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1 Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
* To whom correspondence should be addressed. E-mail: kgauth{at}mcw.edu.
Rabbit aortic endothelium metabolizes arachidonic acid (AA) by the 15-lipoxygenase pathway to vasodilatory eicosanoids, hydroxy-epoxyeicosatrienoic acids (HEETAs) and trihydroxyeicosatrienoic acids (THETAs). The present study determined the chemical identity of the vasoactive THETA and investigated its role in acetylcholine-induced relaxation in the rabbit aorta. AA caused endothelium-dependent, concentration-related relaxations of the rabbit aorta. Increasing the extracellular potassium chloride (KCl) concentration from 4.8 to 20 mM inhibited the relaxations to AA by ~ 60% implicating K+ channel activation in the relaxations. In addition, AA caused an endothelium-dependent hyperpolarization of aortic smooth muscle from -39.6 ± 2.7 to -56.1 ± 3.4 mV. In rabbit aortic rings, 14C-AA was metabolized to the prostaglandins, HEETAs, THETAs and 15-hydroxyeicosatetraenoic acid. Further purification of the THETAs by HPLC resolved the mixture into its 14C-labelled products. Gas chromatography/mass spectrometry identified the metabolites as isomers of 11,12,15-THETA and 11,14,15-THETA. 11,12,15-THETA relaxed and hyperpolarized the rabbit aorta, whereas 11,14,15-THETA had no vasoactive effect. The relaxations to 11,12,15-THETA were blocked by 20 mM KCl. In aortic rings pretreated with inhibitors of nitric oxide and prostaglandin synthesis, acetylcholine caused a concentration-related relaxation that was completely blocked by 20 mM KCl. Pretreatment with the phospholipase A2 inhibitors mepacrine and 7,7-dimethyl-5,8-eicosadienoic acid (DEDA), the lipoxygenase inhibitors cinnamyl-3,4-dihydroxy-
-cyanocinnamate (CDC), nordihydroguaiaretic acid (NDGA) and ebselen, or the hydroperoxide isomerase inhibitors miconazole and clotrimazole also blocked acetylcholine-induced relaxations. Acetylcholine caused a 3-fold increase in THETA release. These studies indicate that AA is metabolized by endothelial cells to 11,12,15-THETA, which activates K+ channels to hyperpolarize the aortic smooth muscle membrane and induce relaxation. Additionally, this lipoxygenase pathway mediates the non-nitric oxide, non-prostaglandin relaxations to acetylcholine in the rabbit aorta by acting as a source of an endothelium-derived hyperpolarizing factor.
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