Mesenteric vasodilation mediated by endothelial anandamide receptors

Cannabinoids, including the endogenous ligand anandamide (arachidonyl ethanolamide), elicit pronounced hypotension in rats via activation of peripherally located CB1 cannabinoid receptors, which have been also implicated in endotoxin (lipopolysaccharide [LPS])-induced hypotension. The present study was designed to test the role of vascular CB1 receptors in cannabinoid- and endotoxin-induced mesenteric vasodilation. In the isolated, buffer-perfused rat mesenteric arterial bed precontracted with phenylephrine, anandamide induced long-lasting (up to 60 minutes) dose-dependent vasodilation (ED50: 79+/-3 nmol; maximal relaxation: 77+/-2%), inhibited by 0.5 to 5.0 micromol/L of the selective CB1 receptor antagonist SR141716A. Low doses of the calcium ionophore ionomycin also caused mesenteric vasodilation inhibited by SR141716A. The metabolically stable analogue R-methanandamide elicited mesenteric vasodilation (ED50: 286+/-29 nmol), whereas the potent synthetic CB1 receptor agonists WIN 55212-2 and HU-210 caused no change in vascular tone or only a minor dilator effect not affected by SR141716A, respectively. The endogenous ligand 2-arachidonyl glycerol caused no change in vascular tone, whereas Delta9-tetrahydrocannabinol and arachidonic acid caused mesenteric vasoconstriction. After endothelial denudation, the dilator response to anandamide was slightly reduced and was no longer inhibited by SR141716A. In preparations from LPS-pretreated rats, SR141716A alone caused a significant and prolonged increase in perfusion pressure, whereas it had no such effect in control preparations perfused in vitro with or without LPS or after endothelial denudation in preparations from rats pretreated with LPS. We conclude that anandamide-induced mesenteric vasodilation is mediated by an endothelially located SR141716A-sensitive "anandamide receptor" distinct from CB1 cannabinoid receptors and that activation of such receptors by an endocannabinoid, possibly anandamide, contributes to LPS-induced mesenteric vasodilation in vivo.