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

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 (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 (Ͻ135 m in diameter) precontracted with endothelin. The five EDP regioisomers had dilation EC 50 values ranging from 0

Epoxy metabolites of docosahexaenoic acid (DHA) inhibit angiogenesis, tumor growth, and metastasis

“…Compared with EETs, EDPs are more potent than the EETs for vasodilation (∼1,000 times more potent than EETs) (24) and anti-inflammation (22). These results further argue that a replacement of EETs with EDPs upon omega-3 supplementation causes multiple beneficial effects.…”

“…EETs and EDPs have been investigated as autocrine and paracrine mediators to regulate inflammation and vascular tone (21)(22)(23)(24). In comparison, EDPs have been reported to have more potency on vasodilation and antiinflammation than EETs (22,24). Cumulatively, these results imply that EDPs could mediate some of the health-promoting effects of DHA.…”

“…EETs and EDPs are best described as regulators of inflammation and vascular tone (21)(22)(23)(24). Compared with EETs, EDPs are more potent than the EETs for vasodilation (∼1,000 times more potent than EETs) (24) and anti-inflammation (22).…”

“…DHA, which is the most abundant omega-3 fatty acid in most tissues (17,18), can efficiently compete with ARA for the metabolism by CYP epoxygenases, leading to replacement of EETs with EDPs in vivo (16,19,20). EETs and EDPs have been investigated as autocrine and paracrine mediators to regulate inflammation and vascular tone (21)(22)(23)(24). In comparison, EDPs have been reported to have more potency on vasodilation and antiinflammation than EETs (22,24).…”

Arachidonic Acid-metabolizing Cytochrome P450 Enzymes Are Targets of ω-3 Fatty Acids*

“…17,18-EEQ also hyperpolarizes and relaxes human pulmonary artery and bronchial smooth muscle cells (67). DHA-derived epoxides were up to 1000-fold more potent than EETs in activating BK channels in rat coronary arterioles (66). Thus, an exchange of EETs for EEQs and EDPs could explain the observation that n-3 PUFAs improve vascular function by increasing the response to vasodilator hormones.…”