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1 Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA
2 Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USA
* To whom correspondence should be addressed. E-mail: wbcamp{at}mcw.edu.
Acetylcholine (ACh) stimulates arachidonic acid (AA) release from membrane phospholipids of vascular endothelial cells (ECs). In rabbit aorta, AA is metabolized through the 15-LO pathway to form vasodilatory eicosanoids 15-hydroxy-11,12 epoxyeicosatrienoic acid (HEETA) and 11,12,15- trihydroxyeicosatrienoic acid (THETA). AA is released from phosphatidylcholine (PC) and phosphatidylethanolamine (PE) by phospholipase A2 (PLA2), or from phosphatidylinositol (PI) by phospholipase C (PLC) pathway. The diacylglycerol (DAG) lipase can convert DAG into 2-arachidonoylglycerol (2-AG) from which free AA can be released by monoacylglycerol (MAG) lipase or fatty acid amidohydrolase (FAAH). We used specific inhibitors to determine the involvement of the PLC pathway in ACh-induced AA release. In rabbit aortic rings precontracted by phenylephrine, ACh induced relaxation in the presence of indomethacin and L-nitroarginine (L-NA). These relaxations were blocked by the PLC inhibitor U73122, DAG lipase inhibitor RHC80267 and MAG lipase /FAAH inhibitor URB532. Cultured rabbit aortic ECs were labeled with 14C-AA and stimulated with methacholine (10-5 M). Free 14C-AA was released by methacholine. Methacholine decreased the 14C-AA content of PI, DAG, and MAG fractions but not PC or PE fractions. Methacholine-induced release of 14 C-AA was blocked by U73122, RHC80267, URB532 but not by U73343, an inactive analogue of U73122. The data suggested that ACh activates PLC, DAG lipase, MAG lipase pathway to release AA from membrane lipids. This pathway is important in regulating vasodilatory eicosanoid synthesis and vascular relaxation in rabbit aorta.
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