title: Synthesis of lipoxygenase and epoxygenase products of arachidonic acid by normal and stenosed canine coronary arteries.
abstract: Coronary vascular injury promotes blood cell-vessel wall interactions that influence arachidonic acid metabolism and coronary blood flow patterns. Since lipoxygenase and cytochrome P-450 epoxygenase metabolites of arachidonic acid are synthesized by vascular and inflammatory cells and have a variety of important biological actions, we investigated the metabolism of arachidonic acid by these pathways in normal and stenosed, endothelially injured canine coronary arteries. We found and confirmed by gas chromatography/mass spectrometry that primarily 12- and 15-hydroxyeicosatetraenoic acids (HETEs) are synthesized by both coronary artery segments. Lesser amounts of 11-, 9-, 8-, and 5-HETEs are also produced. 15-Ketoeicosatetraenoic acid is also synthesized. The synthesis of 14C-HETEs is fivefold to 10-fold greater by the stenosed than the normal coronary artery. Specific radioimmunoassays indicated that the stenosed coronary artery synthesized 93 +/- 14 and 1,102 +/- 154 ng/g of tissue of 15- and 12-HETE, respectively, while the normal coronary artery produced 17 +/- 3 and 162 +/- 68 ng/g of tissue of 15- and 12-HETE, respectively. Products comigrating with 14,15-; 11,12-; 8,9-; and 5,6-epoxyeicosatrienoic acids (EETs) and the corresponding dihydroxyeicosatrienoic acids (DHETs) were detected predominantly in stenosed coronary arteries by high-pressure liquid chromatography. The structures of the EETs were confirmed by GC/MS. The EETs and prostaglandin I2 produced endothelium-independent, concentration-related relaxations of dog coronary artery rings. These data indicate that normal and stenotic coronary arteries metabolize arachidonic acid to HETEs, DHETs, and EETs along with prostaglandins; however, the synthesis of these metabolites is greater in the stenosed, endothelially injured vessel. The EETs may be synthesized during the development of cyclic flow variations and counteract the vasoconstrictor effects of thromboxane A2.
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas 75235-9041.
authors.forename: M
authors.initials: M
authors.lastname: Rosolowsky
authors.forename: J R
authors.initials: JR
authors.lastname: Falck
authors.forename: J T
authors.initials: JT
authors.lastname: Willerson
authors.forename: W B
authors.initials: WB
authors.lastname: Campbell
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000096:biosynthesis / Q000378:metabolism*; D003251:Constriction, Pathologic; D003327:Coronary Disease / Q000378:metabolism*; D003331:Coronary Vessels / Q000378:metabolism*; D000090762:Cytochrome P-450 CYP2J2; D003577:Cytochrome P-450 Enzyme System; D004285:Dogs; D006893:Hydroxyeicosatetraenoic Acids / Q000096:biosynthesis; D008084:Lipoxygenase / Q000096:biosynthesis*; D010105:Oxygenases / Q000096:biosynthesis*; D011453:Prostaglandins / Q000096:biosynthesis; D012016:Reference Values
chemical_list: D001095:Arachidonic Acids; D006893:Hydroxyeicosatetraenoic Acids; D011453:Prostaglandins; D016718:Arachidonic Acid; C040776:5,6-epoxy-8,11,14-eicosatrienoic acid; C054992:15-keto-5,8,11,13-eicosatetraenoic acid; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases; D008084:Lipoxygenase; D000090762:Cytochrome P-450 CYP2J2; D015126:8,11,14-Eicosatrienoic Acid