ReviewEndocannabinoids as cardiovascular modulators
Section snippets
Background
The psychoactive properties of marijuana have been known to man for thousands of years, but it is only during the last few decades that the biological basis of the effects of marijuana and its bioactive ingredients, collectively called cannabinoids, has begun to unfold. The following are major milestones on this road to understanding.
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The correct chemical structure of Δ9-tetrahydrocannabinol (THC), the primary psychoactive ingredient of the marijuana plant, is established (Gaoni and Mechoulam,
Cardiovascular effects of cannabinoids mediated by CB1 receptors
The discovery in 1992 of anandamide as the first endocannabinoid has logically raised the question whether it possesses cardiovascular activity similar to THC. Upon its intravenous bolus injection into urethane-anesthetized rats, anandamide was found to elicit a triphasic blood pressure response and bradycardia (Varga et al., 1995), similar to that reported earlier for THC (Siqueira et al., 1979). The first phase consists of a precipitous drop in heart rate and blood pressure that last a few
Anandamide-induced vasodilation via a non-CB1/non-CB2 mechanism
Although in the absence of CB1 receptors anandamide fails to elicit hypotension or bradycardia, recent evidence indicates that anandamide can cause localized vasodilation in the rat mesenteric vasculature by mechanisms that do not involve CB1 receptors. Micromolar concentrations of anandamide can bind to the capsaicin-sensitive vanilloid receptor (VR1), and at nanomolar concentrations anandamide can release calcitonin gene related peptide (CGRP), which can be prevented by the VR1 antagonist,
Possible cellular sources of vasoactive anandamide
The presence of multiple vascular sites at which anandamide can elicit vasodilation raises the question whether endogenous anandamide is active at these sites and, if yes, what is its cellular origin. The lack of an in vivo pressor response to treatment with a CB1 antagonist (Lake et al., 1997a, Lake et al., 1997b, Wagner et al., 1997) or with the transport inhibitor AM404 (Calignano et al., 1997) suggests the absence of a cannabinoid-mediated vasodilator ‘tone’ under normal conditions.
Acknowledgements
The authors’ work was supported by NIH grants HL59257 and HL49938 to GK. ZJ and JAW were supported by fellowships from Sanofi Recherche and the Deutsche Forschungsgemeinschaft, respectively.
References (78)
- et al.
Biosynthesis, uptake, and degradation of anandamide and palmitoylethanolamide in leukocytes
J. Biol. Chem.
(1997) - et al.
Potentiation of anandamide hypotension by the transport inhibitor AM404
Eur. J. Pharmacol.
(1997) - et al.
Effects of diethyl ether, halothane, ketamine and urethane on sympathetic activity in the rat
Eur. J. Pharmacol.
(1987) - et al.
Enzymatic synthesis and degradation of anandamide, a cannabinoid receptor agonist
Biochem. Pharmacol.
(1993) - et al.
Morphine and anandamide stimulate intracellular calcium transients in human arterial endothelial cells: coupling to nitric oxide release
Cell. Signal.
(1999) - et al.
Binding of the non-classical cannabinoid CP 55 940, and the diarylpyrazole AM251 to rodent brain cannabinoid receptors
Life Sci.
(1997) - et al.
Enzymes of porcine brain hydrolyzing 2-arachidonoylglycerol, an endogenous ligand of cannabinoid receptors
Biochem. Pharmacol.
(1999) - et al.
3-(1′,l′-Dimethylbutyl)-1-deoxy-Δ9-THC and related compounds: synthesis of selective ligands for the CB2 receptor
Bioorg. Med. Chem.
(1999) - et al.
Cardiovascular effects of endocannabinoids — the plot thickens
Prostag. Lipid Med.
(2000) - et al.
Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors
Biochem. Pharmacol.
(1995)
Carbachol, an acetylcholine receptor agonist, enhances production in rat aorta of 2-arachidonoyl glycerol, a hypotensive endocannabinoid
Eur. J. Pharmacol.
