title: Brain synthesis and cerebrovascular action of epoxygenase metabolites of arachidonic acid.
abstract: The purpose of this study was to determine if whole brain makes epoxygenase metabolites of arachidonic acid and, if so, whether they are vasoactive on the cerebral microcirculation. Blood-free mouse brain slices were incubated with exogenous radiolabeled arachidonic acid, and the extracted metabolites were resolved by HPLC. Metabolite structures were confirmed by gas chromatography/mass spectrometry. In addition to prostaglandins, leukotriene B4, and hydroxyeicosatetraenoic acids, mouse brain metabolized arachidonic acid into several other compounds. Among them, we identified 5,6- and 14,15-epoxyeicosatrienoic acid. Next, we tested the effect of topical application of brain-synthesized 5,6-epoxyeicosatrienoic acid and synthetic epoxyeicosatrienoic acids on in vivo rabbit cerebral arteriolar diameter using the cranial window technique and in vivo microscopy. Brain-synthesized 5,6-epoxyeicosatrienoic acid caused a transient 28% arteriolar dilation, similar to that produced by 5 micrograms/ml of synthetic 5,6-epoxyeicosatrienoic acid. A concentration of synthetic 14,15- and 11,12-epoxyeicosatrienoic acid of 5 micrograms/ml CSF had little or no effect on diameter, whereas 8,9-epoxyeicosatrienoic acid caused a maximum dilation of 8%. These studies suggest that brain-synthesized 5,6-epoxyeicosatrienoic acid may play a role in the normal or pathophysiological regulation of the cerebral microcirculation.
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond.
authors.forename: S C
authors.initials: SC
authors.lastname: Amruthesh
authors.forename: J R
authors.initials: JR
authors.lastname: Falck
authors.forename: E F
authors.initials: EF
authors.lastname: Ellis
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D002851:Chromatography, High Pressure Liquid; D000090762:Cytochrome P-450 CYP2J2; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D008401:Gas Chromatography-Mass Spectrometry; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010105:Oxygenases / Q000378:metabolism*
chemical_list: C040776:5,6-epoxy-8,11,14-eicosatrienoic acid; C046782:14,15-epoxy-5,8,11-eicosatrienoic acid; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases; D000090762:Cytochrome P-450 CYP2J2; D015126:8,11,14-Eicosatrienoic Acid