The synthesis of 20-HETE in small porcine coronary arteries antagonizes EDHF-mediated relaxation

Voahanginirina Randriamboavonjy, Ladislau Kiss, J R Falck, Rudi Busse, Ingrid Fleming

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Abstract

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 Ca 2+. 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. 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, respectively, and was inhibited by the CYP 4A inhibitor N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS). In vascular reactivity studies, DDMS attenuated U46619-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 A 2 inhibitors AACOCF 3 and ONO-RS-082, as well as by the ω-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 Cα (PKCα). This effect was reversed by the PKC inhibitor Ro-318220 and mimicked by the PKC activator phorbol-12 myristate 13-acetate. 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 PKCα-dependent mechanism, probably involving the inhibition of the Na-K-ATPase.

Original languageEnglish (US)
Pages (from-to)487-494
Number of pages8
JournalCardiovascular Research
Volume65
Issue number2
DOIs
StatePublished - Feb 1 2005

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Keywords

  • Endothelial factors
  • Na/K-pump
  • Protein kinase C
  • Stretch/m-e coupling
  • Vasoconstriction/dilation

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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