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U-46619 but not serotonin increases endocannabinoid content in middle cerebral artery: evidence for functional relevance

Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin

Submitted 23 September 2004 ; accepted in final form 28 January 2005

Cerebral vascular smooth muscle cells express the CB₁ cannabinoid receptor, and CB₁ receptor agonists produce vasodilation of cerebral arteries. The purpose of this study was to determine whether vasoconstriction of rat middle cerebral artery (MCA) results in the local formation of endocannabinoids (eCBs), which, via activation of CB₁ receptors, oppose the vasoconstriction in a feedback manner. The thromboxane A₂ (TXA₂) mimetic U-46619 significantly increased N-arachidonylethanolamine (AEA) and 2-arachidonylglycerol (2-AG) content of isolated MCA, whereas 5-hydroxytrypamine (5-HT) decreased AEA and 2-AG content. If eCBs play a feedback role in the regulation of MCA tone, then CB₁ receptor antagonists should enhance the constriction of MCA produced by U-46619 but not 5-HT. U-46619 caused concentration-dependent constrictions of endothelium-denuded MCA. Two CB₁ receptor antagonists SR-141716 and AM-251 decreased the EC₅₀ value for U-46619 to constrict endothelium-denuded MCA without affecting the maximal effect. A low concentration of CB₁ receptor agonist Win-55212-2 (30 nM) produced vasodilation of MCAs constricted with low but not saturating concentrations of U-46619. SR-141716 had no effect on the 5-HT concentration-contraction relationship. These data suggest that TXA₂ receptor activation increases MCA eCB content, which, via activation of CB₁ receptors, reduces the constriction produced by moderate concentrations of the TXA₂ agonist. Although 5-HT-induced vasoconstriction is reduced by exogenous CB₁ receptor agonist, activation of 5-HT receptors does not increase eCB content. These results suggest that MCA production of eCBs is not regulated by constriction per se but likely via a signaling pathway that is specific for TXA₂ receptors and not 5-HT receptors.

CB₁ receptor; cannabinoids; SR-141716; AM-251; N-arachidonylethanolamine; 2-arachidonylglycerol; mass spectrometry