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(Hypertension. 2000;35:679.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Cardiovascular Effects of 2-Arachidonoyl Glycerol in Anesthetized Mice
From the Department of Pharmacology and Toxicology, Medical College of Virginia of Virginia Commonwealth University, Richmond (Z.J., J.A.W., S.K.G., L.W., G.K.); Organix, Inc, Woburn, Mass (R.K.R.); the Faculty of Pharmaceutical Sciences, Teikyo University, Sagamiko, Kanagawa, Japan (T.S.); and the Section on Genetics, National Institute of Mental Health, Bethesda, Md (A.M.Z., T.I.B., A.Z.). J.A.W. is now with the Department of Medicine, University of Wuerzburg, Wuerzburg, Germany.
Correspondence to Dr George Kunos, Department of Pharmacology and Toxicology, MCV/VCU, 410 North 12th St, PO Box 980613, Richmond, VA 23298. E-mail gkunos{at}hsc.vcu.edu
Abstract—Cannabinoids, including the endogenous ligand anandamide, elicit pronounced hypotension and bradycardia through the activation of CB1 cannabinoid receptors. A second endogenous cannabinoid, 2-arachidonoyl glycerol (2-AG), has been proposed to be the natural ligand of CB1 receptors. In the present study, we examined the effects of 2-AG on mean arterial pressure and heart rate 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 its isomer 1-AG elicit dose-dependent hypotension and moderate tachycardia that are unaffected by the CB1 receptor antagonist SR141716A. The same dose of SR141716A (6 nmol/g IV) completely blocks the hypotensive effect and attenuates the bradycardic effect of anandamide. 2-AG elicits a similar hypotensive effect, resistant to blockade by either SR141716A or the CB2 antagonist SR144528, in both CB1-/- mice and their homozygous (CB1+/+) control littermates. In ICR mice, arachidonic acid (AA, 15 nmol/g IV) elicits hypotension and tachycardia, and indomethacin (14 nmol/g IV) inhibits the hypotensive effect of both AA and 2-AG. Synthetic 2-AG incubated with mouse blood is rapidly (<2 minutes) and completely degraded with the parallel appearance of AA, whereas anandamide is stable under the same conditions. A metabolically stable ether analogue of 2-AG causes prolonged hypotension and bradycardia in ICR mice, and both effects are completely blocked by SR141716A, whereas the same dose of 2-AG-ether does not influence blood pressure and heart rate in CB1-/- mice. These findings are interpreted to indicate that exogenous 2-AG is rapidly degraded in mouse blood, probably by a lipase, which masks its ability to interact with CB1 receptors. Although the observed cardiovascular effects of 2-AG probably are produced by an arachidonate metabolite through a noncannabinoid mechanism, the CB1 receptor–mediated cardiovascular effects of a stable analogue of 2-AG leaves open the possibility that endogenous 2-AG may elicit cardiovascular effects through CB1 receptors.
Key Words: receptors • mice • hypotension • cannabinoid
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