Cannabinoid-induced mesenteric vasodilation through an endothelial site distinct from CB1 or CB2 receptors

Cannabinoids, including the endogenous ligand arachidonyl ethanolamide (ana ndamide), elicit not only neurobehavioral but also cardiovascular effects. Two cannabinoid receptors, CBI and CBZ, have been cloned, and studies with the selective CB1 receptor antagonist SR141716A have implicated peripherall y located CBI receptors in the hypotensive action of cannabinoids. In rat m esenteric arteries, anandamide-induced vasodilation is inhibited by SR14171 6A, but other potent CBI receptor agonists, such as HU210, do not cause vas odilation, 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 CBI receptors, yet causes SR1417 16A-sensitive hypotension and mesenteric vasodilation in wild-type mice and in mice lacking CBI receptors or both CB1 and CBZ receptors. Hypotension b y Abn-cbd is also inhibited by cannabidiol (20 mu g/g), which does not infl uence anandamide- or HU-210-induced hypotension. In the rat mesenteric arte rial bed, Abn-cbd-induced vasodilation is unaffected by blockade of endothe lial NO synthase, cyclooxygenase. or capsaicin receptors, but it is abolish ed by endothelial denudation. Mesenteric vasodilation by Abn-cbd, but not b y acetylcholine, sodium nitroprusside, or capsaicine, is blocked by SR14171 6A (1 mu M) or by cannabidiol (10 mu M). Abn-cbd-induced vasodilation is al so blocked in the presence of charybdotoxin (100 nM) plus apamin (100 nM), a combination of Kf-channel toxins reported to block the release of an endo thelium-derived hyperpolarizing factor (EDHF). These findings suggest that Abn-cbd and cannabidiol are a selective agonist and antagonist, respectivel y, of an as-yet-unidentified endothelial receptor for anandamide, activatio n of which elicits NO-independent mesenteric vasodilation. possibly by mean s of the release of EDHF.