Cytochrome p-450 epoxygenase metabolites of docosahexaenoate potently dilate coronary arterioles by activating large-conductance calcium-activated potassium channels.
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 (BK(Ca)) 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 microm in diameter) precontracted with endothelin. The five EDP regioisomers had dilation EC(50) values 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 EC(50) value of 30 +/- 22 nM (n = 7), whereas docosahexaenoate only dilated vessels at > or =1.0 microM (n = 7). Using patch-clamp techniques in the inside-out configuration, we determined that the 13,14-EDP regioisomer potently activated (EC(50) value of 6.6 +/- 0.6 pM; n = 5) BK(Ca) channels in myocytes from the porcine coronary arterioles. Moreover, 13,14-EDP potently activated BK(Ca) channels in myocytes from rat coronary small arteries (150-300 microm in diameter); with an EC(50) value of 2.2 +/- 0.6 pM (n = 7), 13,14-EDP was 1000-fold more potent than EETs in activating BK(Ca) channels. We conclude that EDPs potently dilate coronary microvessels and are the most potent fatty epoxides known to activate BK(Ca) channels in coronary smooth muscle cells. Both actions may contribute to the hypotensive effects of dietary fish oils.
Ye
Dan
D
Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.
Zhang
David
D
Oltman
Christine
C
Dellsperger
Kevin
K
Lee
Hon-Chi
HC
VanRollins
Mike
M
D000465:Algorithms; D000818:Animals; D001160:Arterioles / Q000187:drug effects; D002469:Cell Separation; D003331:Coronary Vessels / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000090762:Cytochrome P-450 CYP2J2; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004281:Docosahexaenoic Acids / Q000378:metabolism* / Q000494:pharmacology*; D004852:Epoxy Compounds / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects; D010105:Oxygenases / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D024681:Potassium Channels, Calcium-Activated / Q000819:agonists* / Q000378:metabolism; D051381:Rats; D013552:Swine; D014665:Vasodilator Agents / Q000494:pharmacology*
D004852:Epoxy Compounds; D024681:Potassium Channels, Calcium-Activated; D014665:Vasodilator Agents; D004281:Docosahexaenoic Acids; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases; D000090762:Cytochrome P-450 CYP2J2