牛冠状动脉将肾上腺酸代谢为血管舒张性1α,1β-二高-环氧二十碳三烯酸

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

作者信息

Yi Xiu-Yu, Gauthier Kathryn M, Cui Lijie, Nithipatikom Kasem, Falck John R, Campbell William B

机构信息

Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.

出版信息

Am J Physiol Heart Circ Physiol. 2007 May;292(5):H2265-74. doi: 10.1152/ajpheart.00947.2006. Epub 2007 Jan 5.

DOI:10.1152/ajpheart.00947.2006

PMID:17209008

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.

摘要

肾上腺酸（二十二碳四烯酸）是血管中一种丰富的脂肪酸，由花生四烯酸经两碳链延长生成。尽管其含量丰富且与花生四烯酸相似，但对其在血管张力调节中的作用却知之甚少。对牛冠状动脉和内皮细胞裂解物进行气相色谱/质谱分析，结果显示花生四烯酸浓度分别为2.06±0.01和6.18±0.60微克/毫克蛋白，肾上腺酸浓度分别为0.29±0.01和1.56±0.16微克/毫克蛋白。在用血栓素类似物U - 46619预收缩的牛冠状动脉环中，肾上腺酸（10⁻⁹ - 10⁻⁵摩尔/升）诱导出与浓度相关的舒张反应（最大舒张率 = 83±4%），这与花生四烯酸的舒张反应相似。肾上腺酸引起的舒张反应可被去除内皮和钾通道抑制剂iberiotoxin（100纳摩尔）阻断，并被环氧化酶抑制剂吲哚美辛（10微摩尔，最大舒张率 = 53±4%）和细胞色素P - 450抑制剂咪康唑（10微摩尔，最大舒张率 = 52±5%）抑制。反相高效液相色谱和液相色谱/质谱法从冠状动脉中分离并鉴定出多种肾上腺酸代谢产物，包括双高（DH）-环氧二十碳三烯酸（EETs）和DH -前列腺素。DH - EET [16,17 -、13,14 -、10,11 -和7,8 -（10⁻⁹ - 10⁻⁵摩尔/升）]诱导出类似的与浓度相关的舒张反应（最大舒张率平均为83±3%）。肾上腺酸（10⁻⁶摩尔/升）和DH - 16,17 - EET（10⁻⁶摩尔/升）使冠状动脉平滑肌超极化。DH - 16,17 - EET（10⁻⁸ - 10⁻⁶摩尔/升）激活了iberiotoxin敏感的分离平滑肌细胞的全细胞钾电流。因此，在牛冠状动脉中，肾上腺酸引起内皮依赖性舒张，这是由环氧化酶和细胞色素P - 450代谢产物介导的。肾上腺酸代谢产物DH - 16,17 - EET激活平滑肌钾通道，导致超极化和舒张。我们的结果表明肾上腺酸代谢产物，特别是DH - EETs作为冠状动脉循环中内皮源性超极化因子发挥作用。