TY - JOUR
T1 - Metabolism of adrenic acid to vasodilatory 1α,1β-dihomo- epoxyeicosatrienoic acids by bovine coronary arteries
AU - Yi, Xiu Yu
AU - Gauthier, Kathryn M.
AU - Cui, Lijie
AU - Nithipatikom, Kasem
AU - Falck, J R
AU - Campbell, William B.
PY - 2007/5
Y1 - 2007/5
N2 - 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.
AB - 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.
KW - Cyclooxygenase
KW - Cytochrome P-450
KW - Endothelium-dependent relaxation
KW - Endothelium-derived hyperpolarizing factor
KW - Potassium channels
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U2 - 10.1152/ajpheart.00947.2006
DO - 10.1152/ajpheart.00947.2006
M3 - Article
C2 - 17209008
AN - SCOPUS:34250902918
SN - 0363-6135
VL - 292
SP - H2265-H2274
JO - American Journal of Physiology - Heart and Circulatory Physiology
JF - American Journal of Physiology - Heart and Circulatory Physiology
IS - 5
ER -