title: Modulation of endothelin receptors in the failing right ventricle of the heart and vasculature of the lung in human pulmonary arterial hypertension.
abstract: OBJECTIVE
  In pulmonary arterial hypertension (PAH), increases in endothelin-1 (ET-1) contribute to elevated pulmonary vascular resistance which ultimately causes death by right ventricular (RV) heart failure. ET antagonists are effective in treating PAH but lack efficacy in treating left ventricular (LV) heart failure, where ETA receptors are significantly increased. The aim was to quantify the density of ETA and ETB receptors in cardiopulmonary tissue from PAH patients and the monocrotaline (MCT) rat, which recapitulates some of the pathophysiological features, including increased RV pressure.
  
  
  METHODS
  Radioligand binding assays were used to quantify affinity, density and ratio of ET receptors.
  
  
  RESULTS
  In RV from human PAH hearts, there was a significant increase in the ratio of ETA to ETB receptors compared with normal hearts. In the RV of the MCT rat, the ratio also changed but was reversed. In both human and rat, there was no change in LV. In human PAH lungs, ETA receptors were significantly increased in the medial layer of small pulmonary arteries with no change detectable in MCT rat vessels.
  
  
  CONCLUSIONS
  Current treatments for PAH focus mainly on pulmonary vasodilatation. The increase in ETA receptors in arteries provides a mechanism for the beneficial vasodilator actions of ET antagonists. The increase in the ratio of ETA in RV also implicates changes to ET signalling although it is unclear if ET antagonism is beneficial but the results emphasise the unexploited potential for therapies that target the RV, to improve survival in patients with PAH.
authors.affiliation: Clinical Pharmacology Unit, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors.forename: Rhoda E
authors.initials: RE
authors.lastname: Kuc
authors.affiliation: Clinical Pharmacology Unit, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors.forename: Myrna
authors.initials: M
authors.lastname: Carlebur
authors.affiliation: Clinical Pharmacology Unit, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors.forename: Janet J
authors.initials: JJ
authors.lastname: Maguire
authors.affiliation: Clinical Pharmacology Unit, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors.forename: Peiran
authors.initials: P
authors.lastname: Yang
authors.affiliation: Department of Medicine, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors.forename: Lu
authors.initials: L
authors.lastname: Long
authors.affiliation: Department of Medicine, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Toshner
authors.affiliation: Department of Medicine, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Morrell
authors.affiliation: Clinical Pharmacology Unit, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK. Electronic address: apd10@medschl.cam.ac.uk.
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Davenport
mesh_terms: D000818:Animals; D001345:Autoradiography; D001381:Azepines / Q000378:metabolism; D001667:Binding, Competitive; D016022:Case-Control Studies; D006333:Heart Failure / Q000378:metabolism*; D006352:Heart Ventricles / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism*; D007211:Indoles / Q000378:metabolism; D007700:Kinetics; D008168:Lung / Q000098:blood supply* / Q000473:pathology; D008297:Male; D016686:Monocrotaline; D011651:Pulmonary Artery / Q000473:pathology*; D017207:Rats, Sprague-Dawley; D017466:Receptors, Endothelin / Q000378:metabolism*
chemical_list: D001381:Azepines; D007211:Indoles; D017466:Receptors, Endothelin; C079574:FR 139317; D016686:Monocrotaline
keywords: Affinity constant; Endothelin; FR139317; Pulmonary arterial hypertension; Radioligand binding; Receptor density