Characterization of endothelin receptors in the human pulmonary vasculature using bosentan, SB209670, and 97-139.

Endothelin-1 (ET-1) is believed to have a role in the pathogenesis of pulmonary hypertension, and ET antagonists may therefore be useful in the treatment of the disease. Here we have characterized ET receptors and ligands in human pulmonary tissues. Autoradiography showed ETA receptors located in resistance and conduit arteries and ETB receptors present in airway smooth muscle. Competition binding studies in human pulmonary artery (HPA) showed a predominance of the ETA subtype (90%). Bosentan (Ro470203) (Kd ETA = 12.5 nM, Kd ETB = 1.1 microM), SB209670 (Kd ETA = 14.3 nM, Kd ETB = 5.0 microM), and 97-139 (Kd ETA = 5.3 nM, Kd ETB = 19.6 microM) labeled ETA receptors with higher affinity than BMS182874 (50% [125I]ET-1 inhibition at 1 microM). Sarafotoxin S6c labeled ETB receptors with high affinity (Kd ETA = 0.16 microM, Kd ETB = 2.7 nM), whereas BQ788 competed with low affinity for [125I]ET-1 binding sites (Kd = 1.0 microM). This study indicates that an ETA-selective antagonist may be useful in reversing vasoconstriction associated with pulmonary hypertension without affecting ETB-mediated contractile effects in airway smooth muscle or ETB-mediated release of endothelium-derived vasodilators.