We investigated the effects of two types of endothelin receptor antagonists on pulmonary hypertension induced by pulmonary air embolization in awake sheep. We prepared awake sheep with indwelling catheters inserted in blood vessels for continuous monitoring of pulmonary artery pressure, left atrial pressure and systemic arterial pressure. Cardiac output was measured every 30 min. The study consisted of two experiments, one with FR139317 (100 microg/kg/min; (R)2-[(R)-2-[(S)-2-[1-(hexahydro-1H-azepinyl)]-carbonyl]amino-4-++ +methy l-pentanoyl]amino-3-[3-(1-methyl-1H-indolyl)]propionyl)amino-3-(2-pyr idyl)propionic acid), a selective endothelin ET(A) receptor antagonist, and the other with TAK-044 (100 microg/kg/h; cyclo[D-alpha-aspartyl-3-[(4-phenylpiperazin-yl)carbonyl]-L-alanyl -L- alpha- aspartyl-D-2-(2-thienyl) glycyl-L-leucyl-D-tryptophyl] disodium salt), an endothelin ET(A) and ET(B) receptor antagonist. In the paired experiments, air was continuously (4.06 ml/min) infused into the main pulmonary artery for 3 h after the baseline pressures were stabilized. Sheep were treated or not treated with FR139317 or TAK-044. Pulmonary artery pressure was significantly higher than the baseline pressure after the start of air infusion. Both FR139317 and TAK-044 significantly attenuated the increase in pulmonary artery pressure during air embolization. Plasma endothelin -1 levels in both pulmonary and systemic arteries were equally and significantly increased after the start of air infusion. The results indicate that endothelin-1 release is attributable to the development of pulmonary hypertension during the course of air embolization in awake sheep.