An Endogenous Cannabinoid as an Endothelium-Derived Vasorelaxant

Since the identification of nitric oxide (NO) as an important mediator of endothelium-dependent relaxation, it has become clear that there is an additional endothelial relaxant factor, termed the endothelium-derived hyperpolarizing factor (EDHF). The identity of EDHF has remained elusive, but it is...

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Bibliographic Details
Published in:Biochemical and biophysical research communications 1996-12, Vol.229 (1), p.114-120
Main Authors: Randall, Michael D., Alexander, Stephen P.H., Bennett, Terence, Boyd, E.Andrew, Fry, Jeffrey R., Gardiner, Sheila M., Kemp, Philip A., Mcculloch, Audrey I., Kendall, David A.
Format: Article
Language:English
Subjects:
Animals
Arachidonic Acid - metabolism
Arachidonic Acids - metabolism
Biological Factors - metabolism
Cannabinoids - antagonists & inhibitors
Cannabinoids - metabolism
Endocannabinoids
Endothelium, Vascular - metabolism
Humans
Male
Mesenteric Artery, Superior
Perfusion
Piperidines - pharmacology
Polyunsaturated Alkamides
Pyrazoles - pharmacology
Rats
Rats, Wistar
Receptors, Cannabinoid
Receptors, Drug - antagonists & inhibitors
Splanchnic Circulation
Vasodilator Agents - metabolism
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Summary:Since the identification of nitric oxide (NO) as an important mediator of endothelium-dependent relaxation, it has become clear that there is an additional endothelial relaxant factor, termed the endothelium-derived hyperpolarizing factor (EDHF). The identity of EDHF has remained elusive, but it is thought to be an arachidonic acid metabolite. We now report that EDHF-mediated relaxations in the rat mesenteric arterial bed are blocked by a highly selective cannabinoid receptor antagonist, SR141716A, consistent with EDHF being a cannabinoid-like substance. Furthermore, in conscious rats, the NO-independent depressor and regional vasodilator effects of bradykinin were inhibited by SR141716A. The relaxations in the isolated mesentery were accompanied by the accumulation of an arachidonic acid metabolite, which co-eluted on TLC separation with arachidonoylethanolamide (anandamide), an endogenous cannabinoid derived from arachidonate. We further report that anandamide is a potent vasorelaxant in the mesentery, acting via a hyperpolarizing mechanism. These findings suggest that an endogenous cannabinoid is an endothelium-derived vasorelaxant, which may be EDHF.
ISSN:0006-291X
1090-2104
DOI:10.1006/bbrc.1996.1766