Cannabinoid-induced mesenteric vasodilation through an endothelial site distinct from CB1 or CB2 receptors.
Cannabinoids, including the endogenous ligand arachidonyl ethanolamide (anandamide), elicit not only neurobehavioral but also cardiovascular effects. Two cannabinoid receptors, CB1 and CB2, have been cloned, and studies with the selective CB1 receptor antagonist SR141716A have implicated peripherally located CB1 receptors in the hypotensive action of cannabinoids. In rat mesenteric arteries, anandamide-induced vasodilation is inhibited by SR141716A, but other potent CB1 receptor agonists, such as HU-210, do not cause vasodilation, which implicates an as-yet-unidentified receptor in this effect. Here we show that "abnormal cannabidiol" (Abn-cbd) is a neurobehaviorally inactive cannabinoid that does not bind to CB1 receptors, yet causes SR141716A-sensitive hypotension and mesenteric vasodilation in wild-type mice and in mice lacking CB1 receptors or both CB1 and CB2 receptors. Hypotension by Abn-cbd is also inhibited by cannabidiol (20 microgram/g), which does not influence anandamide- or HU-210-induced hypotension. In the rat mesenteric arterial bed, Abn-cbd-induced vasodilation is unaffected by blockade of endothelial NO synthase, cyclooxygenase, or capsaicin receptors, but it is abolished by endothelial denudation. Mesenteric vasodilation by Abn-cbd, but not by acetylcholine, sodium nitroprusside, or capsaicine, is blocked by SR141716A (1 microM) or by cannabidiol (10 microM). Abn-cbd-induced vasodilation is also blocked in the presence of charybdotoxin (100 nM) plus apamin (100 nM), a combination of K(+)-channel toxins reported to block the release of an endothelium-derived hyperpolarizing factor (EDHF). These findings suggest that Abn-cbd and cannabidiol are a selective agonist and antagonist, respectively, of an as-yet-unidentified endothelial receptor for anandamide, activation of which elicits NO-independent mesenteric vasodilation, possibly by means of the release of EDHF.
Járai
Z
Z
Department of Pharmacology, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298, USA.
Wagner
J A
JA
Varga
K
K
Lake
K D
KD
Compton
D R
DR
Martin
B R
BR
Zimmer
A M
AM
Bonner
T I
TI
Buckley
N E
NE
Mezey
E
E
Razdan
R K
RK
Zimmer
A
A
Kunos
G
G
D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D002185:Cannabidiol / Q000494:pharmacology; D002186:Cannabinoids / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013759:Dronabinol / Q000031:analogs & derivatives / Q000494:pharmacology; D063388:Endocannabinoids; D004730:Endothelium, Vascular / Q000378:metabolism; D008638:Mesenteric Arteries / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides; D015221:Potassium Channels / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000235:genetics / Q000502:physiology*; D000077285:Rimonabant; D014664:Vasodilation / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology
D001095:Arachidonic Acids; D002186:Cannabinoids; C469526:Cnr2 protein, rat; D063388:Endocannabinoids; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D015221:Potassium Channels; D011720:Pyrazoles; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D014665:Vasodilator Agents; C088155:methanandamide; D002185:Cannabidiol; D009569:Nitric Oxide; D013759:Dronabinol; D011451:Prostaglandin-Endoperoxide Synthases; C062018:HU 211; D000077285:Rimonabant; C078814:anandamide