Cardiovascular effects of endocannabinoids—the plot thickens☆
Introduction
Owing to its psychoactive properties, marijuana has been one of the most widely used recreational drugs in modern societies. There has been growing public interest in the medicinal use of the marijuana plant, which underlies a resurgent interest in the spectrum of physiological actions of its bioactive ingredients, called cannabinoids. From the researcher’s perspective, cannabinoid research has become exciting first as a result of the discovery of specific cannabinoid receptors, and then by the identification of endogenous ligands for such receptors, collectively named endocannabinoids.
In the 1980s, ligand binding studies using radiolabeled synthetic cannabinoids have led to the identification of high affinity, saturable binding sites in the brain [1]. Subsequently, two cannabinoid receptors have been cloned: the CB1 receptor originally identified in the brain [2] but also present in a number of peripheral tissues [2], [3], [4], and the CB2 receptor expressed almost exclusively by cells of the immune system [5]. These two receptors have fairly similar affinities for various cannabinoid agonists [6]. It was through the introduction of highly selective CB1 [7] and CB2 receptor antagonists [8] by researchers at the Sanofi company that probing the physiological functions of these receptors has become possible. The recent introduction of genetically modified mice lacking CB1 [9], [10] and CB2 receptors [11] has provided an additional powerful tool for such studies.
It has not been long since cannabinoid receptors were considered orphan receptors, i.e. lacking an endogenous ligand. Within 2 years of the cloning of the brain cannabinoid receptor, the first endocannabinoid was isolated from porcine brain and identified as arachidonyl ethanolamide (anandamide) [12], followed by the discovery of another endocannabinoid, 2-arachidonoyl glycerol (2-AG) [13], [14]. These lipid-like substances bind to cannabinoid receptors and mimic many of the biological actions of plant-derived cannabinoids [15], [16]. Specific pathways for their biosynthesis [17], enzymatic degradation [18] and facilitated uptake [19] have been identified and discussed in more detail in an adjoining review in this issue [20]. Evidence for the presence of these substances in neurons and their stimulation-induced release [21], [22], [23] suggests that they represent a novel class of lipid mediators.
Well before these momentous developments, it was evident that Δ9-tetrahydrocannabinol (THC), the main psychoactive constituent of the marijuana plant, can potently influence cardiovascular variables, such as blood pressure and heart rate. Although casual smoking of marijuana is usually associated with isolated tachycardia [24], the main effects observed in chronic users as well as in experimental animals treated with THC are prolonged hypotension and bradycardia [25], [26]. In the absence of knowledge about specific receptors at the time, early studies have focused on the role of the sympathetic nervous system in these effects, and suggested that centrally mediated sympatho-inhibition is the mechanism underlying these depressor effects [27]. For a brief summary of the cardiovascular effects of plant-derived cannabinoids, the reader is referred to an earlier review [28]. The present overview will focus on the cardiovascular actions of endogenous cannabinoids.
Section snippets
Cardiovascular effects of anandamide
Soon after its discovery, anandamide was tested in an anesthetized rat model in which it was found to produce complex, yet reproducible, cardiovascular effects, consisting of a triphasic blood pressure response and bradycardia [29]. Upon its bolus i.v. injection, anandamide causes a transient, vagally mediated bradycardia associated with a drop in blood pressure, which is followed by a brief pressor response and a more prolonged decrease in blood pressure [29]. THC also causes a brief pressor
Central versus peripheral mechanisms of cannabinoid-induced hypotension
In studies in the 1970s, interventions resulting in a decrease in sympathetic vasoconstrictor tone resulted in a major decrease or disappearance of the depressor response to THC, leading to the conclusion that a centrally mediated decrease in sympathetic tone is involved [27]. The hypotensive effect of anandamide is similarly reduced after α-adrenergic blockade or spinal cord transection [29], and it is also reduced or absent in conscious, unrestrained animals in which sympathetic tone is known
Cardiovascular effects of 2-arachidonoyl glycerol (2-AG)
Compared to anandamide, less is known of the cardiovascular effects of a second endogenous cannabinoid, 2-AG. In two recent studies, 2-AG was found to elicit brief hypotension in anesthetized rats [43], [44]. However, this response was less effectively inhibited by SR141716A than the hypotensive response to anandamide, and it was associated with tachycardia rather than bradycardia [43]. Even though 2-AG has been proposed to be the natural ligand for CB1 receptors [45], both its hypotensive and
Is the endothelium-derived hyperpolarizing factor (EDHF) an endocannabinoid?
It has been known for a long time that acetylcholine and other endothelium-dependent vasodilators do not completely lose their vasodilator activity after blockade of endothelial nitric oxide (NO) synthase and cyclooxygenase, and that the residual vasodilator effect under these conditions is associated with hyperpolarization of vascular smooth muscle [49]. This NO-independent mechanism, which is potentiated in the absence of NO [50], [51], has been attributed to an EDHF. The identity of EDHF has
Mechanisms of the vasodilator effect of anandamide
Rapidly accumulating information on the cardiovascular effects of anandamide has uncovered an unparalleled complexity as far as the mechanism of its vasodilator activity is concerned. Fig. 2 attempts to schematically summarize information available at the end of 1999. The obligatory role of CB1 receptors in anandamide-induced hypotension is clearly indicated by its inability to elicit hypotension in CB1 receptor-knockout mice [9], [33], although the location of the receptors involved is not
Cellular source of vasoactive endocannabinoids
If anandamide is to be considered an endogenous cardiovascular regulator, one needs to clarify its cellular source. Under normal physiological conditions, endogenous cannabinoids do not seem to maintain a vasodilator ‘tone’, as indicated by the lack of a pressor response to CB1 or CB2 receptor antagonists [32], [46], [79], or the lack of a depressor response to the anandamide transport inhibitor AM404 [80]. However, there is evidence that an endogenous cannabinoid system is activated and
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Work done in the authors’ laboratory 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.
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Present address: Dept. of Medicine, University of Wuerzburg, Wuerzburg, Germany.