Stable 5,6-epoxyeicosatrienoic acid analog relaxes coronary arteries through potassium channel activation

Wenqi Yang, Kathryn M. Gauthier, L. Manmohan Reddy, Bhavani Sangras, Kamalesh K. Sharma, Kasem Nithipatikom, J R Falck, William B. Campbell

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

5,6-Epoxyeicosatrienoic acid (5,6-EET) is a cytochrome P450 epoxygenase metabolite of arachidonic acid that causes vasorelaxadon. However, investigations of its role in biological systems have been limited by its chemical instability. We developed a stable agonist of 5,6-EET, 5-(pentadeca-3(Z),6(Z),9(Z)-trienyloxy)pentanoic acid (PTPA), in which the 5,6-epoxide was replaced with a 5-ether. PTPA obviates chemical and enzymatic hydrolysis. In bovine coronary artery rings precontracted with U46619, PTPA (1 nmol/L to 10 μmol/L) induced concentration-dependent relaxations, with maximal relaxation of 86±5% and EC50 of 1 μmol/L. The relaxations were inhibited by the cyclooxygenase inhibitor indomethacin (10 μmol/L; max relaxation 43±9%); the ATP-sensitive K+ channel inhibitor glybenclamide (10 μmol/L; max relaxation 49±6%); and the large conductance calcium-activated K+ channel inhibitor iberiotoxin (100 nmol/L; max relaxation 38±6%) and abolished by the combination of iberiotoxin with indomethacin or glybenclamide or increasing extracellular K+ to 20 mmol/L. Whole-cell outward K+ current was increased nearly 6-fold by PTPA (10 μmol/L), which was also blocked by iberiotoxin. Additionally, we synthesized 5-(pentadeca-6(Z),9(Z)-dienyloxy) pentanoic acid and 5-(pentadeca-3(Z),9(Z)-dienyloxy)pentanoic acid (PDPA), PTPA analogs that lack the 8,9 or 11,12 double bonds of arachidonic acid and therefore are not substrates for cyclooxygenase. The PDPAs caused concentration-dependent relaxations (max relaxations 46±13% and 52±7%, respectively; EC50 1 μmol/L), which were not altered by glybenclamide but blocked by iberiotoxin. These studies suggested that PTPA induces relaxation through 2 mechanisms: (1) cyclooxygenase-dependent metabolism to 5-ether-containing prostaglandins that activate ATP-sensitive K+ channels and (2) activation of smooth muscle large conductance calcium-activated K+ channels. PDPAs only activate large conductance calcium-activated K+ channels.

Original languageEnglish (US)
Pages (from-to)681-686
Number of pages6
JournalHypertension
Volume45
Issue number4 SUPPL.
DOIs
StatePublished - Apr 1 2005

Keywords

  • Arachidonic acids
  • Cyclooxygenase
  • Endothelium-derived factors

ASJC Scopus subject areas

  • Internal Medicine

Fingerprint Dive into the research topics of 'Stable 5,6-epoxyeicosatrienoic acid analog relaxes coronary arteries through potassium channel activation'. Together they form a unique fingerprint.

  • Cite this

    Yang, W., Gauthier, K. M., Reddy, L. M., Sangras, B., Sharma, K. K., Nithipatikom, K., Falck, J. R., & Campbell, W. B. (2005). Stable 5,6-epoxyeicosatrienoic acid analog relaxes coronary arteries through potassium channel activation. Hypertension, 45(4 SUPPL.), 681-686. https://doi.org/10.1161/01.HYP.0000153790.12735.f9