Endothelium‐dependent metabolism by endocannabinoid hydrolases and cyclooxygenases limits vasorelaxation to anandamide and 2‐arachidonoylglycerol

Endothelium‐dependent metabolism by endocannabinoid hydrolases and cyclooxygenases limits... Background and purpose: The endocannabinoids, N‐arachidonoylethanolamide (anandamide) and 2‐arachidonoylglycerol (2‐AG) are rapidly degraded by fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL). Whilst these lipid mediators are known to modulate vascular tone, the extent to which they are inactivated via local metabolism in the vasculature remains unclear. Experimental approach: In rat isolated small mesenteric arteries, the regulatory role of FAAH, MGL and cyclooxygenase (COX) in relaxant responses to anandamide and 2‐AG was evaluated by using inhibitors of these enzymes. Relaxations to non‐hydrolysable analogues of endocannabinoids and arachidonic acid were also examined. Key results: Relaxation to anandamide but not 2‐AG was potentiated by the selective FAAH inhibitor, URB597 (1 μM). In contrast, MAFP (10 μM; an inhibitor of FAAH and MGL) enhanced responses to both anandamide and 2‐AG. Inhibition of COX‐1 by indomethacin (10 μM) potentiated relaxations to 2‐AG, whereas inhibition of COX‐2 by nimesulide (10 μM) potentiated anandamide‐induced relaxation. With the exception of MAFP, effects of FAAH and COX inhibitors were dependent on the endothelium. Relaxation to methanandamide and noladin ether, the non‐hydrolysable analogues of anandamide and 2‐AG respectively, were insensitive to the enzyme inhibitors. Conclusion and implications: This study shows that local activity of FAAH, MGL and COX, which is present largely in the endothelium, limits the vasodilator action of endocannabinoids in rat small mesenteric arteries. Despite the differential roles played by these enzymes on relaxation to anandamide versus 2‐AG, our results suggest that inhibitors of these enzymes enhance the vascular impact of endocannabinoids. British Journal of Pharmacology (2007) 150, 641–651. doi:10.1038/sj.bjp.0707141 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png British Journal of Pharmacology Wiley

Endothelium‐dependent metabolism by endocannabinoid hydrolases and cyclooxygenases limits vasorelaxation to anandamide and 2‐arachidonoylglycerol

British Journal of Pharmacology, Volume 150 (5) – Mar 1, 2007

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Publisher
Wiley
Copyright
2007 British Pharmacological Society
ISSN
0007-1188
eISSN
1476-5381
DOI
10.1038/sj.bjp.0707141
pmid
17245358
Publisher site
See Article on Publisher Site

Abstract

Background and purpose: The endocannabinoids, N‐arachidonoylethanolamide (anandamide) and 2‐arachidonoylglycerol (2‐AG) are rapidly degraded by fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL). Whilst these lipid mediators are known to modulate vascular tone, the extent to which they are inactivated via local metabolism in the vasculature remains unclear. Experimental approach: In rat isolated small mesenteric arteries, the regulatory role of FAAH, MGL and cyclooxygenase (COX) in relaxant responses to anandamide and 2‐AG was evaluated by using inhibitors of these enzymes. Relaxations to non‐hydrolysable analogues of endocannabinoids and arachidonic acid were also examined. Key results: Relaxation to anandamide but not 2‐AG was potentiated by the selective FAAH inhibitor, URB597 (1 μM). In contrast, MAFP (10 μM; an inhibitor of FAAH and MGL) enhanced responses to both anandamide and 2‐AG. Inhibition of COX‐1 by indomethacin (10 μM) potentiated relaxations to 2‐AG, whereas inhibition of COX‐2 by nimesulide (10 μM) potentiated anandamide‐induced relaxation. With the exception of MAFP, effects of FAAH and COX inhibitors were dependent on the endothelium. Relaxation to methanandamide and noladin ether, the non‐hydrolysable analogues of anandamide and 2‐AG respectively, were insensitive to the enzyme inhibitors. Conclusion and implications: This study shows that local activity of FAAH, MGL and COX, which is present largely in the endothelium, limits the vasodilator action of endocannabinoids in rat small mesenteric arteries. Despite the differential roles played by these enzymes on relaxation to anandamide versus 2‐AG, our results suggest that inhibitors of these enzymes enhance the vascular impact of endocannabinoids. British Journal of Pharmacology (2007) 150, 641–651. doi:10.1038/sj.bjp.0707141

Journal

British Journal of PharmacologyWiley

Published: Mar 1, 2007

References

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