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1 Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA
* To whom correspondence should be addressed. E-mail: kgauth{at}mcw.edu.
Acetylcholine stimulates the release of endothelium-derived arachidonic acid (AA) metabolites including prostacyclin and epoxyeicosatrienoic acids, which relax coronary arteries. However, mechanisms of endothelial cell (EC) AA activation remain undefined. We propose that 2-arachidonylglycerol (2-AG) plays an important role in this pathway. An AA metabolite isolated from bovine coronary ECs was identified as 2-AG by mass spectrometry. In ECs pretreated with the fatty acid amidohydrolase inhibitor, diazomethylarachidonyl ketone (DAK, 20 µmol/L), methacholine (10 µmol/L) stimulated 2-AG release was blocked by the phospholipase C inhibitor, U73122 (10 µmol/L) or the diacylglycerol lipase inhibitor, RHC80267 (40 µmol/L). In U46619-preconstricted bovine coronary arterial rings, 2-AG relaxations averaging 100% at 10 µmol/L were inhibited by endothelium removal, DAK, the hydrolase inhibitor, methyl arachidonylfluorophosphate (10 µmol/L), the cyclooxygenase inhibitor, indomethacin (10 µmol/L) but not the CB1 cannabinoid receptor antagonist, SR141716 (1 µmol/L). The cytochrome P450 inhibitor, SKF525a (10 µmol/L) or the EET antagonist, 14,15-EEZE (10 µmol/L) further attenuated the indomethacin-resistant relaxations. The non-hydrolyzable 2-AG analogs, noladin ether, 2-AG amide and 14,15-EET glycerol amide did not induce relaxation. Nitro-L-arginine-resistance relaxations to methacholine were also inhibited by U73122, RHC80267 and DAK. 14,15-EET glycerol ester increased opening of large-conductance K+ channels 12-fold in cell-attached patches of isolated smooth muscle cells and induced relaxations averaging 95%. These results suggest that methacholine stimulates EC 2-AG production through phospholipase C and diacylglycerol lipase activation. 2-AG is further hydrolyzed to AA, which is metabolized to vasoactive eicosanoids. These studies reveal a role for 2-AG in EC AA release and the regulation of coronary tone.
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