ENDOTHELIN BLOCKADE AUGMENTS PULMONARY VASODILATION IN THE OVINE FETUS

The physiological role of endothelin-l (ET-1) in regulation of vascula r tone in the perinatal lung is controversial. Recent studies suggest that ET-1 contributes to high basal pulmonary vascular resistance in t he normal fetus, but its role in the modulation of pulmonary vascular tone remains uncertain. We hypothesized that high ET-1 activity oppose s the vasodilator response to some physiological stimuli such as incre ased pressure. To test the hypothesis that ET-1 modulates fetal pulmon ary vascular responses to acute and prolonged physiological stimuli, w e performed a series of experiments in the late-gestation ovine fetus. We studied the hemodynamic effects of two ET-1 antagonists, BQ-123 (a selective ETA-receptor antagonist) and phosphoramidon (a nonselective ET-1-converting enzyme inhibitor) during mechanical increases in pres sure due to partial ductus arteriosus compression in chronically prepa red late-gestation fetal lambs. In control studies, partial ductus art eriosus compression decreased the ratio of pulmonary arterial pressure to pulmonary artery flow in the left lung 34 +/- 6% from baseline. In trapulmonary infusions of BQ-123 (0.5 mu g/min for 10 min; 0.025 mu g/ min for 2 h) or phosphoramidon (1.0 mg/min for 10 min) augmented the p eak vasodilator response during ductus arteriosus compression (52 +/- 3 and 49 +/- 6% from baseline, respectively, P < 0.05 vs. control). In addition, unlike the transient vasodilator response to ductus arterio sus compression in control studies, ET-I blockade with BQ-123 or phosp horamidon prolonged the increase in flow caused by ductus arteriosus c ompression. In summary, ET(A)-receptor blockade and ET-l-converting en zyme inhibition augment and prolong fetal pulmonary vasodilation durin g partial compression of the ductus arteriosus. We conclude that ET-1 activity modulates acute and prolonged responses of the fetal pulmonar y circulation to changes in vascular pressure. We speculate that ET-1 contributes to regulation and maintenance of high pulmonary vascular r esistance in the normal ovine fetal lung.