title: Therapeutic efficacy of TBC3711 in monocrotaline-induced pulmonary hypertension.
abstract: BACKGROUND
  Endothelin-1 signalling plays an important role in pathogenesis of pulmonary hypertension. Although different endothelin-A receptor antagonists are developed, a novel therapeutic option to cure the disease is still needed. This study aims to investigate the therapeutic efficacy of the selective endothelin-A receptor antagonist TBC3711 in monocrotaline-induced pulmonary hypertension in rats.
  
  
  METHODS
  Monocrotaline-injected male Sprague-Dawley rats were randomized and treated orally from day 21 to 35 either with TBC3711 (Dose: 30 mg/kg body weight/day) or placebo. Echocardiographic measurements of different hemodynamic and right-heart hypertrophy parameters were performed. After day 35, rats were sacrificed for invasive hemodynamic and right-heart hypertrophy measurements. Additionally, histologic assessment of pulmonary vascular and right-heart remodelling was performed.
  
  
  RESULTS
  The novel endothelin-A receptor antagonist TBC3711 significantly attenuated monocrotaline-induced pulmonary hypertension, as evident from improved hemodynamics and right-heart hypertrophy in comparison with placebo group. In addition, muscularization and medial wall thickness of distal pulmonary vessels were ameliorated. The histologic evaluation of the right ventricle showed a significant reduction in fibrosis and cardiomyocyte size, suggesting an improvement in right-heart remodelling.
  
  
  CONCLUSIONS
  The results of this study suggest that the selective endothelin-A receptor antagonist TBC3711 demonstrates therapeutic benefit in rats with established pulmonary hypertension, thus representing a useful therapeutic approach for treatment of pulmonary hypertension.
authors.affiliation: University of Giessen Lung Center, Giessen, Germany.
authors.forename: Djuro
authors.initials: D
authors.lastname: Kosanovic
authors.forename: Baktybek
authors.initials: B
authors.lastname: Kojonazarov
authors.forename: Himal
authors.initials: H
authors.lastname: Luitel
authors.forename: Bhola K
authors.initials: BK
authors.lastname: Dahal
authors.forename: Akylbek
authors.initials: A
authors.lastname: Sydykov
authors.forename: Teodora
authors.initials: T
authors.lastname: Cornitescu
authors.forename: Wiebke
authors.initials: W
authors.lastname: Janssen
authors.forename: Ralf P
authors.initials: RP
authors.lastname: Brandes
authors.forename: Neil
authors.initials: N
authors.lastname: Davie
authors.forename: Hossein A
authors.initials: HA
authors.lastname: Ghofrani
authors.forename: Norbert
authors.initials: N
authors.lastname: Weissmann
authors.forename: Friedrich
authors.initials: F
authors.lastname: Grimminger
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.forename: Ralph T
authors.initials: RT
authors.lastname: Schermuly
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D015150:Echocardiography, Doppler; D065130:Endothelin A Receptor Antagonists; D005355:Fibrosis; D006439:Hemodynamics / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D007555:Isoxazoles / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D016686:Monocrotaline; D011651:Pulmonary Artery / Q000187:drug effects / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A / Q000378:metabolism; D013450:Sulfones / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors; D016278:Ventricular Function, Right / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D000959:Antihypertensive Agents; D065130:Endothelin A Receptor Antagonists; D007555:Isoxazoles; C485107:N-(2-acetyl-4,6-dimethylphenyl)-3-(3,4-dimethylisoxazol-5-ylsulfamoyl)thiophene-2-carboxamide; D044022:Receptor, Endothelin A; D013450:Sulfones; D016686:Monocrotaline