Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide

The endogenous cannabinoid receptor agonist anandamide(1) is a powerful vas odilator of isolated vascular preparations(2-4), but its mechanism of actio n is unclear. Here we show that the vasodilator response to anandamide in i solated arteries is capsaicin-sensitive and accompanied by release of calci tonin-gene-related peptide (CGRP), The selective CGRP-receptor antagonist 8 -37 CGRP (ref. 5), but not the cannabinoid CB1 receptor blocker SR141716A ( ref. 7), inhibited the vasodilator effect of anandamide, Other endogenous ( 2-arachidonylglycerol, palmitylethanolamide) and synthetic (HU 210, WIN 55, 212-2, CP 55,940) CB1 and CB2 receptor agonists' could not mimic the action of anandamide. The selective 'vanilloid receptor' antagonist capsazepine(6 ,7) inhibited anandamide-induced vasodilation and release of CGRP. In patch -clamp experiments on cells expressing the cloned vanilloid receptor (VR1)( 8), anandamide induced a capsazepine-sensitive current in whale cells and i solated membrane patches. Our results indicate that anandamide induces vaso dilation by activating: vanilloid receptors on perivascular sensory nerves and causing release of CGRP. The vanilloid receptor may thus be another mol ecular target for endogenous anandamide, besides cannabinoid receptors, in the nervous and cardiovascular systems.