Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You and Your Team.

Learn More →

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

Ho, W‐Sv; Randall, M D
British Journal of Pharmacology , Volume 150 (5) – Mar 1, 2007
Download PDF
11 pages
Read Article

Loading next page...
 
/lp/wiley/endothelium-dependent-metabolism-by-endocannabinoid-hydrolases-and-LzHM4iItD8
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 Pharmacology – Wiley

Published: Mar 1, 2007

References

You’re reading a free preview. Subscribe to read the entire article.

Try 2 weeks free now

DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

or browse the journals available

Search

Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly

Organize

Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.

Access

Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve

Freelancer

DeepDyve

Pro

Price

FREE

$49/month
$499/year

Save searches from
Google Scholar,
PubMed

Create folders to
organize your research

Export folders, citations

Read DeepDyve articles

Abstract access only

Unlimited access to over
18 million full-text articles

Print

20 pages / month

Sign up
for free
Start 14 day
Free Trial