We previously demonstrated that rats exposed to chronic hypoxia exhibit increased pulmonary artery pressure (PAP) and selective enhancement in lung endothelin-1 (ET-1) and ET-A receptor mRNA levels. The current study tested the hypothesis that A-127722, an orally active antagonist of the ET-A receptor, retards the development of pulmonary hypertension in rats exposed to chronic hypoxia. A-127722 (10mg/kg/day) or placebo was given in drinking water to 9-wk old male Sprague-Dawley rats for 4wk during continued hypoxic exposure (10% O2, 1 atm, 6wk). Mean PAP and mean systemic arterial pressure (SAP) were measured in conscious rats. Body weight (BW) was obtained and the right ventricle wall (RV) was weighed at the end of hypoxic or air exposure. Results are (means±SE): MPAP(mmHg) MSAP(mmHg) RV/BW (mg/g) 21% O2±placebo (13) 17±0.7 111±3.2 0.51± 0.02 2wk(10%O2+placebo) (11) 35±1.2*# 124±4.4 1.07±0.09*# 2wk 10%O2+4wk(10%O2+placebo)(3) 50±2.0* 115±2.9 1.36±0.12* 2wk 10%O2+4wk(10%O2+A127722)(8) 37±1.7*# 111±2.1 1.10±0.05*# * p<0.05, compared to air control group; # p<0.05, compared to 6wk hypoxia group. These findings support the hypothesis that ET-1 synthesized in the lung in response to hypoxia acts locally on ET-A receptors to cause pulmonary hypertension and right heart hypertrophy. The ET-A receptor antagonist both prevents and reverses these processes. This class of drugs offers promise for the treatment of hypoxic pulmonary hypertension in humans.