title: Vascular Effects of Endothelin Receptor Antagonists Depends on Their Selectivity for ETA Versus ETB Receptors and on the Functionality of Endothelial ETB Receptors.
abstract: BACKGROUND
  The goal of this study was to characterize the role of Endothelin (ET) type B receptors (ETB) on vascular function in healthy and diseased conditions and demonstrate how it affects the pharmacological activity of ET receptor antagonists (ERAs).
  
  
  METHODS
  The contribution of the ETB receptor to vascular relaxation or constriction was characterized in isolated arteries from healthy and diseased rats with systemic (Dahl-S) or pulmonary hypertension (monocrotaline). Because the role of ETB receptors is different in pathological vis-à-vis normal conditions, we compared the efficacy of ETA-selective and dual ETA/ETB ERAs on blood pressure in hypertensive rats equipped with telemetry.
  
  
  RESULTS
  In healthy vessels, ETB receptors stimulation with sarafotoxin S6c induced vasorelaxation and no vasoconstriction. In contrast, in arteries of rats with systemic or pulmonary hypertension, endothelial ETB-mediated relaxation was lost while vasoconstriction on stimulation by sarafotoxin S6c was observed. In hypertensive rats, administration of the dual ETA/ETB ERA macitentan on top of a maximal effective dose of the ETA-selective ERA ambrisentan further reduced blood pressure, indicating that ETB receptors blockade provides additional benefit.
  
  
  CONCLUSIONS
  Taken together, these data suggest that in pathology, dual ETA/ETB receptor antagonism can provide superior vascular effects compared with ETA-selective receptor blockade.
authors.affiliation: Drug Discovery Department, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
authors.forename: Marc
authors.initials: M
authors.lastname: Iglarz
authors.forename: Pauline
authors.initials: P
authors.lastname: Steiner
authors.forename: Daniel
authors.initials: D
authors.lastname: Wanner
authors.forename: Markus
authors.initials: M
authors.lastname: Rey
authors.forename: Patrick
authors.initials: P
authors.lastname: Hess
authors.forename: Martine
authors.initials: M
authors.lastname: Clozel
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D065130:Endothelin A Receptor Antagonists / Q000494:pharmacology*; D065131:Endothelin B Receptor Antagonists / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000378:metabolism; D066298:In Vitro Techniques; D009569:Nitric Oxide / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism; D020303:Rats, Inbred Dahl; D017208:Rats, Wistar; D044022:Receptor, Endothelin A / Q000378:metabolism*; D044023:Receptor, Endothelin B / Q000378:metabolism*; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D009569:Nitric Oxide