Background - Primary pulmonary hypertension results from progressive narrowing of the precapillary pulmonary vasculature. A variety of endothelial abnormalities have been identified, including a net reduction in pulmonary clearance of the vasoconstrictor and smooth muscle mitogen endothelin-1. In many patients, net pulmonary release of endothelin-1 is observed. Chronic infusions of epoprostenol (prostacyclin) improve functional capacity, survival, and hemodynamics in patients with advanced primary pulmonary hypertension. We hypothesized that the epoprostenol infusions, as compared with conventional therapy, might alter the abnormal pulmonary endothelin-1 homeostasis. Methods and Results - Using a subset of patients from a larger randomized study comparing epoprostenol plus conventional therapy (n=11 in the present study) with conventional therapy alone (n=7 in the present study), we determined the ratio of plasma endothelin-1 levels in systemic arterial blood leaving the lung to levels in mixed venous blood entering the lung both before randomization and after 88 days of continuous therapy. There were no differences between the 2 groups before therapy, but by day 88, the epoprostenol-treated group had a greater proportion of patients (82%) with an arterial/venous ratio <1 than did the conventional therapy group, in which only 29% of patients had a ratio <1 (P<0.05). Conclusions - These results suggest that continuous epoprostenol therapy may have a beneficial effect on the balance between endothelin-1 clearance and release in many patients with primary pulmonary hypertension and may provide one explanation for the salutary effect of epoprostenol in this disease.