Abstract
Endothelin (ET) receptor antagonists used for the treatment of pulmonary arterial hypertension present different pharmacological profiles depending on their selectivity and affinity for ET receptors. Macitentan (MACI) is a new dual ETA/ETB tissue targeting receptor antagonist designed to achieve a more complete ET receptor blockade. To investigate this property, we designed a study in which rats were given MACI on top of maximally effective doses of either ambrisentan (AMBRI, ETA selective) or bosentan (BOS, dual ETA/ETB).
First, we measured the effects of single doses of the compounds on mean arterial blood pressure (MAP) in conscious Dahl salt-sensitive rats equipped with telemetry, and constructed dose-response curves. Maximal effective doses were 30 mg/kg for MACI and AMBRI and 100 mg/kg for BOS.
Next, we tested the potential for an additive effect of MACI on top of the now defined maximal effective doses of AMBRI and BOS.
MACI 30 mg/kg further decreased MAP by 17 mmHg when given on top of AMBRI 30 mg/kg (p<0.05 vs vehicle). In contrast, addition of AMBRI 30 mg/kg on top of AMBRI 30 mg/kg had no additional effect (5 mmHg vs vehicle, p=0.47), confirming use of the maximal effective dose of AMBRI. Conversely, AMBRI 30 mg/kg given on top of MACI 30 mg/kg failed to induce any additional MAP decrease.
In a similar experiment, MACI on top of maximal effective dose of BOS elicited a further MAP decrease of 21 mmHg (p<0.02 vs vehicle), whereas addition of BOS had no additional effect.
The add-on effect of macitentan on top of ambrisentan or bosentan confirms that this novel compound is able to achieve a more complete blockade of ET receptors and provides evidence for superior efficacy potential.
- © 2012 ERS
