title: Comparison of Macitentan and Bosentan on Right Ventricular Remodeling in a Rat Model of Non-vasoreactive Pulmonary Hypertension.
abstract: OBJECTIVE
  We compared the efficacy of macitentan, a novel dual endothelin A/endothelin B receptor antagonist, with that of another dual endothelin receptor antagonist, bosentan, in a rat model of non-vasoreactive pulmonary hypertension (PH) with particular emphasis on right ventricular (RV) remodeling.
  
  
  RESULTS
  Unlike monocrotaline or hypoxic/sugen rats, bleomycin-treated rats presented a non-vasoreactive PH characterized by the absence of pulmonary dilatation to adenosine. We therefore chose the bleomycin rat model to compare the effects of the maximally effective doses of macitentan and bosentan on pulmonary vascular and RV remodeling. Macitentan (100 mg·kg(-1)·d(-1)), but not bosentan (300 mg·kg(-1)·d(-1)), significantly prevented pulmonary vascular remodeling, RV hypertrophy, and cardiomyocyte diameter increase. Cardiac protection by macitentan was associated with a significant attenuation of genes related to cell hypertrophy and extracellular matrix remodeling. Microautoradiography and high performance liquid chromatography analysis showed greater distribution of macitentan than bosentan in the RV and pulmonary tissue.
  
  
  CONCLUSIONS
  Macitentan was more efficacious than bosentan in preventing the development of pulmonary and RV hypertrophies in a model of non-vasoreactive PH. Greater ability to distribute into the tissue could contribute to the greater structural improvement by macitentan compared with bosentan.
authors.affiliation: *Drug Discovery Department, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland; and †Covance Laboratories Ltd, Harrogate, North Yorkshire, England.
authors.forename: Marc
authors.initials: M
authors.lastname: Iglarz
authors.forename: Kyle
authors.initials: K
authors.lastname: Landskroner
authors.forename: Yasmina
authors.initials: Y
authors.lastname: Bauer
authors.forename: Magali
authors.initials: M
authors.lastname: Vercauteren
authors.forename: Markus
authors.initials: M
authors.lastname: Rey
authors.forename: Berengère
authors.initials: B
authors.lastname: Renault
authors.forename: Rolf
authors.initials: R
authors.lastname: Studer
authors.forename: Enrico
authors.initials: E
authors.lastname: Vezzali
authors.forename: Diego
authors.initials: D
authors.lastname: Freti
authors.forename: Hakim
authors.initials: H
authors.lastname: Hadana
authors.forename: Manuela
authors.initials: M
authors.lastname: Schläpfer
authors.forename: Christophe
authors.initials: C
authors.lastname: Cattaneo
authors.forename: Céline
authors.initials: C
authors.lastname: Bortolamiol
authors.forename: Edgar
authors.initials: E
authors.lastname: Weber
authors.forename: Brian R
authors.initials: BR
authors.lastname: Whitby
authors.forename: Stéphane
authors.initials: S
authors.lastname: Delahaye
authors.forename: Daniel
authors.initials: D
authors.lastname: Wanner
authors.forename: Pauline
authors.initials: P
authors.lastname: Steiner
authors.forename: Oliver
authors.initials: O
authors.lastname: Nayler
authors.forename: Patrick
authors.initials: P
authors.lastname: Hess
authors.forename: Martine
authors.initials: M
authors.lastname: Clozel
mesh_terms: D000818:Animals; D001761:Bleomycin; D000077300:Bosentan; D004195:Disease Models, Animal; D065128:Endothelin Receptor Antagonists / Q000494:pharmacology*; D005786:Gene Expression Regulation; D006352:Heart Ventricles / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D011743:Pyrimidines / Q000494:pharmacology*; D017208:Rats, Wistar; D013449:Sulfonamides / Q000494:pharmacology*; D013997:Time Factors; D066253:Vascular Remodeling / Q000187:drug effects; D016278:Ventricular Function, Right / Q000187:drug effects*; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D065128:Endothelin Receptor Antagonists; D011743:Pyrimidines; D013449:Sulfonamides; D001761:Bleomycin; D000077300:Bosentan; C533860:macitentan