Biochemical and molecular biological evidence indicates that endothelin (ET)-1 and its receptors are selectively upregulated in the lung during exposure to hypoxia, while functional evidence indicates that ET-1 is a major mediator of hypoxia-induced pulmonary vasoconstriction and vascular remodeling. Hypoxia stimulates ET-1 gene transcription and peptide synthesis in cultured endothelial cells, and plasma ET-1 levels are increased in patients with primary pulmonary hypertension, and in humans exposed to high altitude, while immunoreactive ET-1 and ET-1 mRNA levels are increased in pulmonary artery endothelial cells of patients with primary pulmonary hypertension. Rats exposed to normobaric hypoxia exhibit increased pulmonary artery pressure, increased ET-1 peptide levels in plasma and lung, and selective increases in steady-state ET-1 and ET A and ET B receptor mRNA levels in lung but not in organs perfused by the systemic vasculature. The observations that both ET-1 and its major vascular smooth-muscle cell receptor are upregulated in response to hypoxia suggest that ET-1 may be a mediator of hypoxia-induced pulmonary hypertension. Moreover, hypoxic pulmonary vasocon-striction and vascular remodeling can be prevented and reversed by administration of either an ET A-selective or a combined ET A and ET B receptor antagonist. These findings support the hypothesis that endogenous ET-1 plays a major role in hypoxic pulmonary vasoconstriction/hypertension, right heart hypertrophy, and pulmonary vascular remodeling and suggest that ET-receptor blockers may be useful in the treatment and prevention of hypoxic pulmonary hypertension in humans.