Abstract 648: Metabolism of Adrenic Acid to Vasodilatory 1α, 1β-Dihomo-epoxyeicosatrienoic Acids by Bovine Coronary Arteries
Adrenic acid (docosatetraenoic acid), an abundant fatty acid in the vasculature, is produced by 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 spectrometry of bovine coronary artery and endothelial cell lysates revealed arachidonic acid concentrations of 2.06±0.01 and 6.18±0.60 μg/mg protein and adrenic acid concentrations of 0.29±0.01 and 1.56±0.16 μg/mg protein, respectively. In bovine coronary arterial rings preconstricted with the thromboxane mimetic, U46619, adrenic acid (10-9-10-5M) induced concentration-related relaxations (maximal relaxation=76±3%) that were similar to arachidonic acid relaxations. Adrenic acid relaxations were blocked by endothelial cell removal and the potassium channel inhibitor, iberiotoxin (100 nM) and inhibited by the cyclooxygenase inhibitor, indomethacin (10 μM, maximal relaxation=53±3%) and the cytochrome P450 inhibitor, miconazole (10 μM, maximal relaxation=32±4%). Reverse-phase high pressure liquid chromatography 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 regioisomers (16,17-, 13,14-, 10,11- and 7,8- (10-9-10-5M)) induced similar concentration-related relaxations (maximal relaxations averaged 83±3%). DH-16,17-EET (10-8-10-6 M) activated whole-cell outward potassium current of isolated smooth muscle cells which was inhibited by iberiotoxin. Thus, in bovine coronary arteries, adrenic acid causes endothelium-dependent relaxations that are mediated by cyclooxygenase and cytochrome P450 metabolites. The adrenic acid metabolite, 16,17-DH-EET activates smooth muscle potassium channels to cause relaxation. Our results suggest a role of adrenic acid metabolites, specifically, DH-16,17-EET as endothelium-derived hyperpolarizing factors (EDHF) in the coronary circulation.