Effects of chronic estrogen-receptor blockade on ovine perinatal pulmonary circulation

• Published in: American journal of physiology. Heart and circulatory physiology Vol. 281; no. 3; pp. H1005 - H1014
• Main Authors: Parker, Thomas A, Afshar, Sam, Kinsella, John P, Grover, Theresa R, Gebb, Sarah, Geraci, Mark, Shaul, Philip W, Cryer, Chad M. T, Abman, Steven H
• Format: Journal Article
• Language: English
• Published: United States 01.09.2001
• Subjects: Animals; Animals, Newborn; Blotting, Western; Cyclooxygenase 1; Cyclooxygenase 2; Cytochrome P-450 Enzyme System - metabolism; Drug Administration Schedule; Estradiol - administration & dosage; Estradiol - analogs & derivatives; Estrogen Antagonists - administration & dosage; Female; Fetus - blood supply; Fetus - drug effects; Fetus - physiology; Hemodynamics - drug effects; Infusions, Intra-Arterial - methods; Intramolecular Oxidoreductases - metabolism; Isoenzymes - metabolism; Lung - drug effects; Lung - embryology; Lung - enzymology; Nitric Oxide - metabolism; Nitric Oxide - pharmacology; Nitric Oxide Synthase - metabolism; Nitric Oxide Synthase Type III; Organ Specificity; Pregnancy; Prenatal Exposure Delayed Effects; Prostaglandin-Endoperoxide Synthases - metabolism; Pulmonary Artery - embryology; Pulmonary Artery - physiology; Pulmonary Circulation - drug effects; Pulmonary Circulation - physiology; Pulmonary Ventilation - drug effects; Receptors, Estrogen - antagonists & inhibitors; Sheep; Vasodilation - drug effects; Vasodilation - physiology
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.2001.281.3.h1005

The Pediatric Heart Lung Center, Departments of 1  Pediatrics and 2  Internal Medicine, University of Colorado School of Medicine, Denver, Colorado 80262; and 3  Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75235 Prolonged infusions of 17 -estradiol reduce fetal pulmonary vascular resistance (PVR), but the effects of endogenous estrogens in the fetal pulmonary circulation are unknown. To test the hypothesis that endogenous estrogen promotes pulmonary vasodilation at birth, we studied the hemodynamic effects of prolonged estrogen-receptor blockade during late gestation and at birth in fetal lambs. We treated chronically prepared fetal lambs with ICI-182,780 (ICI, a specific estrogen-receptor blocker, n  = 5) or 1% DMSO (CTRL, n  = 5) for 7 days and then measured pulmonary hemodynamic responses to ventilation with low- and high-fraction inspired oxygen (F I O 2 ). Treatment with ICI did not change basal fetal PVR or arterial blood gas tensions. However, treatment with ICI abolished the vasodilator response to ventilation with low F I O 2 [change in PVR 30 ± 6% (CTRL) vs. +10 ± 13%, (ICI), P  < 0.05] without reducing the vasodilator response to ventilation with high F I O 2 [change in PVR, 73 ± 3% (CTRL) vs. 77 ± 4%, (ICI); P  = not significant]. ICI treatment reduced prostacyclin synthase (PGIS) expression by 33% ( P  < 0.05) without altering expression of endothelial nitric oxide synthase or cyclooxygenase-1 and -2. In situ hybridization and immunohistochemistry revealed that PGIS is predominantly expressed in the airway epithelium of late gestation fetal lambs. We conclude that prolonged estrogen-receptor blockade inhibits the pulmonary vasodilator response at birth and that this effect may be mediated by downregulation of PGIS. We speculate that estrogen exposure during late gestation prepares the pulmonary circulation for postnatal adaptation. prostacyclin; prostacyclin synthase; cyclooxygenase; newborn