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Research ArticleCARDIOVASCULAR

Cytochrome P-450 Epoxygenase Metabolites of Docosahexaenoate Potently Dilate Coronary Arterioles by Activating Large-Conductance Calcium-Activated Potassium Channels

Dan Ye, David Zhang, Christine Oltman, Kevin Dellsperger, Hon-Chi Lee and Mike VanRollins
Journal of Pharmacology and Experimental Therapeutics November 2002, 303 (2) 768-776; DOI: https://doi.org/10.1124/jpet.303.2.768
Dan Ye
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David Zhang
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Christine Oltman
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Kevin Dellsperger
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Hon-Chi Lee
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Mike VanRollins
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Abstract

Diets enriched in docosahexaenoic acid, a major n-3 fatty acid in fish oil, have hypotensive properties. One mechanism that can lower blood pressure is the direct dilation of arterioles by docosahexaenoic metabolites. Vascular endothelium contains cytochrome P-450 epoxygenases that transform the n-6 fatty acid arachidonate into epoxyeicosatrienoic acids (EETs), potent dilators of coronary arterioles and activators of large-conductance calcium-activated potassium (BKCa) channels. To test whether analogous activations occur for docosahexaenoate, we compared the potency of docosahexaenoate and its five cytochrome P-450 epoxygenase metabolites, epoxydocosapentaenoates (EDPs), in dilating porcine coronary arterioles (<135 μm in diameter) precontracted with endothelin. The five EDP regioisomers had dilation EC50values ranging from 0.5 to 24 pM (n = 5–6). In contrast, the EDP hydrolysis product 13,14-dihydroxydocosapentaenoic acid (13,14-DHDP) had an EC50 value of 30 ± 22 nM (n = 7), whereas docosahexaenoate only dilated vessels at ≥1.0 μM (n = 7). Using patch-clamp techniques in the inside-out configuration, we determined that the 13,14-EDP regioisomer potently activated (EC50 value of 6.6 ± 0.6 pM; n = 5) BKCachannels in myocytes from the porcine coronary arterioles. Moreover, 13,14-EDP potently activated BKCa channels in myocytes from rat coronary small arteries (150–300 μm in diameter); with an EC50 value of 2.2 ± 0.6 pM (n = 7), 13,14-EDP was 1000-fold more potent than EETs in activating BKCa channels. We conclude that EDPs potently dilate coronary microvessels and are the most potent fatty epoxides known to activate BKCa channels in coronary smooth muscle cells. Both actions may contribute to the hypotensive effects of dietary fish oils.

Footnotes

  • This work was supported by the National Institutes of Health Grants R01-HL-56670-02 (to M.V.R.), P01-HL-49264 (to M.V.R.), and HL-63754-01 (H.-C.L.); by the Department of Veterans Affairs, Juvenile Diabetes Foundation Diabetes Research Center (to K.C.D.); Merit Review Program (to K.C.D., M.V.R., and H.-C.L.) and Merit Review Early Program (to C.L.O.); by the American Heart Association 96012380 (to M.V.R.) and 0051311Z (to H.-C.L.); and by the American Heartland Affiliate, Beginning Grant-in-Aid (to C.L.O.).

  • Abbreviations:
    EET
    epoxyeicosatrienoic acid
    EDHF
    endothelial-dependent hyperpolarization factor
    BKCa
    large-conductance calcium-activated potassium channel
    EDP
    epoxydocosapentaenoic acid
    EEQ
    epoxyeicosaquatraenoic acid
    DHDP
    dihydroxydocosapentaenoic acid
    HPLC
    high-performance liquid chromatography
    Po
    single channel open probability
    DHET
    dihydroxyeicosatrienoic acid
    • Received November 8, 2001.
    • Accepted August 5, 2002.
  • U.S. Government
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Journal of Pharmacology and Experimental Therapeutics: 303 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 303, Issue 2
1 Nov 2002
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Research ArticleCARDIOVASCULAR

Cytochrome P-450 Epoxygenase Metabolites of Docosahexaenoate Potently Dilate Coronary Arterioles by Activating Large-Conductance Calcium-Activated Potassium Channels

Dan Ye, David Zhang, Christine Oltman, Kevin Dellsperger, Hon-Chi Lee and Mike VanRollins
Journal of Pharmacology and Experimental Therapeutics November 1, 2002, 303 (2) 768-776; DOI: https://doi.org/10.1124/jpet.303.2.768

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Research ArticleCARDIOVASCULAR

Cytochrome P-450 Epoxygenase Metabolites of Docosahexaenoate Potently Dilate Coronary Arterioles by Activating Large-Conductance Calcium-Activated Potassium Channels

Dan Ye, David Zhang, Christine Oltman, Kevin Dellsperger, Hon-Chi Lee and Mike VanRollins
Journal of Pharmacology and Experimental Therapeutics November 1, 2002, 303 (2) 768-776; DOI: https://doi.org/10.1124/jpet.303.2.768
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