Abstract
Endothelin-1 (ET-1) mediates the development of pulmonary hypertension (PHT) in newborn rats exposed to 60% O(2) for 14 days, a model for human chronic neonatal lung injury. ET-1 production by d-14 rat pulmonary artery smooth muscle cells in vitro was markedly increased by thromboxane (TX) A(2) receptor agonists and inhibited by a competitive antagonist. We hypothesized that stimulation of the TX A(2) receptor contributed to O(2)-mediated PHT in vivo. Newborn rat pups received daily intraperitoneal injections of L670596, a competitive TX A(2) receptor antagonist, or 5,5-dimethyl-3-(3-fluorophenyl)4-(4-methylsulfonyl)phenyl-2(5H)-furanone (DFU), a cyclooxygenase-2 inhibitor, during 14 days of 60% O(2) or air exposure. L670596, but not DFU, prevented 60% O(2)-mediated right ventricular and small pulmonary vessel smooth muscle hypertrophy. Lung ET-1 content was significantly reduced by L670596 in 60% O(2)-exposed animals. We conclude that TX A(2) receptor activation, though not by TX A(2), caused upregulation of ET-1 and PHT in this model. A likely mediator is the stable lipid peroxidation product, 8-iso-prostane, which acts as an incidental ligand of the TX A(2) receptor and is a potent inducer of ET-1 production by cultured d-14 rat pulmonary artery smooth muscle cells in vitro.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / pharmacology
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Animals
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Animals, Newborn
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Blotting, Western
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Carbazoles / pharmacology
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Cells, Cultured
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Cyclooxygenase Inhibitors / pharmacology
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Dinoprost* / analogs & derivatives*
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Endothelin-1 / metabolism
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F2-Isoprostanes / metabolism
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F2-Isoprostanes / pharmacology
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Furans / pharmacology
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Hypertension, Pulmonary / metabolism
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Hypertension, Pulmonary / physiopathology*
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Hypertrophy, Right Ventricular / physiopathology
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Immunohistochemistry
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Lung / metabolism
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Muscle, Smooth, Vascular / metabolism
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Oxygen / physiology
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Oxygen / toxicity*
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Prostaglandin Antagonists / pharmacology
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Prostaglandin-Endoperoxide Synthases / physiology*
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Pulmonary Artery / metabolism
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Rats
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Receptors, Thromboxane / antagonists & inhibitors
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Receptors, Thromboxane / physiology*
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Thromboxane B2 / metabolism
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Up-Regulation
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Vasoconstrictor Agents / pharmacology
Substances
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5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl-2(5H)-furanone
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Carbazoles
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Cyclooxygenase Inhibitors
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Endothelin-1
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F2-Isoprostanes
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Furans
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Prostaglandin Antagonists
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Receptors, Thromboxane
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Vasoconstrictor Agents
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L 670596
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8-epi-prostaglandin F2alpha
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Thromboxane B2
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15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
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Dinoprost
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Prostaglandin-Endoperoxide Synthases
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Oxygen