Inhibition of 2-arachidonoylglycerol catabolism modulates vasoconstriction of rat middle cerebral artery by the thromboxane mimetic, U-46619

C. J. Hillard, W. S V Ho, J. Thompson, K. M. Gauthier, C. E. Wheelock, H. Huang, B. D. Hammock

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

Background and purpose: Cerebrovascular smooth muscle cells express the CB 1 cannabinoid receptor and CB 1 agonists produce vasodilatation of the middle cerebral artery (MCA). The thromboxane A 2 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 CB 1 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.

Original languageEnglish (US)
Pages (from-to)691-698
Number of pages8
JournalBritish Journal of Pharmacology
Volume152
Issue number5
DOIs
StatePublished - Nov 2007

Keywords

  • 2-arachidonoylglycerol
  • Cannabinoid receptor
  • CB receptor
  • DETFP
  • Endocannabinoid
  • Fatty acid amide hydrolase
  • Middle cerebral artery
  • Monoacylglycerol lipase
  • U-46619
  • URB754

ASJC Scopus subject areas

  • Pharmacology

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