5,6-Epoxyeicosatrienoic acid, a novel arachidonate metabolite. Mechanism of vasoactivity in the rat

M. A. Carroll, M. P. Garcia, J R Falck, J. C. McGiff

Research output: Contribution to journalArticle

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Abstract

We have reported that 5,6-epoxyeicosatrienoic acid (5,6-EET) was the only cytochrome P-450-dependent arachidonic acid (AA) epoxide to dilate the isolated, perfused caudal artery of the rat. We have investigated the mechanisms by which 5,6-EET dilates the rat-tail artery by studying the effect of deendothelialization and inhibition of AA metabolic pathways (cyclooxygenase, lipoxygenase, and cytochrome P-450 monooxygenase) on the vascular action of the epoxide. Rat isolated caudal arteries were perfused with Krebs-Henseleit solution at 37°C, pH 7.4, and gassed with 95% O2-5% CO2. Arterial tone was elevated with phenylephrine; acetylcholine (0.5 nmol) was used to detect the presence of intact, functional endothelium. Doses of 5,6-EET, from 6.25 to 25.0 nmol, were injected close-arterially. After obtaining control responses, the same doses were randomly retested after deendothelialization or in the presence of inhibitors of AA metabolism. Removal of the endothelium decreased by 70% the vasodilator responses to 5,6-EET. The endothelial dependency was a function of the epoxide interacting with cyclooxygenase of the endothelium, because indomethacin (3 μM) and aspirin (50 μM) prevented the vasodilator response to 5,6-EET while not affecting the response to acetylcholine. SKF-525A (1.1 μM) and metyrapone (150 μM) did not affect the responses to the 5,6-EET, whereas clotrimazole (0.7 μM) and nordihydroguariaretic acid (2.5 μM) had nonspecific effects, decreasing responses to 5,6-EET and acetylcholine. Because 5,6-EET failed to stimulate detectable release of prostanoids into the effluent from the caudal artery, we conclude that 5,6-EET requires conversion by cyclooxygenase for expression of its vasoactivity.

Original languageEnglish (US)
Pages (from-to)1082-1088
Number of pages7
JournalCirculation research
Volume67
Issue number5
DOIs
StatePublished - Jan 1 1990

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Keywords

  • arachidonic acid
  • cyclooxygenase
  • cytochrome P-450 monooxygenase
  • epoxides
  • vasoactivity

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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