TY - JOUR
T1 - Cytochrome P450-dependent eicosapentaenoic acid metabolites are novel BK channel activators
AU - Lauterbach, Birgit
AU - Barbosa-Sicard, Eduardo
AU - Wang, Mong Heng
AU - Honeck, Horst
AU - Kärgel, Eva
AU - Theuer, Jürgen
AU - Schwartzman, Michal L.
AU - Haller, Hermann
AU - Luft, Friedrich C.
AU - Gollasch, Maik
AU - Schunck, Wolf Hagen
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2002
Y1 - 2002
N2 - 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.
AB - 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.
KW - Cytochrome P450
KW - Endothelium-derived factors
KW - Potassium channels
KW - Vascular smooth muscle cells
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U2 - 10.1161/hy0202.103293
DO - 10.1161/hy0202.103293
M3 - Article
C2 - 11882617
AN - SCOPUS:18244378308
SN - 0194-911X
VL - 39
SP - 609
EP - 613
JO - Hypertension
JF - Hypertension
IS - 2 II
ER -