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

Research output: Contribution to journalArticle

91 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)609-613
Number of pages5
JournalHypertension
Volume39
Issue number2 II
DOIs
StatePublished - Mar 4 2002
Externally publishedYes

Fingerprint

Large-Conductance Calcium-Activated Potassium Channels
Eicosapentaenoic Acid
Cytochrome P-450 Enzyme System
Calcium-Activated Potassium Channels
4-Aminopyridine
Tetraethylammonium
Cerebral Arteries
Potassium Channels
Patch-Clamp Techniques
Vascular Smooth Muscle
Arachidonic Acid
Smooth Muscle Myocytes
Blood Vessels
Diet
Acids
17,18-epoxy-5,8,11,14-eicosatetraenoic acid

Keywords

  • Cytochrome P450
  • Endothelium-derived factors
  • Potassium channels
  • Vascular smooth muscle cells

ASJC Scopus subject areas

  • Internal Medicine

Cite this

Lauterbach, B., Barbosa-Sicard, E., Wang, M-H., Honeck, H., Kärgel, E., Theuer, J., ... Schunck, W. H. (2002). Cytochrome P450-dependent eicosapentaenoic acid metabolites are novel BK channel activators. Hypertension, 39(2 II), 609-613. https://doi.org/10.1161/hy0202.103293

Cytochrome P450-dependent eicosapentaenoic acid metabolites are novel BK channel activators. / Lauterbach, Birgit; Barbosa-Sicard, Eduardo; Wang, Mong-Heng; Honeck, Horst; Kärgel, Eva; Theuer, Jürgen; Schwartzman, Michal L.; Haller, Hermann; Luft, Friedrich C.; Gollasch, Maik; Schunck, Wolf Hagen.

In: Hypertension, Vol. 39, No. 2 II, 04.03.2002, p. 609-613.

Research output: Contribution to journalArticle

Lauterbach, B, Barbosa-Sicard, E, Wang, M-H, Honeck, H, Kärgel, E, Theuer, J, Schwartzman, ML, Haller, H, Luft, FC, Gollasch, M & Schunck, WH 2002, 'Cytochrome P450-dependent eicosapentaenoic acid metabolites are novel BK channel activators', Hypertension, vol. 39, no. 2 II, pp. 609-613. https://doi.org/10.1161/hy0202.103293
Lauterbach B, Barbosa-Sicard E, Wang M-H, Honeck H, Kärgel E, Theuer J et al. Cytochrome P450-dependent eicosapentaenoic acid metabolites are novel BK channel activators. Hypertension. 2002 Mar 4;39(2 II):609-613. https://doi.org/10.1161/hy0202.103293
Lauterbach, Birgit ; Barbosa-Sicard, Eduardo ; Wang, Mong-Heng ; Honeck, Horst ; Kärgel, Eva ; Theuer, Jürgen ; Schwartzman, Michal L. ; Haller, Hermann ; Luft, Friedrich C. ; Gollasch, Maik ; Schunck, Wolf Hagen. / Cytochrome P450-dependent eicosapentaenoic acid metabolites are novel BK channel activators. In: Hypertension. 2002 ; Vol. 39, No. 2 II. pp. 609-613.
@article{0e346583398744b880778de716a03954,
title = "Cytochrome P450-dependent eicosapentaenoic acid metabolites are novel BK channel activators",
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",
author = "Birgit Lauterbach and Eduardo Barbosa-Sicard and Mong-Heng Wang and Horst Honeck and Eva K{\"a}rgel and J{\"u}rgen Theuer and Schwartzman, {Michal L.} and Hermann Haller and Luft, {Friedrich C.} and Maik Gollasch and Schunck, {Wolf Hagen}",
year = "2002",
month = "3",
day = "4",
doi = "10.1161/hy0202.103293",
language = "English (US)",
volume = "39",
pages = "609--613",
journal = "Hypertension",
issn = "0194-911X",
publisher = "Lippincott Williams and Wilkins",
number = "2 II",

}

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

PY - 2002/3/4

Y1 - 2002/3/4

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

UR - http://www.scopus.com/inward/record.url?scp=18244378308&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=18244378308&partnerID=8YFLogxK

U2 - 10.1161/hy0202.103293

DO - 10.1161/hy0202.103293

M3 - Article

C2 - 11882617

AN - SCOPUS:18244378308

VL - 39

SP - 609

EP - 613

JO - Hypertension

JF - Hypertension

SN - 0194-911X

IS - 2 II

ER -