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J Appl Physiol 81: 2481-2487, 1996;
8750-7587/96 $5.00
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Journal of Applied Physiology
Vol. 81, No. 6, pp. 2481-2487, December 1996
PULMONARY CIRCULATION AND LUNG FLUID BALANCE

Endothelin blockade augments pulmonary vasodilation in the ovine fetus

D. Dunbar Ivy, John P. Kinsella, and Steven H. Abman

Divisions of Cardiology, Neonatology, and Pulmonary Medicine and Critical Care, and Department of Pediatrics, University of Colorado School of Medicine and The Children's Hospital, Denver, Colorado 80218

Received 23 February 1996; accepted in final form 8 August 1996.

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) in regulation of vascular tone in the perinatal lung is controversial. Recent studies suggest that ET-1 contributes to high basal pulmonary vascular resistance in the normal fetus, but its role in the modulation of pulmonary vascular tone remains uncertain. We hypothesized that high ET-1 activity opposes the vasodilator response to some physiological stimuli such as increased pressure. To test the hypothesis that ET-1 modulates fetal pulmonary vascular responses to acute and prolonged physiological stimuli, we 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 pressure due to partial ductus arteriosus compression in chronically prepared late-gestation fetal lambs. In control studies, partial ductus arteriosus compression decreased the ratio of pulmonary arterial pressure to pulmonary artery flow in the left lung 34 ± 6% from baseline. Intrapulmonary infusions of BQ-123 (0.5 µg/min for 10 min; 0.025 µg/min for 2 h) or phosphoramidon (1.0 mg/min for 10 min) augmented the peak 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 arteriosus compression in control studies, ET-1 blockade with BQ-123 or phosphoramidon prolonged the increase in flow caused by ductus arteriosus compression. In summary, ETA-receptor blockade and ET-1-converting enzyme inhibition augment and prolong fetal pulmonary vasodilation during partial compression of the ductus arteriosus. We conclude that ET-1 activity modulates acute and prolonged responses of the fetal pulmonary circulation to changes in vascular pressure. We speculate that ET-1 contributes to regulation and maintenance of high pulmonary vascular resistance in the normal ovine fetal lung.

endothelin receptors; pulmonary hypertension; persistent pulmonary hypertension of the newborn; nitric oxide; pulmonary circulation; BQ-123; phosphoramidon

0161-7567/96 $5.00 Copyright © 1996 the American Physiological Society




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