A soluble epoxide hydrolase inhibitor--8-HUDE increases pulmonary vasoconstriction through inhibition of K(ATP) channels. Pulm Pharmacol Ther 2012 Feb;25(1):69-76
Date
12/14/2011Pubmed ID
22155000DOI
10.1016/j.pupt.2011.11.005Scopus ID
2-s2.0-84856780301 (requires institutional sign-in at Scopus site) 5 CitationsAbstract
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.
Author List
Liu Y, Zhang J, Yu L, Cao F, Rao J, Li J, Jiang C, Falck JR, Jacobs ER, Zhu DMESH terms used to index this publication - Major topics in bold
8,11,14-Eicosatrienoic AcidATP-Binding Cassette Transporters
Animals
Blotting, Western
Cells, Cultured
Enzyme Inhibitors
Epoxide Hydrolases
Fatty Acids, Monounsaturated
Female
HEK293 Cells
Humans
KATP Channels
Male
Muscle Contraction
Muscle, Smooth, Vascular
Myocytes, Smooth Muscle
Patch-Clamp Techniques
Potassium Channel Blockers
Potassium Channels, Inwardly Rectifying
Pulmonary Artery
Pulmonary Circulation
Rats
Rats, Wistar
Real-Time Polymerase Chain Reaction
Receptors, Drug
Sulfonylurea Receptors
Vasoconstriction
Vasodilator Agents
