| 11882617 |
Lauterbach B, Barbosa-Sicard E, Wang MH, Honeck H, Kargel E, Theuer J, Schwartzman ML, Haller H, Luft FC, Gollasch M, Schunck WH: Cytochrome P450-dependent eicosapentaenoic acid metabolites are novel BK channel activators. Hypertension. 2002 Feb;39(2 Pt 2):609-13.
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. |
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