The orally active nonpeptide endothelin A-receptor antagonist A-127722 prevents and reverses hypoxia-induced pulmonary hypertension and pulmonary vascular remodeling in Sprague-Dawley rats.
Exposure to hypoxia is associated with increased pulmonary artery pressure and plasma endothelin (ET-1) levels and with selective enhancement of ET-1 peptide and messenger RNA (mRNA) and endothelin-A (ET-A) receptor mRNA in rat lung. Our study tested the hypothesis that A-127722, an orally active antagonist of the ET-A receptor, can prevent hypoxia-induced pulmonary hypertension and vascular remodeling in the rat. Pretreatment with A-127722 (3, 10, and 30 mg/kg/day in drinking water for 2 days) caused dose-dependent inhibition of the pulmonary vasoconstrictor response to short-term hypoxia (10% O2, 90 min). Long-term A-127722 treatment (10 mg/kg/day in drinking water for 2 weeks) instituted 48 h before hypoxic exposure attenuated the subsequent development of pulmonary hypertension, the associated right atrial hypertrophy, and pulmonary vascular remodeling. Institution of A-127722 treatment (10 mg/kg/day in drinking water for 4 weeks) after 2 weeks of hypoxia retarded the progression of established hypoxia-induced pulmonary hypertension and right atrial hypertrophy and reversed the pulmonary vascular remodeling despite continuing hypoxic exposure. 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-A receptor blockers may be useful in the treatment and prevention of hypoxic pulmonary hypertension in humans.
Chen
S J
SJ
Vascular Biology and Hypertension Program, Division of Cardiovascular Disease, University of Alabama at Birmingham, 35294-0007, USA.
Chen
Y F
YF
Opgenorth
T J
TJ
Wessale
J L
JL
Meng
Q C
QC
Durand
J
J
DiCarlo
V S
VS
Oparil
S
S
D000818:Animals; D000077868:Atrasentan; D001794:Blood Pressure / Q000187:drug effects; D006332:Cardiomegaly / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood; D006339:Heart Rate / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D000860:Hypoxia / Q000150:complications / Q000503:physiopathology*; D008297:Male; D011651:Pulmonary Artery / Q000187:drug effects* / Q000473:pathology; D011759:Pyrrolidines / Q000627:therapeutic use*; D051381:Rats; D044022:Receptor, Endothelin A
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; D000077868:Atrasentan