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.