Endothelium-derived 2-arachidonylglycerol: an intermediate in vasodilatory eicosanoid release in bovine coronary arteries

American Journal of Physiology - Heart and Circulatory Physiology - Tập 288 Số 3 - Trang H1344-H1351 - 2005
Kathryn M. Gauthier1, David Baewer2, Sarah B. Hittner2, Cecilia J. Hillard2, Kasem Nithipatikom2, D. Sudarshan Reddy3, John R. Falck, William B. Campbell2
1Department of Pharmacology & Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
2Medical College of Wisconsin
3University of Texas Southwestern Medical Center

Tóm tắt

Acetylcholine stimulates the release of endothelium-derived arachidonic acid (AA) metabolites including prostacyclin and epoxyeicosatrienoic acids (EETs), 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 U-73122 (10 μmol/l) or the diacylglycerol lipase inhibitor RHC-80267 (40 μmol/l). In U-46619-preconstricted bovine coronary arterial rings, 2-AG relaxations averaging 100% at 10 μmol/l were inhibited by endothelium removal, by DAK, by the hydrolase inhibitor methyl arachidonylfluorophosphate (10 μmol/l), by the cyclooxygenase inhibitor indomethacin (10 μmol/l), but not by the CB1 cannabinoid receptor antagonist SR-141716 (1 μmol/l). The cytochrome P-450 inhibitor SKF-525a (10 μmol/l) and the 14,15-epoxyeicosa-5 Z-enoic acid EET antagonist (14,15-EEZE; 10 μmol/l) further attenuated the indomethacin-resistant relaxations. The nonhydrolyzable 2-AG analogs noladin ether, 2-AG amide, and 14,15-EET glycerol amide did not induce relaxation. N-nitro-l-arginine-resistant relaxations to methacholine were also inhibited by U-73122, RHC-80267, 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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American Journal of Physiology - Heart and Circulatory Physiology

Tập 288 Số 3

H1344-H1351

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