Abstract
Oxygen promotes closure of the ductus arteriosus at birth. We have previously presented a scheme for oxygen action with a cytochrome P450 (CYP450) hemoprotein and endothelin-1 (ET-1) being, respectively, sensor and effector, and a hypothetical monooxygenase product serving as a coupling link. We have also found in the vessel arachidonic acid (AA) 12(S)-lipoxygenase (12-lipoxygenase) undergoing upregulation at birth. Here, we examined the feasibility of a sensor-to-effector messenger originating from AA monooxygenase and 12-lipoxygenase pathways. The epoxygenase inhibitor, N-methylsulfonyl-6-(2-)hexanamide, suppressed the tonic contraction of ductus to oxygen. A similar effect was obtained with 12-lipoxygenase inhibitors baicalein and PD 146176. By contrast, none of the inhibitors modified the endothelin-1 contraction. Furthermore, an AA ω-hydroxylation product, 20-hydroxyeicosatetraenoic acid (20-HETE), reportedly responsible for oxygen contraction in the systemic microvasculature, had no such effect on the ductus. We conclude that AA epoxygenase and 12-lipoxygenase jointly produce a hitherto uncharacterized compound acting as oxygen messenger in the ductus.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amides / pharmacology
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Animals
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Arachidonate 12-Lipoxygenase / metabolism*
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Cytochrome P-450 CYP2J2
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Cytochrome P-450 CYP3A
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Cytochrome P-450 Enzyme Inhibitors
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Cytochrome P-450 Enzyme System / genetics
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Cytochrome P-450 Enzyme System / metabolism*
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Dose-Response Relationship, Drug
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Ductus Arteriosus / drug effects*
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Ductus Arteriosus / enzymology
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Ductus Arteriosus / physiology
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Endothelin-1 / pharmacology
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Enzyme Inhibitors / pharmacology
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Fetus / physiology
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Flavanones / pharmacology
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Fluorenes / pharmacology
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Hydroxyeicosatetraenoic Acids / pharmacology
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Lipoxygenase Inhibitors / pharmacology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Oxygen / pharmacology*
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Prostaglandin Endoperoxides, Synthetic / pharmacology
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Signal Transduction / physiology
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Thromboxane A2 / analogs & derivatives
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Thromboxane A2 / pharmacology
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Vasoconstriction / drug effects*
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Vasoconstriction / physiology
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Vasoconstrictor Agents / pharmacology
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Vasodilator Agents / pharmacology
Substances
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6,11-dihydro-5-thia-11-aza-benzo(a)-fluorene
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Amides
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Cytochrome P-450 Enzyme Inhibitors
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Endothelin-1
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Enzyme Inhibitors
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Flavanones
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Fluorenes
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Hydroxyeicosatetraenoic Acids
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Lipoxygenase Inhibitors
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N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide
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Prostaglandin Endoperoxides, Synthetic
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Vasoconstrictor Agents
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Vasodilator Agents
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baicalein
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U 44069
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Thromboxane A2
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20-hydroxy-5,8,11,14-eicosatetraenoic acid
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STA 2
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Cytochrome P-450 Enzyme System
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Arachidonate 12-Lipoxygenase
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CYP3A protein, mouse
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Cytochrome P-450 CYP2J2
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Cytochrome P-450 CYP3A
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Oxygen