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 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) 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 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 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.