Endothelin receptors antagonists 
Endothelin-1 (ET-1) is a potent vasoconstrictor and therefore plays an important role in the pathogenesis of PAH. In addition, it is responsible for smooth muscle cell proliferation [158]. Elevated ET-1 plasma levels are found in patients suffering from PAH and are correlated with poor prognosis. There are two existing isoforms of ET-1 receptors: endothelin A (ETRA) and endothelin B (ETRB). Activation of ETRA and ETRB on pulmonary artery smooth muscle cells induce proliferation and vasoconstriction, whereas activation of ETRB on pulmonary endothelial cells leads to release of NO and prostacyclin and participate to the clearance of circulating ET-1.
Bosentan Bosentan is an oral active dual ETRA and ETRB antagonist. Bosentan has been evaluated in PAH (idiopathic, associated with CTD, and Eisenmenger’s syndrome) in five RCT’s (Pilot, BREATHE-1, BREATHE-2, BREATHE-5, and EARLY) that have shown improvement in exercise capacity, functional class, haemodynamic, echocardiographic and Doppler variables, and time to clinical worsening [107,225-228]. The first placebo-controlled study included 32 patients affected by idiopathic PAH or scleroderma presenting with PAH showing significant exercise improvement with a gain of 76 meters after three months of treatment with bosentan as compared to placebo [225].
The BREATHE 1 study confirmed the efficacity of treatment with Bosentan in more than 200 assessed patients in NYHA functional class III or IV compared to placebo in a three month trial. After three months of treatment with bosentan, improvements in NYHA functional class were observed in 42% of patients receiving bosentan compared with 30% in the placebo arm. 6-MWD was improved overall to 44 meters in favor of bosentan. Furthermore, delayed time to clinical worsening was also noted as well as better results in dynpnea scores [226]. One accepted common side effect of treatment is increase in liver enzymes; this is why monthly monitoring of liver transaminases is mandatory in all patients receiving bosentan. Treatment is started at a dose of 62.5 mg twice a day and increased to the dose of 125 mg twice daily after one month of treatment.
Subsequently published data of treatment with bosentan suggested persistent improvements in pulmonary hemodynamics, exercise capacity and modified NYHA functional class and possibly survival rate of patients [229-231]. Results from the EARLY study (double-blind, randomised controlled 6 months trial) showed that the effect of the dual endothelin receptor antagonist bosentan in patients with mildly symptomatic PAH could be beneficial for PAH patients in NYHA functional class II [228].
Ambrisentan Ambrisentan is a selective ETA receptor antagonist administrated once daily at a dose of 5 mg or 10 mg. Two large RCTs (ARIES I and II, i.e. Ambrisentan in Pulmonary Hypertension, Randomized, Double blind, Placebo-controlled Multicenter, Efficacy Studies I and II) have demonstrated efficacy on symptoms, haemodynamics and time to clinical worsening of patients with idiopathic PAH and associated to CTD and HIV infection [232]. An extension study of the ARIES study is the recently published ARIES-E study by Klinger and colleagues [233]. They followed patients for a mean period of 60 weeks in where patients underwent hemodynamic evaluation. The authors concluded that treatment with ambrisentan leads to hemodynamic stability in PAH patients.