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 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.
Randall
M D
MD
Department of Physiology and Pharmacology, University of Nottingham Medical School, Queen's Medical Centre, United Kingdom.
Alexander
S P
SP
Bennett
T
T
Boyd
E A
EA
Fry
J R
JR
Gardiner
S M
SM
Kemp
P A
PA
McCulloch
A I
AI
Kendall
D A
DA
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001095:Arachidonic Acids / Q000378:metabolism*; D001685:Biological Factors / Q000378:metabolism*; D002186:Cannabinoids / Q000037:antagonists & inhibitors / Q000378:metabolism*; D063388:Endocannabinoids; D004730:Endothelium, Vascular / Q000378:metabolism*; D006801:Humans; D008297:Male; D017538:Mesenteric Artery, Superior; D010477:Perfusion; D010880:Piperidines / Q000494:pharmacology*; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000037:antagonists & inhibitors; D000077285:Rimonabant; D013152:Splanchnic Circulation; D014665:Vasodilator Agents / Q000378:metabolism*
D001095:Arachidonic Acids; D001685:Biological Factors; D002186:Cannabinoids; D063388:Endocannabinoids; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D014665:Vasodilator Agents; C067410:endothelium-dependent hyperpolarization factor; D016718:Arachidonic Acid; D000077285:Rimonabant; C078814:anandamide