Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide

Abstract

The endogenous cannabinoid receptor agonist anandamide1 is a powerful vasodilator of isolated vascular preparations2,3,4, 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 agonists1 could not mimic the action of anandamide. The selective ‘vanilloid receptor’ antagonist capsazepine6,7 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 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.

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Figure 1: Effects of capsaicin and the CGRP receptor antagonist 8-37 CGRP on relaxations induced by anandamide (AEA) and acetylcholine (ACh) in rat and guinea-pig arteries.
Figure 2: Release of CGRP from sensory nerves and effects of anandamide (AEA) and CGRP on cAMP levels in the rat hepatic artery.
Figure 3: Relaxant effects of endogenous and synthetic cannabinoid receptor agonists in rat hepatic and guinea-pig basilar arteries.
Figure 4: Effect of the vanilloid receptor antagonist capsazepine on relaxations elicited by anandamide, methanandamide and capsaicin in rat and guinea-pig arteries.
Figure 5: Anandamide activates the cloned vanilloid receptor (VR1).

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Acknowledgements

This work was supported by the Swedish Medical Research Council, the Medical Faculty of Lund (ALF) and the Crafoords Foundation (E.D.H.), the National Institutes of Health and the McKnight Foundation for Neuroscience (H.C. and D.J.) and the Ministero dell Universita e dela Ricerca Scientifica (V.D.M.). P.M.Z. was supported by the Swedish Society for Medical Research and the Swedish Medical Research Council. J.P. was supported by the Medical Faculty of Lund (ALF).

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Correspondence to Edward D. Högestätt.

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Zygmunt, P., Petersson, J., Andersson, D. et al. Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature 400, 452–457 (1999). https://doi.org/10.1038/22761

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