Reduced pulmonary clearance of endothelin-1 in pulmonary hypertension

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.

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+/-152 pg/min, p = 0.037).

PHT is associated with a reduced pulmonary clearance of ET-1 that contributes to the increase in circulating levels.