Endothelin receptor blockade attenuates air embolization-induced pulmonaryhypertension in sheep

We investigated the effects of two types of endothelin receptor antagonists on pulmonary hypertension induced by pulmonary air embolization in awake s heep. We prepared awake sheep with indwelling catheters inserted in blood v essels 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 mu g /kg/min; (R)2-[(R)-2-[(S)-2-[1-(hexahydro-1H-azepinyl)]-carbonyl]amino-4-me thyl-pentanoyl]amino-3-[3-(1-methyl-1H-indolyl)]propionyl)amino- 3-(2-pyrid yl)propionic acid), a selective endothelin ETA receptor antagonist, and the other with TAK-044 (100 mu g/kg/h; cyclo[D-alpha-aspartyl-3-[(4-phenylpipe razin-yl)carbonyl]-L-alanyl-L-alpha- aspartyl-D-2-(2-thienyl) glycyl-L-leuc yl-D-tryptophyl] disodium salt), an endothelin ETA and ETB receptor antagon ist. 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 st abilized. Sheep were treated or not treated with FR139317 or TAK-044. Pulmo nary artery pressure was significantly higher than the baseline pressure af ter the start of air infusion. Both FR139317 and TAK-044 significantly atte nuated the increase in pulmonary artery pressure during air embolization. P lasma endothelin -1 levels in both pulmonary and systemic arteries were equ ally and significantly increased after the start of air infusion. The resul ts indicate that endothelin-1 release is attributable to the development of pulmonary hypertension during the course of air embolization in awake shee p. (C) 1999 Elsevier Science B.V. All rights reserved.