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

19 Citations (Scopus)

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 2005

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Pentanoic Acids
Potassium Channels
Calcium-Activated Potassium Channels
Glyburide
Coronary Vessels
Indomethacin
Ether
Adenosine Triphosphate
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
Cyclooxygenase 1
Cyclooxygenase Inhibitors
Epoxy Compounds
Prostaglandin-Endoperoxide Synthases
Arachidonic Acid
Cytochrome P-450 Enzyme System
Prostaglandins
Smooth Muscle
Hydrolysis
iberiotoxin
5,6-epoxy-8,11,14-eicosatrienoic acid

Keywords

  • Arachidonic acids
  • Cyclooxygenase
  • Endothelium-derived factors

ASJC Scopus subject areas

  • Internal Medicine

Cite this

Yang, W., Gauthier, K. M., Reddy, L. M., Sangras, B., Sharma, K. K., Nithipatikom, K., ... 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

Stable 5,6-epoxyeicosatrienoic acid analog relaxes coronary arteries through potassium channel activation. / Yang, Wenqi; Gauthier, Kathryn M.; Reddy, L. Manmohan; Sangras, Bhavani; Sharma, Kamalesh K.; Nithipatikom, Kasem; Falck, J R; Campbell, William B.

In: Hypertension, Vol. 45, No. 4 SUPPL., 04.2005, p. 681-686.

Research output: Contribution to journalArticle

Yang, W, Gauthier, KM, Reddy, LM, Sangras, B, Sharma, KK, Nithipatikom, K, Falck, JR & Campbell, WB 2005, 'Stable 5,6-epoxyeicosatrienoic acid analog relaxes coronary arteries through potassium channel activation', Hypertension, vol. 45, no. 4 SUPPL., pp. 681-686. https://doi.org/10.1161/01.HYP.0000153790.12735.f9
Yang, Wenqi ; Gauthier, Kathryn M. ; Reddy, L. Manmohan ; Sangras, Bhavani ; Sharma, Kamalesh K. ; Nithipatikom, Kasem ; Falck, J R ; Campbell, William B. / Stable 5,6-epoxyeicosatrienoic acid analog relaxes coronary arteries through potassium channel activation. In: Hypertension. 2005 ; Vol. 45, No. 4 SUPPL. pp. 681-686.
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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.",
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AU - Yang, Wenqi

AU - Gauthier, Kathryn M.

AU - Reddy, L. Manmohan

AU - Sangras, Bhavani

AU - Sharma, Kamalesh K.

AU - Nithipatikom, Kasem

AU - Falck, J R

AU - Campbell, William B.

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KW - Arachidonic acids

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