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Tmax was determined to be 6?h for bosentan and 24?h for macitentan. The use of maximal effective doses of macitentan and bosentan was confirmed using the add-on protocol: macitentan 30?mg/kg administered on top of macitentan 30?mg/kg did not cause an additional MPAP decrease compared to vehicle on top of macitentan (??18?��?2 and ??13?��?2?mm?Hg, p?=?0.112). Similarly, as shown in Fig.?4, bosentan 300?mg/kg administered when the maximal effect of bosentan 300?mg/kg was reached did not cause an additional MPAP decrease compared to vehicle on top of bosentan (??8?��?1 and ??7?��?1?mm?Hg, respectively). Oral administration of macitentan 30?mg/kg to bleomycin rats, when the maximal effect of bosentan 300?mg/kg http://www.selleckchem.com/products/Neratinib(HKI-272).html had been reached, induced an additional MPAP decrease compared to vehicle administered on top of bosentan 300?mg/kg. The maximal decrease induced by macitentan on top of bosentan was ??11?��?1?mm?Hg (p? http://www.selleckchem.com/products/Roscovitine.html active metabolite ACT-132577, ruling out a modification of macitentan pharmacokinetics by bosentan during the add-on protocol. Comparison of efficacy between compounds is rarely assessed fairly as it requires generating full dose�Cresponse curves in order to appropriately compare maximal effects. In our study, dose�Cresponse curves were established in conscious rats with either systemic or pulmonary hypertension. We compared the maximal efficacy of macitentan and bosentan both in DSS rats and in the bleomycin rat model of PH associated with lung fibrosis. Unlike the monocrotaline rat model that develops rapidly progressing PH leading to death (Ryan et al., 2011?and?Rey et al., 2012), bleomycin-treated rats develop a moderate but constant https://en.wikipedia.org/wiki/Quinapyramine and sustained increase in pulmonary pressure, which allows the study of hemodynamics over a long period of time without dramatic changes in MPAP (Williams et al., 1992). Macitentan achieved a superior blood pressure reduction compared to bosentan in both animal models: ??30?��?5?mm?Hg vs. ??15?��?2?mm?Hg on MAP, respectively, in DSS rats, and ??12?��?3?mm?Hg vs. ??7?��?2?mm?Hg on MPAP, respectively, in bleomycin rats. In addition to these results, we used an ��add-on�� protocol to confirm and demonstrate the superior pharmacological activity of macitentan vs. bosentan. In both models, macitentan was able to induce a further blood pressure reduction when given on top of the maximal efficacious dose of bosentan, whereas the opposite was not true, suggesting that macitentan is able to block more efficiently ET receptors.