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

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 EC50 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. British Journal of Pharmacology (2007) 152, 691–698; doi:10.1038/sj.bjp.0707468; published online 24 September 2007