Effects of two endogenous fatty acid ethanolamides on mouse vasa deferentia
Eur. J. Pharmacol.
Endocannabinoids: a novel class of vasoactive substances
Trends Pharmacol. Sci.
SR141716A, a potent and selective antagonist of the brain cannabinoid receptor
FEBS Lett.
Cannabinoid receptor interactions with the antagonists SR141716A and SR144528
Life Sci.
The triple effect induced by delta 9-tetrahydrocannabinol on the rat blood pressure
Eur. J. Pharmacol.
2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain
Biochem. Biophys. Res. Commun.
Detection of an endogenous cannabinoid molecule, 2-arachidonoylglycerol, and cannabinoid CB1 receptor mRNA in human vascular cells: is 2-arachidonoylglycerol a possible vasomodulator?
Biochem. Biophys. Res. Commun.
Evidence that the cannabinoid CB1 receptor is a 2-arachidonoylglycerol receptor
J. Biol. Chem.
Novel antagonist implicates the CB1 cannabinoid receptor in the hypotensive action of anandamide
Eur. J. Pharmacol.
(R)-methanandamide: a chiral novel anandamide possessing higher potency and metabolic stability
J. Med. Chem.
Marihuana
Harvey Lectures
A cannabinoid with cardiovascular activity but no overt behavioral effects
Experientia
Functional role of high affinity anandamide transport, as revealed by selective inhibition
Science
Cardiovascular effects of prolonged delta-9-tetrahydro-cannabinol ingestion
Clin. Pharmacol. Ther.
Biosynthesis, release and degradation of the novel endogenous cannabimimetic metabolite 2-arachidonoylglycerol in mouse neuroblastoma cells
Biochem. J.
Perivascular sensory nerve Ca2+ receptor and Ca2+-induced relaxation of isolated arteries
Hypertension
The endothelial component of cannabinoid-induced relaxation in rabbit mesenteric artery depends on gap junctional communication
J. Physiol. (London)
Production and physiological actions of anandamide in the vasculature of the rat kidney
J. Clin. Invest.
Determination and characterization of a cannabinoid receptor in rat brain
Mol. Pharmacol.
Isolation and structure of a brain constituent that binds to the cannabinoid receptor
Science
Formation and inactivation of endogenous cannabinoid anandamide in central neurons
Nature (London)
Biosynthesis of anandamide and related acylethanolamides in mouse J774 macrophages and N18 neuroblastoma cells
Biochem. J.
Biosynthesis and inactivation of endocannabinoid 2-arachidonylglycerol in circulating and tumoral macrophages
Eur. J. Biochem.
K+ is an endothelium-derived hyperpolarizing factor in rat arteries
Nature (London)
Ca2+-dependent release from rat brain of cannabinoid receptor binding activity
J. Neurochem.
Endogenous cannabinoid receptor binding activity released from rat brain slices by depolarization
J. Pharmacol. Exp. Ther.
Anandamide, an endogenous cannabimimetic eicosanoid, binds to the cloned cannabinoid receptor and stimulates receptor mediated signal transduction
Proc. Natl. Acad. Sci. USA
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2019, Journal of Clinical AnesthesiaCitation Excerpt :Prolonged sympathetic stimulation may not be enough to compensate these postural hemodynamic changes and orthostatic hypotension ensues as a result of peripheral vasodilation and deregulation of baroreflexes [22]. Moreover, anandamide has been linked to vasodilation in other vascular beds (i.e. mesenteric), probably mediated by the activation of vanilloid receptors (TRPV1-R) expressed in sensory nerve terminals with subsequent release of calcitonin gene related peptide (CGRP) [21,23]. Interestingly, decreased heart rate and tolerance to orthostatic hypotension have been reported after controlled administration of high-doses of THC in chronic users [14].
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Present address: Department of Medicine, University of Wuerzburg, Wuerzburg, Germany.