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 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.
Járai
Z
Z
Department of Pharmacology and Toxicology, Medical College of Virginia of Virginia Commonwealth University, Richmond, VA 23298, USA.
Wagner
J A
JA
Goparaju
S K
SK
Wang
L
L
Razdan
R K
RK
Sugiura
T
T
Zimmer
A M
AM
Bonner
T I
TI
Zimmer
A
A
Kunos
G
G
D000758:Anesthesia; D000818:Animals; D001095:Arachidonic Acids; D001794:Blood Pressure / Q000187:drug effects; D001892:Camphanes / Q000494:pharmacology; D002317:Cardiovascular Agents / Q000494:pharmacology; D002318:Cardiovascular Diseases / Q000139:chemically induced / Q000503:physiopathology* / Q000517:prevention & control; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids; D005260:Female; D005989:Glycerides / Q000097:blood / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D007022:Hypotension / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control; D007213:Indomethacin / Q000494:pharmacology; D008024:Ligands; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000037:antagonists & inhibitors / Q000235:genetics; D000077285:Rimonabant; D013610:Tachycardia / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control
D001095:Arachidonic Acids; D001892:Camphanes; D002317:Cardiovascular Agents; D063388:Endocannabinoids; D005989:Glycerides; D008024:Ligands; D010880:Piperidines; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; C110630:SR 144528; C094503:glyceryl 2-arachidonate; D000077285:Rimonabant; D007213:Indomethacin