2-arachidonoyl glycerol induces contraction of isolated rat aorta: role of cyclooxygenase-derived products

Objectives: Endocannabinoids have been shown to play a role in the regulation of vascular tone. The effects of 2-arachidonoyl glycerol (2-AG) on induced-tone were examined in rat aortic rings in vitro. Methods: Aortic rings from Wistar Kyoto (WKY) rats were suspended in organ chambers for recording isometric tension development in response to 2-AG. The production of TXA(2) in response to 2-AG was also assessed by enzyme immunoassay. Results: In endothelium-intact rings pre-contracted to PGF(2alpha), 2-AG (10 nM-30 muM) induced a biphasic effect: a weak relaxation from 10 nM to 0.1 muM, which turned into a concentration-dependent contraction from 3 to 30 muM. Endothelium-denudation did not change 2-AG-mediated vascular effects. 2-AG-induced contraction was unaffected by both the cannabinoid CB1 receptor antagonist SR141716A (3 muM) and the CB2 receptor antagonist SR144528 (1 muM). In contrast, the anandamine transport inhibitor (AM404, 100 muM) and the amino hydrolase inhibitor (PMSF, 30 muM) attenuated (P < 0.05) the contractile response evoked by 2-AG in endothelium-intact and rubbed aortic rings. In addition, the cyclooxygenase inhibitor (indomethacin, 10 muM) and the thrornboxane A(2) (TXA(2)) receptor (TP receptor) antagonist GR32191 (0.3 muM) totally abolished the contraction elicited by 2-AG in endothelium-intact and rubbed aortic rings. Challenge of isolated aortic rings with 2-AG (10 muM) evoked a significant increase in TXA(2) level (measured as TXB2 level) in endothelium-intact and rubbed aortic rings. Conclusion: These data suggested that the contraction elicited by 2-AG resulted from the vascular smooth muscle cell uptake and conversion of 2-AG to constrictor prostanoid TXA(2), which in turn caused vasoconstriction through the stimulation of TP receptor. (C) 2004 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.