title: Metabolism of adrenic acid to vasodilatory 1alpha,1beta-dihomo-epoxyeicosatrienoic acids by bovine coronary arteries.
abstract: Adrenic acid (docosatetraenoic acid), an abundant fatty acid in the vasculature, is produced by a two-carbon chain elongation of arachidonic acid. Despite its abundance and similarity to arachidonic acid, little is known about its role in the regulation of vascular tone. Gas chromatography/mass spectrometric analysis of bovine coronary artery and endothelial cell lysates revealed arachidonic acid concentrations of 2.06 +/- 0.01 and 6.18 +/- 0.60 microg/mg protein and adrenic acid concentrations of 0.29 +/- 0.01 and 1.56 +/- 0.16 microg/mg protein, respectively. In bovine coronary arterial rings preconstricted with the thromboxane mimetic U-46619, adrenic acid (10(-9)-10(-5) M) induced concentration-related relaxations (maximal relaxation = 83 +/- 4%) that were similar to arachidonic acid relaxations. Adrenic acid relaxations were blocked by endothelium removal and the K(+) channel inhibitor, iberiotoxin (100 nM), and inhibited by the cyclooxygenase inhibitor, indomethacin (10 microM, maximal relaxation = 53 +/- 4%), and the cytochrome P-450 inhibitor, miconazole (10 microM, maximal relaxation = 52 +/- 5%). Reverse-phase HPLC and liquid chromatography/mass spectrometry isolated and identified numerous adrenic acid metabolites from coronary arteries including dihomo (DH)-epoxyeicosatrienoic acids (EETs) and DH-prostaglandins. DH-EET [16,17-, 13,14-, 10,11-, and 7,8- (10(-9)-10(-5) M)] induced similar concentration-related relaxations (maximal relaxations averaged 83 +/- 3%). Adrenic acid (10(-6) M) and DH-16,17-EET (10(-6) M) hyperpolarized coronary arterial smooth muscle. DH-16,17-EET (10(-8)-10(-6) M) activated iberiotoxin-sensitive, whole cell K(+) currents of isolated smooth muscle cells. Thus, in bovine coronary arteries, adrenic acid causes endothelium-dependent relaxations that are mediated by cyclooxygenase and cytochrome P-450 metabolites. The adrenic acid metabolite, DH-16,17-EET, activates smooth muscle K(+) channels to cause hyperpolarization and relaxation. Our results suggest a role of adrenic acid metabolites, specifically, DH-EETs as endothelium-derived hyperpolarizing factors in the coronary circulation.
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
authors.forename: Xiu-Yu
authors.initials: XY
authors.lastname: Yi
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Gauthier
authors.forename: Lijie
authors.initials: L
authors.lastname: Cui
authors.forename: Kasem
authors.initials: K
authors.lastname: Nithipatikom
authors.forename: John R
authors.initials: JR
authors.lastname: Falck
authors.forename: William B
authors.initials: WB
authors.lastname: Campbell
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D003331:Coronary Vessels / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004883:Erucic Acids / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D005231:Fatty Acids, Unsaturated; D066298:In Vitro Techniques; D008657:Metabolic Clearance Rate; D013552:Swine; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
chemical_list: D001095:Arachidonic Acids; D004883:Erucic Acids; D005231:Fatty Acids, Unsaturated; C011395:adrenic acid