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Hypertension. 2002;39:609-613
doi: 10.1161/hy0202.103293
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(Hypertension. 2002;39:609.)
© 2002 American Heart Association, Inc.

Scientific Contributions

Cytochrome P450-Dependent Eicosapentaenoic Acid Metabolites Are Novel BK Channel Activators

Birgit Lauterbach; Eduardo Barbosa-Sicard; Mong-Heng Wang; Horst Honeck; Eva Kärgel; Jürgen Theuer; Michal L. Schwartzman; Hermann Haller; Friedrich C. Luft; Maik Gollasch; Wolf-Hagen Schunck

From the Max Delbrück Center for Molecular Medicine and Franz Volhard Clinic HELIOS Kliniken-Berlin, Medical Faculty of the Charité, Humboldt University of Berlin (B.L., E. B.-S., H.H., E.K., J.T., F.C.L., M.G., W.-H.S.); the New York Medical College (M.H.-W., M.L.S.), Valhalla, NY; and the Department of Internal Medicine-Nephrology, Hannover Medical School (H.H.), Hannover, Germany

Correspondence to Wolf-Hagen Schunck, Max Delbrück Center for Molecular Medicine, Robert-Rössle-Str 10, 13092 Berlin, Germany. E-mail schunck{at}mdc-berlin.de

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.


Key Words: vascular smooth muscle cells • endothelium-derived factors • potassium channels • cytochrome P450




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