CHRONIC INTRAUTERINE PULMONARY-HYPERTENSION ALTERS ENDOTHELIN RECEPTOR ACTIVITY IN THE OVINE FETAL LUNG

Although endothelin (ET) contributes to the regulation of pulmonary va scular tone in the normal fetus, little is known about its role in pul monary hypertension in the perinatal period. To examine the role of th e ET(B) receptor in the normal ovine fetal lung, we studied the hemody namic effects of ET-3 (a selective ET(B) receptor agonist) before and after RES-701 (a selective ET(B) receptor antagonist). RES-701 (10 mu g/min for 10 min) did not change basal pulmonary tone and blocked pulm onary vasodilation to ET-3 (500 ng/min for 10 min). To examine the eff ects of experimental perinatal pulmonary hypertension on activity of t he ET(A) and ET(B) receptors, we studied the hemodynamic effects of ET -3, ET-1 (a nonselective ET(A) and ET(B) receptor agonist), and BQ 123 (a selective ET(A) receptor antagonist) in 12 chronically prepared la te gestation fetal lambs after partial ligation of the ductus arterios us. Serial changes in the pulmonary vascular effects of these agents w ere measured early (1-3 d) and late (7-10 d) after partial ductus arte riosus ligation. Left lung total pulmonary resistance in the normal la te-gestation fetus was 0.62 +/- 0.01 mm Hg/ml/min (n = 4). After parti al ductus arteriosus ligation, total pulmonary resistance increased to 1.2 +/- 0.3 (early; p < 0.05 versus normal), and progressively rose t o 1.9 +/- 0.2 mmHg/ml/min Gate; p < 0.05 versus early). Intrapulmonary infusion of ET-3 (500 ng/min for 10 min) increased pulmonary blood fl ow from 94 +/- 11 to 183 +/- 17 mL/min in the normal fetus, but had no effect during late pulmonary hypertension. Infusions of ET-1 (50 ng/m in for 30 min) caused transient pulmonary vasodilation followed by vas oconstriction during early pulmonary hypertension. During late pulmona ry hypertension, however, infusion of ET-1 caused predominantly vasoco nstriction. Pulmonary vasodilation to BQ 123 (100 mu g/min for 10 min) was greater during late than early pulmonary hypertension (43 versus 21%; p < 0.05). After 10 d of ductus arteriosus ligation, immunoreacti ve ET-1 content in whole lung tissue was 3-fold higher in hypertensive (n = 7) than control (n = 10) lungs (p < 0.05). We conclude that the ET(B) receptor contributes little to regulation of basal vascular tone in the normal ovine fetal lung and that chronic intrauterine pulmonar y hypertension causes the loss of ET(B)-mediated vasodilation, progres sive ET(A)-mediated vasoconstriction, and increased lung ET-1 content. We speculate that diminished ET(B) receptor-mediated vasodilation in combination with enhanced ET(A) receptor-mediated vasoconstriction and increased ET-1 production contributes to high pulmonary vascular resi stance in perinatal pulmonary hypertension.