Objective Pulmonary hypertension (PHT) is associated with increased endothelin-1 (ET-1) levels that correlate with the severity of the disease. The pulmonary circulation is an important site for ET-1 metabolism and may modulate plasma ET-1 through an increase in production, a reduction in removal, or a combination of both. We measured and compared pulmonary metabolism of circulating ET-1 in controls and in patients with PHT. Methods and Results The indicator-dilution technique was combined with measurements of ET-1 levels to quantify pulmonary metabolism of ET-1 in controls (n = 13) and in patients with PHT (n=17). ET-1 levels doubled in PHT (p < 0.05) and, although there was no difference between aortic and pulmonary artery levels in controls (0.68 ± 0.09 and 0.61 ± 0.08 pg/ml, respectively, p=0.22), they tended to be higher in PHT (1.23 ± 0.26 vs 1.07 ± 0.19 pg/ml, p=0.08). Pulmonary extraction of tracer iodine-125–ET-1 was reduced from 47% ± 2.0% in the controls to 34% ±3.6% in PHT (p = 0.005) and inversely correlated with the severity of pulmonary hypertension (r = –0.524, p = 0.03). Consequently, circulating ET-1 clearance was reduced by PHT from 1424± 77 ml/min to 892 ± 119 ml/min (p < 0.001). Pulmonary production of circulating ET-1 (in picograms per minute) was not different but the quantity of ET-1 that survives passage through the lungs was increased by PHT (1860 ± 359 pg/min vs 992±152pg/min, p = 0.037). Conclusion PHT is associated with a reduced pulmonary clearance of ET-1 that contributes to the increase in circulating levels. (Am Heart J 1998;135:614-20.)