title: A soluble epoxide hydrolase inhibitor--8-HUDE increases pulmonary vasoconstriction through inhibition of K(ATP) channels.
abstract: Epoxyeicosatrienoic acids (EETs), cytochrome P450-derived metabolites of arachidonic acid, are endogenously produced epoxides that act as substrates for the soluble epoxide hydrolase (sEH). Recent studies indicate that EETs increase the tension of rat pulmonary arteries (PAs), and inhibition of sEH augments hypoxic pulmonary vasoconstriction. However, the mechanisms underlying the proconstrictive effects of sEH inhibitors in pulmonary artery smooth muscle cells (PASMCs) are unclear. In the present study, we used a sEH inhibitor, 12-(3-hexylureido) dodec-8-enoic acid (8-HUDE), to examine the ionic mechanisms underlying the constriction of PAs. 8-HUDE increased the tension of rat PAs to 145% baseline in a manner which was effectively eliminated by 10 μmol/L glibenclamide, an inhibitor of ATP-sensitive K(+) (K(ATP)) channels. Whole cell currents of HEK cells transfected with Kir6.1 or SUR2B were activated by K(ATP) channel opener pinacidil, inhibited by K(ATP) channel inhibitor glibenclamide or inhibited by 8-HUDE in a concentration-dependent manner with an IC50 value of 40 uM. In addition, 8-HUDE inhibited the expression of Kir6.1 and SUR2B at both mRNA and protein level in rat PASMCs. These observations suggest that 8-HUDE exerts acute effects on K(ATP) channel activity as well as subacute effects through decreased channel expression, and these effects are, at least in part, via the Kir6.1/SUR2B channel.
authors.affiliation: Department of Biopharmaceutical Key Laboratory of Heilongjiang Province, College of Pharmacy, Harbin Medical University, 157 Baojian Road, Nangang District, Harbin, Heilongjiang 150081, PR China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Liu
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Lei
authors.initials: L
authors.lastname: Yu
authors.forename: Fangyuan
authors.initials: F
authors.lastname: Cao
authors.forename: Jingjing
authors.initials: J
authors.lastname: Rao
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Chun
authors.initials: C
authors.lastname: Jiang
authors.forename: J R
authors.initials: JR
authors.lastname: Falck
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Jacobs
authors.forename: Daling
authors.initials: D
authors.lastname: Zhu
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D054086:KATP Channels / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D032389:Myocytes, Smooth Muscle / Q000187:drug effects; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D011651:Pulmonary Artery / Q000187:drug effects; D011652:Pulmonary Circulation / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D011955:Receptors, Drug / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D064233:Sulfonylurea Receptors; D014661:Vasoconstriction / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: C558427:12-(3-hexylureido)dodec-8(Z)-enoic acid; D018528:ATP-Binding Cassette Transporters; D004791:Enzyme Inhibitors; D005229:Fatty Acids, Monounsaturated; D054086:KATP Channels; D026902:Potassium Channel Blockers; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D014665:Vasodilator Agents; C092520:uK-ATP-1 potassium channel; C050715:8,9-epoxyeicosatrienoic acid; D004851:Epoxide Hydrolases; D015126:8,11,14-Eicosatrienoic Acid