n-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide and baicalein

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.

Topics: Amides; Animals; Arachidonate 12-Lipoxygenase; Cytochrome P-450 CYP2J2; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Dose-Response Relationship, Drug; Ductus Arteriosus; Endothelin-1; Enzyme Inhibitors; Fetus; Flavanones; Fluorenes; Hydroxyeicosatetraenoic Acids; Lipoxygenase Inhibitors; Mice; Mice, Inbred C57BL; Mice, Knockout; Oxygen; Prostaglandin Endoperoxides, Synthetic; Signal Transduction; Thromboxane A2; Vasoconstriction; Vasoconstrictor Agents; Vasodilator Agents