title: Endothelin-1 receptor antagonists in fetal development and pulmonary arterial hypertension.
abstract: The Pregnancy Prevention Program (PPP) is in place to prevent drug-induced developmental malformations. Remarkably, among the ten PPP-enlisted drugs are three endothelin-1 (ET-1) receptor antagonists (ERA's: ambrisentan, bosentan and macitentan), which are approved for the treatment of Pulmonary Arterial Hypertension (PAH). This review describes the effects of ERA's in PAH pathobiology and cardiopulmonary fetal development. While ERA's hamper pathological remodeling of the pulmonary vasculature and as such exert beneficial effects in PAH, they disturb fetal development of cardiopulmonary tissues. By blocking ET-1-mediated positive inotropic effects and myocardial fetal gene induction, ERA's may affect right ventricular adaptation to the increased pulmonary vascular resistance in both the fetus and the adult PAH patient.
authors.affiliation: Pulmonary Hypertension Knowledge Center, Department of Pulmonology, VU University Medical Center/Institute for Cardiovascular Research, Amsterdam, The Netherlands.
authors.forename: Michiel Alexander
authors.initials: MA
authors.lastname: de Raaf
authors.affiliation: WIL Research Europe B.V., 's-Hertogenbosch, The Netherlands.
authors.forename: Manon
authors.initials: M
authors.lastname: Beekhuijzen
authors.affiliation: INSERM UMR_S 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France; University of Paris-Sud, School of Medicine, Kremlin-Bicêtre, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Guignabert
authors.affiliation: Pulmonary Hypertension Knowledge Center, Department of Pulmonology, VU University Medical Center/Institute for Cardiovascular Research, Amsterdam, The Netherlands.
authors.forename: Anton
authors.initials: A
authors.lastname: Vonk Noordegraaf
authors.affiliation: Pulmonary Hypertension Knowledge Center, Department of Pulmonology, VU University Medical Center/Institute for Cardiovascular Research, Amsterdam, The Netherlands. Electronic address: hj.bogaard@vumc.nl.
authors.forename: Harm Jan
authors.initials: HJ
authors.lastname: Bogaard
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000633:toxicity*; D062186:Arterial Pressure / Q000187:drug effects; D065128:Endothelin Receptor Antagonists / Q000633:toxicity*; D019332:Endothelin-1 / Q000378:metabolism*; D005260:Female; D005318:Fetal Heart / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005333:Fetus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D011651:Pulmonary Artery / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D017466:Receptors, Endothelin / Q000187:drug effects* / Q000378:metabolism; D018570:Risk Assessment; D015398:Signal Transduction / Q000187:drug effects; D066253:Vascular Remodeling / Q000187:drug effects
chemical_list: D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D017466:Receptors, Endothelin
keywords: ERA; ET-1; Endothelin receptor antagonist; Fetal development; Fetal gene program; PAH; Pulmonary arterial hypertension; Pulmonary vasculature