Comparison of pharmacological activity of macitentan and bosentan in preclinical models of systemic and pulmonary hypertension

Life Sci. 2014 Nov 24;118(2):333-9. doi: 10.1016/j.lfs.2014.02.018. Epub 2014 Feb 26.


Aims: The endothelin (ET) system is a tissular system, as the production of ET isoforms is mostly autocrine or paracrine. Macitentan is a novel dual ETA/ETB receptor antagonist with enhanced tissue distribution and sustained receptor binding properties designed to achieve a more efficacious ET receptor blockade. To determine if these features translate into improved efficacy in vivo, a study was designed in which rats with either systemic or pulmonary hypertension and equipped with telemetry were given macitentan on top of maximally effective doses of another dual ETA/ETB receptor antagonist, bosentan, which does not display sustained receptor occupancy and shows less tissue distribution.

Main methods: After establishing dose-response curves of both compounds in conscious, hypertensive Dahl salt-sensitive and pulmonary hypertensive bleomycin-treated rats, macitentan was administered on top of the maximal effective dose of bosentan.

Key findings: In hypertensive rats, macitentan 30 mg/kg further decreased mean arterial blood pressure (MAP) by 19 mm Hg when given on top of bosentan 100 mg/kg (n=9, p<0.01 vs. vehicle). Conversely, bosentan given on top of macitentan failed to induce an additional MAP decrease. In pulmonary hypertensive rats, macitentan 30 mg/kg further decreased mean pulmonary artery pressure (MPAP) by 4 mm Hg on top of bosentan (n=8, p<0.01 vs. vehicle), whereas a maximal effective dose of bosentan given on top of macitentan did not cause any additional MPAP decrease.

Significance: The add-on effect of macitentan on top of bosentan in two pathological models confirms that this novel compound can achieve a superior blockade of ET receptors and provides evidence for greater maximal efficacy.

Keywords: Blood pressure; Endothelin; Pharmacology; Pulmonary hypertension; Rat.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bleomycin
  • Bosentan
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Endothelin Receptor Antagonists / blood
  • Endothelin Receptor Antagonists / pharmacology
  • Endothelin Receptor Antagonists / therapeutic use
  • Hypertension, Pulmonary / blood
  • Hypertension, Pulmonary / drug therapy*
  • Pyrimidines / blood
  • Pyrimidines / pharmacology*
  • Pyrimidines / therapeutic use
  • Rats
  • Rats, Inbred Dahl
  • Reproducibility of Results
  • Sulfonamides / blood
  • Sulfonamides / pharmacology*
  • Sulfonamides / therapeutic use


  • Endothelin Receptor Antagonists
  • Pyrimidines
  • Sulfonamides
  • Bleomycin
  • Bosentan
  • macitentan