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Metabolism of adrenic acid to vasodilatory 1,1-dihomo-epoxyeicosatrienoic acids by bovine coronary arteries

¹Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin; and ²Department of Biochemistry, University of Texas Southwestern Medical School, Dallas, Texas

Submitted 31 August 2006 ; accepted in final form 5 January 2007

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 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 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 µM, maximal relaxation = 53 ± 4%), and the cytochrome P-450 inhibitor, miconazole (10 µM, 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.

endothelium-dependent relaxation; cytochrome P-450; cyclooxygenase; potassium channels; endothelium-derived hyperpolarizing factor

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