title: Macitentan treatment retards the progression of established pulmonary arterial hypertension in an animal model.
abstract: BACKGROUND
  Macitentan is a new endothelin receptor antagonist that is used to treat pulmonary arterial hypertension in humans. Treatment of established pulmonary hypertension with macitentan was studied using the monocrotaline model of pulmonary hypertension.
  
  
  METHODS
  Three groups of rats were created (n=12): control (CON: macitentan only), monocrotaline (MCT: monocrotaline only) and macitentan (MACI: macitentan and monocrotaline). Monocrotaline (60 mg/kg) was injected in the MCT and MACI groups on day 0; volume matched saline was injected in the CON groups. Macitentan therapy (30 mg/kg/day) was commenced on day 11 in the CON and MACI groups. Serial echocardiography and ECGs were performed. The rats were sacrificed if they showed clinical deterioration.
  
  
  RESULTS
  The MCT and MACI rats showed signs of pulmonary hypertension by day 7 (maximum pulmonary velocity, CON 1.15 ± 0.15m/s vs MCT 1.04 ± 0.10 m/s vs MACI 0.99 ± 0.18 m/s; p<0.05). Both the MCT and MACI groups developed pulmonary hypertension, but this was less severe in the MACI group (day 21 pulmonary artery acceleration time, MCT 17.55 ± 1.56 ms vs MACI 22.55 ± 1.00 ms; pulmonary artery deceleration, MCT 34.72 ± 3.72 m/s(2) vs MACI 17.30 ± 1.89 m/s(2); p<0.05). Right ventricular hypertrophy and QT interval increases were more pronounced in MCT than MACI (right ventricle wall thickness, MCT 0.13 ± 0.1cm vs MACI 0.10 ± 0.1cm; QT interval, MCT 85 ± 13 ms vs MACI 71 ± 14 ms; p<0.05). Survival benefit was not seen in the MACI group (p=0.50).
  
  
  CONCLUSIONS
  Macitentan treatment improves haemodynamic parameters in established pulmonary hypertension. Further research is required to see if earlier introduction of macitentan has greater effects.
authors.affiliation: Institute of Cardiovascular Sciences, University of Manchester, UK. Electronic address: ian.temple@manchester.ac.uk.
authors.forename: I P
authors.initials: IP
authors.lastname: Temple
authors.affiliation: Institute of Cardiovascular Sciences, University of Manchester, UK.
authors.forename: O
authors.initials: O
authors.lastname: Monfredi
authors.affiliation: Institute of Cardiovascular Sciences, University of Manchester, UK.
authors.forename: G
authors.initials: G
authors.lastname: Quigley
authors.affiliation: Institute of Cardiovascular Sciences, University of Manchester, UK.
authors.forename: H
authors.initials: H
authors.lastname: Schneider
authors.affiliation: Institute of Cardiovascular Sciences, University of Manchester, UK.
authors.forename: M
authors.initials: M
authors.lastname: Zi
authors.affiliation: Institute of Cardiovascular Sciences, University of Manchester, UK.
authors.forename: E J
authors.initials: EJ
authors.lastname: Cartwright
authors.affiliation: Institute of Cardiovascular Sciences, University of Manchester, UK.
authors.forename: M R
authors.initials: MR
authors.lastname: Boyett
authors.affiliation: Central Manchester University Hospitals NHS Trust, UK.
authors.forename: V S
authors.initials: VS
authors.lastname: Mahadevan
authors.affiliation: Institute of Cardiovascular Sciences, University of Manchester, UK.
authors.forename: G
authors.initials: G
authors.lastname: Hart
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D065128:Endothelin Receptor Antagonists / Q000627:therapeutic use*; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000473:pathology*; D008297:Male; D011743:Pyrimidines / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D013449:Sulfonamides / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D065128:Endothelin Receptor Antagonists; D011743:Pyrimidines; D013449:Sulfonamides; C533860:macitentan
keywords: ECG; Echocardiogram; Macitentan; Monocrotaline; Pulmonary arterial hypertension; Pulmonary hypertension