(Hypertension. 1999;33:429-434.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Mesenteric Vasodilation Mediated by Endothelial Anandamide Receptors
From the Department of Pharmacology and Toxicology, Medical College of Virginia of Virginia Commonwealth University, Richmond.
Correspondence to George Kunos, MD, PhD, Department of Pharmacology and Toxicology, MCV/VCU, PO Box 980613, Room 746, 410 North 12th St, Richmond, VA 23298. E-mail gkunos{at}hsc.vcu.edu
Abstract—Cannabinoids, including
the endogenous ligand anandamide (arachidonyl
ethanolamide), elicit pronounced hypotension in rats via activation of
peripherally located CB1 cannabinoid receptors, which have
been also implicated in endotoxin (lipopolysaccharide
[LPS])-induced hypotension. The present study was designed to
test the role of vascular CB1 receptors in cannabinoid- and
endotoxin-induced mesenteric vasodilation. In the isolated,
buffer-perfused rat mesenteric arterial bed precontracted
with phenylephrine, anandamide induced long-lasting (up to
60 minutes) dose-dependent vasodilation (ED50: 79±3 nmol;
maximal relaxation: 77±2%), inhibited by 0.5 to 5.0 µmol/L of
the selective CB1 receptor antagonist SR141716A. Low doses
of the calcium ionophore ionomycin also caused mesenteric vasodilation
inhibited by SR141716A. The metabolically stable analogue
R-methanandamide elicited mesenteric vasodilation (ED50:
286±29 nmol), whereas the potent synthetic CB1 receptor agonists WIN
55212-2 and HU-210 caused no change in vascular tone or only a minor
dilator effect not affected by SR141716A, respectively. The
endogenous ligand 2-arachidonyl glycerol caused no change
in vascular tone, whereas 
9-tetrahydrocannabinol and
arachidonic acid caused mesenteric vasoconstriction.
After endothelial denudation, the dilator response to
anandamide was slightly reduced and was no longer inhibited by
SR141716A. In preparations from LPS-pretreated rats, SR141716A alone
caused a significant and prolonged increase in perfusion pressure,
whereas it had no such effect in control preparations perfused in vitro
with or without LPS or after endothelial denudation in
preparations from rats pretreated with LPS. We conclude that
anandamide-induced mesenteric vasodilation is mediated by an
endothelially located SR141716A-sensitive "anandamide
receptor" distinct from CB1 cannabinoid receptors and that activation
of such receptors by an endocannabinoid, possibly anandamide,
contributes to LPS-induced mesenteric vasodilation in vivo.
Key Words: vasodilation • cannabinoids • anandamide • endotoxin
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