Cardiovascular effects of 2-arachidonoyl glycerol in anesthetized mice

Cannabinoids, including the endogenous ligand anandamide, elicit pronounced hypotension and bradycardia through the activation of CB1 cannabinoid rece ptors. A second endogenous cannabinoid, 2-arachidonoyl glycerol (2-AG), has been proposed to be the natural Ligand of CB1 receptors. In the present st udy, we examined the effects of 2-AG on mean arterial pressure and heart ra te in anesthetized mice and assessed the role of CB1 receptors through the use of selective cannabinoid receptor antagonists and CB1 receptor knockout (CB1(-/-)) mice. In control ICR mice, intravenous injections of 2-AG or it s isomer 1-AG elicit dose-dependent hypotension and moderate tachycardia th at are unaffected by the CB1 receptor antagonist SR141716A. The same dose o f SR141716A (6 nmol/g IV) completely blocks the hypotensive effect and atte nuates the bradycardic effect of anandamide. 2-AG elicits a similar hypoten sive effect, resistant to blockade by either SR141716A or the CB2 antagonis t SR144528, in both CB1(-/-) mice and their homozygous (CB1(+/+)) control l ittermates. In ICR mice, arachidonic acid (AA, 15 nmol/g TV) elicits hypote nsion and tachycardia, and indomethacin (14 nmol/g IV) inhibits the hypoten sive effect of both AA and 2-AG. Synthetic 2-AG incubated with mouse blood is rapidly (<2 minutes) and completely degraded with the parallel appearanc e of AA, whereas anandamide is stable under the same conditions. A metaboli cally stable ether analogue of 2-AG causes prolonged hypotension and bradyc ardia in ICR mice, and both effects are completely blocked by SR141716A, wh ereas the same dose of ZAG-ether does not influence blood pressure and hear t rate in CB1(-/-) mice. These findings are interpreted to indicate that ex ogenous 2-AG is rapidly degraded in mouse blood, probably by a lipase, whic h masks its ability to interact with CB1 receptors. Although the observed c ardiovascular effects of 2-AG probably are produced by an arachidonate meta bolite through a noncannabinoid mechanism, the CB1 receptor-mediated cardio vascular effects of a stable analogue of 2-AG leaves open the possibility t hat endogenous 2-AG may elicit cardiovascular effects through CB1 receptors .