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

J Cardiovasc Pharmacol. 1997 Jun;29(6):713-25. doi: 10.1097/00005344-199706000-00003.


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.

MeSH terms

  • Animals
  • Atrasentan
  • Blood Pressure / drug effects
  • Cardiomegaly / drug therapy
  • Cardiomegaly / etiology
  • Cardiomegaly / physiopathology
  • Endothelin Receptor Antagonists*
  • Endothelin-1 / blood
  • Heart Rate / drug effects
  • Hypertension, Pulmonary / drug therapy
  • Hypertension, Pulmonary / etiology
  • Hypertension, Pulmonary / physiopathology
  • Hypertension, Pulmonary / prevention & control*
  • Hypoxia / complications
  • Hypoxia / physiopathology*
  • Male
  • Pulmonary Artery / drug effects*
  • Pulmonary Artery / pathology
  • Pyrrolidines / therapeutic use*
  • Rats
  • Receptor, Endothelin A


  • Endothelin Receptor Antagonists
  • Endothelin-1
  • Pyrrolidines
  • Receptor, Endothelin A
  • Atrasentan