Cytochrome P450-Dependent Eicosapentaenoic Acid Metabolites Are Novel BK Channel Activators
- 1 February 2002
- journal article
- other
- Published by Ovid Technologies (Wolters Kluwer Health) in Hypertension
- Vol. 39 (2), 609-613
- https://doi.org/10.1161/hy0202.103293
Abstract
P450-dependent arachidonic acid (AA) metabolites regulate arterial tone by modulating calcium-activated (BK) potassium channels in vascular smooth muscle cells (VSMC). Because eicosapentaenoic acid (EPA) has been reported to improve vascular function, we tested the hypothesis that P450-dependent epoxygenation of EPA produces alternative vasoactive compounds. We synthesized the 5 regioisomeric epoxyeicosattrienoic acids (EETeTr) and examined them for effects on K + currents in rat cerebral artery VSMCs with the patch-clamp technique. 11(R),12(S)-epoxyeicosatrienoic acid (50 nmol/L) was used for comparison and stimulated K + currents 6-fold at +60 mV. However, 17(R),18(S)-EETeTr elicited a more than 14-fold increase. 17(S),18(R)-EET and the remaining four regioisomers were inactive. The effect of 17(R),18(S)-EETeTr was blocked by tetraethylammonium but not by 4-aminopyridine. VSMCs expressed P450s 4A1 and 4A3. Recombinant P450 4A1 hydroxylated EPA at C-19 and C-20 and epoxygenated the 17,18-double bond, yielding the R, S- and S, R-enantiomers in a ratio of 64:36. We conclude that 17(R),18(S)-EETeTr represents a novel, potent activator of BK potassium channels. Furthermore, this metabolite can be directly produced in VSMCs. We suggest that 17(R),18(S)-EETeTr may function as an important hyperpolarizing factor, particularly with EPA-rich diets.Keywords
This publication has 24 references indexed in Scilit:
- Differential metabolism of benzo[a]pyrene and benzo[a]pyrene-7,8-dihydrodiol by human CYP1A1 variantsCarcinogenesis: Integrative Cancer Research, 2001
- Eicosapentaenoic acid (EPA) induces Ca2+‐independent activation and translocation of endothelial nitric oxide synthase and endothelium‐dependent vasorelaxationFEBS Letters, 2001
- Mechanisms of vasorelaxation induced by eicosapentaenoic acid (20:5n-3) in WKY rat aortaBritish Journal of Pharmacology, 2000
- Is EDHF an epoxyeicosatrienoic acid?Trends in Pharmacological Sciences, 2000
- Cat cerebral arterial smooth muscle cells express cytochrome P450 4A2 enzyme and produce the vasoconstrictor 20‐HETE which enhances L‐type Ca2+ currentThe Journal of Physiology, 1998
- The Highly Stereoselective Oxidation of Polyunsaturated Fatty Acids by Cytochrome P450BM-3Journal of Biological Chemistry, 1996
- HOW DO FISH OILS AFFECT VASCULAR FUNCTION?Clinical and Experimental Pharmacology and Physiology, 1995
- Activation of K+ channel in vascular smooth muscles by cytochrome P450 metabolites of arachidonic acidEuropean Journal of Pharmacology, 1993
- [42] Cytochrome P450 arachidonic acid epoxygenase: Stereochemical characterization of epoxyeicosatrienoic acidsMethods in enzymology, 1991
- Oxidation of 5,8,11,14,17-eicosapentaenoic acid by hepatic and renal microsomesBiochimica et Biophysica Acta (BBA) - General Subjects, 1988