PROLONGED ENDOTHELIN A RECEPTOR BLOCKADE ATTENUATES CHRONIC PULMONARY-HYPERTENSION IN THE OVINE FETUS

Based on past studies of an experimental model of severe intrauterine pulmonary hypertension, we hypothesized that endothelin-1 (ET-1) contr ibutes to high pulmonary vascular resistance (PVR), hypertensive lung structural changes, and right ventricular hypertrophy (RVH) caused by prolonged closure of the ductus arteriosus. To test this hypothesis, w e studied the effects of BQ 123, a selective ET(A) receptor antagonist , after ligation of the ductus arteriosus in utero. In 19 late gestati on fetal lambs (126 +/- 3 d; 147 d, term) we ligated the ductus arteri osus at surgery, and treated animals with either BQ 123 (1 mg/d) or ve hicle (0.1% DMSO, HTN) in the pulmonary artery for 8 d. Chronic BQ 123 treatment attenuated the rise in mean pulmonary artery pressure (PAP) s d after ductus arteriosus ligation (78 +/- 2, HTN vs. 70 +/- 4 mmHg , BQ 123, P < 0.05). To study the effects of ET(A) blockade at birth, 15 animals were delivered by cesarean section and ventilated with 10% oxygen (O-2), 100% O-2 and inhaled nitric oxide (NO). Lambs treated wi th BQ 123 had lower PVR after delivery during ventilation with 10% O-2 , 100% O-2, and inhaled NO (HTN vs. BQ 123, Pt 0.05 for each intervent ion). Acute BQ 123 treatment (2 mg/30 min) lowered PVR in three HTN an imals ventilated with 100% O-2 and inhaled NO (P < 0.05). Chronic BQ 1 23 treatment prevented the development of RVH as determined by the rat io of the right ventricle/left ventricle + septum (0.79 +/- 0.03, HTN vs. 0.57 +/- 0.06, BQ 123, P < 0.05) and attenuated the increase in wa ll thickless of small pulmonary arteries (61 +/- 2, HTN vs. 50 +/- 2%, BQ 123, P < 0.05). In summary, chronic intrauterine ET(A) receptor bl ockade decreased PAP in utero, decreased RVH and distal muscularizatio n of small pulmonary arteries, and increased the fall in PVR at delive ry. We conclude that ET(A) receptor stimulation contributes to the pat hogenesis and pathophysiology of experimental perinatal pulmonary hype rtension.