Copyright © 2004, European Society of Cardiology
The synthesis of 20-HETE in small porcine coronary arteries antagonizes EDHF-mediated relaxation
aVascular Signalling Group, Institut für Kardiovaskuläre Physiologie, Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany
bZentrum der Inneren Medizin, Justus Liebig Universität Gieβen, Klinikstrasse 36, D-35392 Gieβen, Germany
cDepartment of Biochemistry, University of Texas Southwestern Medical Center (J.R.F.), Dallas Texas 75390, USA
* Corresponding author. Tel.: +49 69 6301 6972; fax: +49 69 6301 7668. Email address: fleming{at}em.uni-frankfurt.de
Objective: Exogenous application of 20-hydroxyeicosatetraenoic acid (20-HETE) to small (300–500 µm) porcine coronary arteries elicits contraction by activating the Rho kinase and increasing the sensitivity of contractile proteins to Ca2+. Here, we determined whether 20-HETE is involved in the regulation of coronary artery tone as well as its role in the modulation of endothelium-derived hyperpolarizing factor (EDHF)-mediated responses.
Methods and results: Small porcine coronary arteries expressed cytochrome P450 (CYP) 4A, as demonstrated by Western blot analysis, and generated 20-HETE. Moreover, 20-HETE production was increased two- and threefold over basal levels in response to isometric stretch or the thromboxane analogue U46619
[GenBank]
, respectively, and was inhibited by the CYP 4A inhibitor N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS). In vascular reactivity studies, DDMS attenuated U46619
[GenBank]
-induced contractions and induced a concentration-dependent but endothelium-independent relaxation of precontracted arterial rings. Endogenously generated 20-HETE significantly inhibited the EDHF-mediated relaxation of coronary arteries, which was potentiated by the phospholipase A2 inhibitors AACOCF3 and ONO-RS-082, as well as by the 
-hydroxylase inhibitors 17-octadecynoic acid and DDMS. EDHF-mediated relaxation was not affected by either the nonselective epoxygenase inhibitors miconazole and clotrimazole or the CYP 2C inhibitor sulfaphenazole but was abolished by the Na-K-ATPase inhibitor, ouabain. Exogenous application of 20-HETE inhibited EDHF-mediated relaxations and caused a concomitant increase in the phosphorylation of protein kinase C
(PKC). This effect was reversed by the PKC inhibitor Ro-318220 and mimicked by the PKC activator phorbol-12 myristate 13-acetate.
Conclusions: These results indicate that vascular tone in small porcine coronary arteries is partly determined by the endogenous production of 20-HETE. In addition, 20-HETE functionally antagonizes EDHF-mediated relaxation via a PKC-dependent mechanism, probably involving the inhibition of the Na-K-ATPase.
KEYWORDS Endothelial factors; Na/K-pump; Protein kinase C; Stretch/m-e coupling; Vasoconstriction/dilation
Time for primary review 26 days
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