Endothelin and pulmonary hypertension.
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 vasoconstriction 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.
Chen
Y F
YF
Department of Medicine, Birmingham, Alabama, USA.
Oparil
S
S
D000818:Animals; D002478:Cells, Cultured; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000235:genetics / Q000503:physiopathology*; D000860:Hypoxia / Q000503:physiopathology; D051381:Rats; D017466:Receptors, Endothelin / Q000502:physiology*; D014661:Vasoconstriction / Q000502:physiology
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D017466:Receptors, Endothelin