Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide

• Published in: Nature (London) Vol. 400; no. 6743; pp. 452 - 457
• Main Authors: Högestätt, Edward D, Zygmunt, Peter M, Petersson, Jesper, Andersson, David A, Chuang, Huai-hu, Sørgård, Morten, Di Marzo, Vincenzo, Julius, David
• Format: Journal Article
• Language: English
• Published: London Nature Publishing 29.07.1999; Nature Publishing Group
• Subjects: Animals; Arachidonic Acids - antagonists & inhibitors; Arachidonic Acids - metabolism; Arachidonic Acids - pharmacology; Basic Medicine; Basilar Artery - drug effects; Basilar Artery - innervation; Biological and medical sciences; Blood vessels and receptors; Calcitonin Gene-Related Peptide - metabolism; Calcitonin Gene-Related Peptide - pharmacology; Calcium Channels - metabolism; Capsaicin - analogs & derivatives; Capsaicin - pharmacology; Cell Line; Cells; Endocannabinoids; Farmakologi och toxikologi; Female; Fundamental and applied biological sciences. Psychology; Guinea Pigs; Hepatic Artery - drug effects; Hepatic Artery - innervation; In Vitro Techniques; Medical and Health Sciences; Medicin och hälsovetenskap; Medicinska och farmaceutiska grundvetenskaper; Membranes; Nervous system; Neurons, Afferent - drug effects; Neurons, Afferent - metabolism; Peptide Fragments - pharmacology; Pharmacology and Toxicology; Polyunsaturated Alkamides; Rats; Rats, Wistar; Receptor, Cannabinoid, CB2; Receptors, Calcitonin Gene-Related Peptide - antagonists & inhibitors; Receptors, Cannabinoid; Receptors, Drug - agonists; Receptors, Drug - antagonists & inhibitors; Receptors, Drug - genetics; Receptors, Drug - metabolism; Recombinant Proteins - metabolism; Vasodilator Agents - antagonists & inhibitors; Vasodilator Agents - metabolism; Vasodilator Agents - pharmacology; Vertebrates: cardiovascular system; Xenopus; Agonist; Rat; Rodentia; Cannabinoid; Calcitonine gene related peptide; In vitro; Artery; Vasodilation; Vasomotricity; Vertebrata; Mammalia; Guinea pig; Blood vessel; Sensory nerve; Circulatory system; Biological receptor
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/22761

The endogenous cannabinoid receptor agonist anandamide is a powerful vasodilator of isolated vascular preparations, but its mechanism of action is unclear. Here we show that the vasodilator response to anandamide in isolated arteries is capsaicin-sensitive and accompanied by release of calcitonin-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, inhibited anandamide-induced vasodilation and release of CGRP. In patch-clamp experiments on cells expressing the cloned vanilloid receptor (VR1), anandamide induced a capsazepine-sensitive current in whole cells and isolated membrane patches. Our results indicate that anandamide induces vasodilation by activating vanilloid receptors on perivascular sensory nerves and causing release of CGRP. The vanilloid receptor may thus be another molecular target for endogenous anandamide, besides cannabinoid receptors, in the nervous and cardiovascular systems.