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Cytochrome P450-dependent eicosapentaenoic acid metabolites are novel BK channel activators

Item Type:Article
Title:Cytochrome P450-dependent eicosapentaenoic acid metabolites are novel BK channel activators
Creators Name:Lauterbach, B. and Barbosa-Sicard, E. and Wang, M.H. and Honeck, H. and Kaergel, E. and Theuer, J. and Schwartzman, M.L. and Haller, H. and Luft, F.C. and Gollasch, M. and Schunck, W.H.
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:Cytochrome P450, Endothelium-Derived Factors, Potassium Channels, Vascular Smooth Muscle Cells, Animals, Rats
Source:Hypertension
ISSN:0194-911X
Publisher:American Heart Association (U.S.A.)
Volume:39
Number:2
Page Range:609-613
Date:1 January 2002
PubMed:View item in PubMed

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