Inhibition of 2-arachidonoylglycerol catabolism modulates vasoconstriction of rat middle cerebral artery by the thromboxane mimetic, U-46619. Br J Pharmacol 2007 Nov;152(5):691-8
Date
09/25/2007Pubmed ID
17891162Pubmed Central ID
PMC2190024DOI
10.1038/sj.bjp.0707468Scopus ID
2-s2.0-35649005473 (requires institutional sign-in at Scopus site) 26 CitationsAbstract
BACKGROUND AND PURPOSE: Cerebrovascular smooth muscle cells express the CB1 cannabinoid receptor and CB1 agonists produce vasodilatation of the middle cerebral artery (MCA). The thromboxane A2 mimetic, U-46619, increased the content of the endocannabinoid, 2-arachidonoylglycerol (2-AG) in the MCA and 2-AG moderated the vasoconstriction produced by U46619 in this tissue. The purposes of this study were to examine the extent to which 2-AG is catabolized by cerebral arteries and to determine whether blockade of 2-AG inactivation potentiates its feedback inhibition of U-44619-mediated vasoconstriction.
EXPERIMENTAL APPROACH: The diameters of isolated, perfused MCA from male rats were measured using videomicroscopy.
KEY RESULTS: Exogenous 2-AG produces a CB1 receptor-dependent and concentration-related increase in the diameter of MCA constricted with 5-HT. The E (max) for 2-AG dilation is increased 4-fold in the presence of the metabolic inhibitors 3-(decylthio)-1,1,1-trifluropropan-2-one (DETFP), URB754 and URB597. To examine the role of catabolism in the effects of endogenous 2-AG, vasoconstriction induced by U-46619 was studied. DETFP and URB754, but not the fatty acid amide hydrolase inhibitor, URB597, significantly increased the EC(50) for U-46619. These data support a physiological role for endocannabinoid feedback inhibition in the effects of U-46619 and indicate that endogenously produced 2-AG is also efficiently catabolized within the MCA.
CONCLUSIONS AND IMPLICATIONS: MCA express mechanisms for the efficient inactivation of 2-AG, providing further support for an endocannabinoid feedback mechanism that opposes thromboxane-mediated vasoconstriction. These data suggest that potentiation of endogenously produced 2-AG could be a novel therapeutic approach to the treatment of thrombotic stroke.
Author List
Hillard CJ, Ho WS, Thompson J, Gauthier KM, Wheelock CE, Huang H, Hammock BDAuthors
Cecilia J. Hillard PhD Associate Dean, Center Director, Professor in the Pharmacology and Toxicology department at Medical College of WisconsinJonathan R. Thompson MD Assistant Professor in the Medicine department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic AcidAmidohydrolases
Aniline Compounds
Animals
Arachidonic Acid
Arachidonic Acids
Benzamides
Benzoxazines
Carbamates
Dose-Response Relationship, Drug
Drug Synergism
Endocannabinoids
Enzyme Inhibitors
Glycerides
In Vitro Techniques
Male
Middle Cerebral Artery
Morpholines
Naphthalenes
Nimodipine
Piperidines
Pyrazoles
Rats
Rats, Sprague-Dawley
Receptor, Cannabinoid, CB1
Thromboxanes
Vasoconstriction
Vasoconstrictor Agents
