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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Pertwee, R. G. Pharmacology of cannabinoid CB1and CB2receptors. Pharmacol. Ther. 74, 129–180 (1997).
Plane, F., Holland, M., Waldron, G. J., Garland, C. J. & Boyle, J. P. Evidence that anandamide and EDHF act via different mechanisms in rat isolated mesenteric arteries. Br. J. Pharmacol. 121, 1509–1511 (1997).
Zygmunt, P. M.et al. Studies on the effects of anandamide in rat hepatic artery. Br. J. Pharmacol. 122, 1679–1686 (1997).
Wagner, J. A., Varga, K., Jarai, Z. & Kunos, G. Mesenteric vasodilation mediated by endothelial anandamide receptors. Hypertension 33, 429–434 (1999).
Han, S.-P., Naes, L. & Westfall, T. C. Inhibition of periarterial nerve stimulation-induced vasodilation of the mesenteric arterial bed by CGRP (8-37) and CGRP receptor desensitization. Biochem. Biophys. Res. Commun. 168, 786–791 (1990).
Bevan, S.et al. Capsazepine: a competitive antagonist of the sensory neurone excitant capsaicin. Br. J. Pharmacol. 107, 544–552 (1992).
Szallasi, A. & Blumberg, P. M. Vanilloid (capsaicin) receptors and mechanisms. Pharmacol. Rev. 51, 159–212 (1999).
Caterina, M. J.et al. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389, 816–824 (1997).
Devane, W. A.et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258, 1946–1949 (1992).
Deutsch, D. G.et al. Production and physiological actions of anandamide in the vasculature of the rat kidney. J. Clin. Invest. 100, 1538–1546 (1997).
Di Marzo, V., De Petrocellis, L., Sepe, N. & Buono, A. Biosynthesis of anandamide and related acylethanolamides in mouse J774 macrophages and N18neuroblastoma cells. Biochem. J. 316, 977–984 (1996).
Varga, K., Lake, K. D., Huangfu, D., Guyenet, P. G. & Kunos, G. Mechanism of the hypotensive action of anandamide in anesthetized rats. Hypertension 28, 682–686 (1996).
Wagner, J. A.et al. Activation of peripheral CB1cannabinoid receptors in haemorrhagic shock. Nature 390, 518–521 (1997).
Varga, K., Wagner, J. A., Bridgen, D. T. & Kunos, G. Platelet- and macrophage-derived endogenous cannabinoids are involved in endotoxin-induced hypotension. FASEB J. 12, 1035–1044 (1998).
Ishac, E. J. N.et al. Inhibition of exocytotic noradrenaline release by presynaptic cannabinoid CB1receptors on peripheral sympathetic nerves. Br. J. Pharmacol. 118, 2023–2028 (1996).
Sugiura, T.et al. Detection of an endogenous cannabimimetic molecule 2-arachidonoylglycerol, and cannabinoid CB1 receptor mRNA in human vascular cells: is 2-arachidonoylglycerol a possible vasomodulator? Biochem. Biophys. Res. Commun. 243, 838–843 (1998).
White, R. & Hiley, C. R. The actions of some cannabinoid receptor ligands in the rat isolated mesenteric artery. Br. J. Pharmacol. 125, 533–541 (1998).
Kawasaki, H., Takasaki, K., Saito, A. & Goto, K. Calcitonin gene-related peptide acts as a novel vasodilator neurotransmitter in mesenteric resistance vessels of the rat. Nature 335, 164–167 (1988).
Edvinsson, L., Ekman, R., Jansen, I., McCulloch, J. & Uddman, R. Calcitonin gene-related peptide and cerebral blood vessels: distribution and vasomotor effects. J. Cereb. Blood Flow Metab. 7, 720–728 (1987).
Pratt, P. F., Hillard, C. J., Edgemond, W. S. & Campbell, W. B. N -arachidonylethanolamide relaxation of bovine coronary artery is not mediated by CB1 cannabinoid receptor. Am. J. Physiol. 274, H375–H381 (1998).
White, R. & Hiley, C. R. The actions of the cannabinoid receptor antagonist, SR 141716A, in the rat isolated mesenteric artery. Br. J. Pharmacol. 125, 689–696 (1998).
Di Marzo, V.et al. Interactions between synthetic vanilloids and the endogenous cannabinoid system. FEBS Lett. 436, 449–454 (1998).
Zygmunt, P. M., Edwards, G., Weston, A. H., Davis, S. C. & Högestätt, E. D. Effects of cytochrome P450 inhibitors on EDHF-mediated relaxation in the rat hepatic artery. Br. J. Pharmacol. 118, 1147–1152 (1996).
Petersson, J., Zygmunt, P. M., Jönsson, P. & Högestätt, E. D. Characterization of endothelium-dependent relaxation in guinea pig basilar artery—effects of hypoxia and role of cytochrome P450mono-oxygenase. J. Vasc. Res. 35, 285–294 (1998).
Chyb, S., Raghu, P. & Hardie, R. Polyunsaturated fatty acids activate the drosophila light-sensitive channels TRP and TRPL. Nature 397, 255–259 (1999).
Hofmann, T.et al. Direct activation of human TRPC6 and TRPC3 channels by diacylglycerol. Nature 397, 259–263 (1999).
Olivera, B. M., Miljanich, G. P., Ramachandran, J. & Adams, M. E. Calcium channel diversity and neurotransmitter release: the omega-conotoxins and omega-agatoxins. Annu. Rev. Biochem. 63, 823–867 (1994).
Geppert, M.et al. Neurexin Ia is a major α-latrotoxin receptor that cooperates in α-latrotoxin action. J. Biol. Chem. 273, 1705–1710 (1998).
Tominaga, M.et al. The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron 21, 531–543 (1998).
Zygmunt, P. M., Grundemar, L. & Högestätt, E. D. Endothelium-dependent relaxation resistant to Nω-nitro-L-arginine in the rat hepatic artery and aorta. Acta Physiol. Scand. 152, 107–114 (1994).
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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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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