Phosphodiesterase type-5 inhibitors 
NO is a potent pulmonary arteries SMC relaxant that disposed vasodilator activity through up-regulation of its associated down-stream signalling molecule, cyclic GMP (cGMP), metabolism of which is dependent on the activation of a number of PDEs [208]. Phosphodiesterase type 3, 4 and 5 are the three main types of this enzyme found in pulmonary artery contractive cells. PDE-5 is the most abundantly expressed isoform in pulmonary circulation which was confirmed by several experimental investigations showing a beneficial effect of PDE-5 inhibitors on vascular remodelling and vasodilatation [234,235].
Sildenafil Sildenafil is an oral PDE-5 inhibitor that is available in Europe since 2005 for PAH patients in functional class II-III whereas this drug is licensed in Canada and the USA for patients in functional class II-IV. Basis for the authorization of this drug in the setting of PAH was a large randomized, placebo-controlled trial in which different doses of sildenafil were assessed in 278 patients presenting with idiopathic PAH, PAH related to CTD or congenital systemic to pulmonary shunts surgically corrected. The majority of study patients were in functional class II-III. After three months of treatment, the mean placebo-adjusted changes in 6-MWD for 20 mg, 40 mg and 80 mg doses of sildenafil were 45 meters, 46 meters and 50 meters, respectively. Furthermore, significant hemodynamic and functional class improvements were noted in every sildenafil group as compared to placebo. Common side effects of treatment with sildenafil include headache, flushing and dyspepsia but no hepatic enzymes increase was noted as compared with endothelin receptor antagonists. Long term extension data from 222 patients who completed one year of sildenafil monotherapy with a dose of 80 mg three times daily showed encouraging results with a gain in 6-MWD, suggesting a durable treatment effect [236]. However, sildenafil approval in Europe is currently limited to 20 mg three times a day. No data is currently available on the long-term efficacy of this lower dosage.
Tadalafil Another PDE-5 inhibitor is tadalafil which was granted for use in patients with PAH in Europe and North America in 2009. Galiè and colleagues [237] assessed in the PHIRST trial 405 randomly assigned patients who were either treatment naïve or already receiving bosentan therapy to placebo or one of the several proposed doses of tadalafil 2.5 mg or 10 mg or 20 mg or 40 mg once daily for a period of three months. At study completion, patients receiving tadalafil showed an overall mean placebo-correlated increase in 6-MWD of 33 meters [208]. Thus, this increase was dose-dependent, with only the 40 mg dose achieving the prespecified value for statistical significance for improvement. Data analysis of comparative hemodynamic data from 93 patients who underwent repeat RHC has significant reduction in mPAP and PVR under treatment with tadalafil. Barst and co-authors [238] underlined favourable effects with tadalafil 40 mg among patients receiving background bosentan, although improvements were less marked compared with treatment naïve cohort.