelial cells of pulmonary arteries with medial thickening and intimal fibrosis. Likewise, endothelin-1 messenger RNA was increased in the patients with pulmonary hypertension and was expressed primarily at sites of endothelin-1-like immunoreactivity. There was a strong correlation between the intensity of endothelin-1-like immunoreactivity and pulmonary vascular resistance in the patients with plexogenic pulmonary arteriopathy, but not in those with secondary pulmonary hypertension. Pulmonary hypertension is associated with the increased expression of endothelin-1 in vascular endothelial cells, suggesting that the local production of endothelin-1 may contribute to the vascular abnormalities associated with this disorder.
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                Author and article information

                Contributors
                Role: ASSOCIATE EDITOR
                Journal
                Pharmacol Rev
                Pharmacol. Rev
                pharmrev
                Pharmacol Rev
                PharmRev
                Pharmacological Reviews
                The American Society for Pharmacology and Experimental Therapeutics (Bethesda, MD )
                0031-6997
                1521-0081
                April 2016
                April 2016
                April 2016
                : 68
                : 2
                : 357-418
                Affiliations
                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
                Author notes
                Address correspondence to: Anthony P. Davenport, Experimental Medicine and Immunotherapeutics, University of Cambridge, Level 6, Centre for Clinical Investigation, Box 110, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK. E-mail: apd10@ 123456medschl.cam.ac.uk

                A.P.D. and K.A.H. contributed equally to this work.

                Article
                PHARMREV_011833
                10.1124/pr.115.011833
                4815360
                26956245
                Copyright © 2016 The Author(s)

                This is an open access article distributed under the CC-BY Attribution 4.0 International license.

                Page count
                Pages: 62
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