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Vol. 303, Issue 2, 768-776, November 2002

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

Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota (D.Y., H.-C.L.); Department of Internal Medicine, College of Medicine, University of Iowa, Iowa City, Iowa (D.Z., C.O., K.D., M.V.); and Department of Veteran Affairs Medical Center, University of Iowa, Iowa City, Iowa (C.O., K.D., M.V.)

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 EC50 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 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) BKCa channels 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.

0022-3565/02/3032-0768$00.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2002 by U.S. Government


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