Sitaxentan is a highly selective endothelin (ET)(A) receptor antagonist, with an approximately 6500 higher affinity for ET(A) than ET(B) receptors. In pulmonary arterial hypertension (PAH), elevated ET-1 levels are strongly correlated with disease severity and prognosis. Sitaxentan 100 mg once daily was efficacious in the management of moderate to severe PAH in the pivotal, 12-18 week, large (n > or = 98), well designed, placebo-controlled STRIDE-1, -2 and -4 trials. In the STRIDE-1 and -2 trials (the majority of patients had New York Heart Association [NYHA]/WHO functional class III PAH), sitaxentan-treated patients experienced significantly greater improvements from baseline in distance walked over 6 minutes (6MWD; primary endpoint in STRIDE-2) and in NYHA/WHO functional class than placebo recipients. In STRIDE-4, although there was no between-group difference in terms of improvements in 6MWD in the primary analysis of patients across all WHO functional classes (61% were functional class II) [primary endpoint], improvements in 6MWD significantly favoured sitaxentan versus placebo-treated patients in a post hoc subgroup analysis of those with WHO functional class III or IV disease. The beneficial effects of sitaxentan therapy on exercise capacity and NYHA/WHO functional class were maintained after up to 2 years' treatment. Treatment with sitaxentan for up to 2 years was generally well tolerated in clinical trials.