Endothelin blockade augments pulmonary vasodilation in the ovine fetus

Ivy, D. Dunbar, John P. Kinsella, and Steven H. Abman.Endothelin blockade augments pulmonary vasodilation in the ovine fetus. J. Appl. Physiol. 81(6):2481-2487, 1996.The physiological role of endothelin-1 (ET-1) inregulation of vascular tone in the perinatal lung is controversial.Recent studies suggest that ET-1 contributes to high basal pulmonaryvascular resistance in the normal fetus, but its role in the modulationof pulmonary vascular tone remains uncertain. We hypothesized that highET-1 activity opposes the vasodilator response to some physiological stimuli such as increased pressure. To test the hypothesis that ET-1modulates fetal pulmonary vascular responses to acute and prolongedphysiological stimuli, we performed a series of experiments in thelate-gestation ovine fetus. We studied the hemodynamic effects of twoET-1 antagonists, BQ-123 (a selectiveET_A-receptor antagonist) andphosphoramidon (a nonselective ET-1-converting enzyme inhibitor) duringmechanical increases in pressure due to partial ductus arteriosuscompression in chronically prepared late-gestation fetal lambs. Incontrol studies, partial ductus arteriosus compression decreased theratio of pulmonary arterial pressure to pulmonary artery flow in theleft lung 34 ± 6% from baseline. Intrapulmonary infusions ofBQ-123 (0.5 µg/min for 10 min; 0.025 µg/min for 2 h) orphosphoramidon (1.0 mg/min for 10 min) augmented the peak vasodilatorresponse 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 arteriosus compression in control studies, ET-1blockade with BQ-123 or phosphoramidon prolonged the increase in flowcaused by ductus arteriosus compression. In summary,ET_A-receptor blockade andET-1-converting enzyme inhibition augment and prolong fetal pulmonaryvasodilation during partial compression of the ductus arteriosus. Weconclude that ET-1 activity modulates acute and prolonged responses ofthe fetal pulmonary circulation to changes in vascular pressure. Wespeculate that ET-1 contributes to regulation and maintenance of highpulmonary vascular resistance in the normal ovine fetal lung.