A soluble epoxide hydrolase inhibitor-8-HUDE increases pulmonary vasoconstriction through inhibition of K ATP channels

Yun Liu, Jing Zhang, Lei Yu, Fangyuan Cao, Jingjing Rao, Jing Li, Chun Jiang, J R Falck, Elizabeth R. Jacobs, Daling Zhu

Research output: Contribution to journalReview article

4 Scopus citations

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 10μmol/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 40uM. 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.

Original languageEnglish (US)
Pages (from-to)69-76
Number of pages8
JournalPulmonary Pharmacology and Therapeutics
Volume25
Issue number1
DOIs
StatePublished - Feb 1 2012

Keywords

  • 12-(3-hexylureido)dodec-8-enoic acid
  • 8-HUDE
  • ATP-sensitive K (K ) channels
  • Epoxyeicosatrienoic acids (EETs)
  • Pulmonary arteries

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Biochemistry, medical
  • Pharmacology (medical)

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