Rosolowsky M, Falck J R, Willerson J T, Campbell W B
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas 75235-9041.
Circ Res. 1990 Mar;66(3):608-21. doi: 10.1161/01.res.66.3.608.
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.
冠状动脉损伤会促进血细胞与血管壁的相互作用，从而影响花生四烯酸代谢和冠状动脉血流模式。由于花生四烯酸的脂氧合酶和细胞色素P-450环氧合酶代谢产物是由血管和炎症细胞合成的，且具有多种重要的生物学作用，我们研究了正常和狭窄、内皮损伤的犬冠状动脉中这些途径对花生四烯酸的代谢情况。我们通过气相色谱/质谱法发现并证实，两个冠状动脉节段主要合成12-和15-羟基二十碳四烯酸（HETEs）。也会产生少量的11-、9-、8-和5-HETEs。还会合成15-酮基二十碳四烯酸。狭窄冠状动脉合成14C-HETEs的量比正常冠状动脉高5至10倍。特异性放射免疫分析表明，狭窄冠状动脉分别合成15-HETE和12-HETE的量为93±14和1102±154 ng/g组织，而正常冠状动脉分别产生15-HETE和12-HETE的量为17±3和162±68 ng/g组织。通过高压液相色谱法在狭窄冠状动脉中主要检测到与14,15-；11,12-；8,9-；和5,6-环氧二十碳三烯酸（EETs）以及相应的二羟基二十碳三烯酸（DHETs）共迁移的产物。EETs的结构通过气相色谱/质谱法得到证实。EETs和前列腺素I2可使犬冠状动脉环产生不依赖内皮的、浓度相关的舒张作用。这些数据表明，正常和狭窄的冠状动脉会将花生四烯酸代谢为HETEs、DHETs和EETs以及前列腺素；然而，在狭窄、内皮损伤的血管中这些代谢产物的合成量更大。EETs可能在周期性血流变化的发展过程中合成，并抵消血栓素A2的血管收缩作用。
