Hemodynamic effects of cannabinoids: coronary and cerebral vasodilation mediated by cannabinoid CB1 receptors
Introduction
The psychoactive properties of cannabinoids, constituents of the marijuana plant, have long been recognized, and similar effects can be elicited by the endogenous ligand arachidonyl ethanolamide (anandamide) (Hillard, 2000). Recent research has revealed that cannabinoids elicit not only neurobehavioral but also cardiovascular effects (Kunos et al., 2000). The biological effects of cannabinoids are mediated by specific receptors, of which two subtypes have been identified, cannabinoid CB1 receptors present in the brain but also in some peripheral tissues (Matsuda et al., 1990) and cannabinoid CB2 receptors expressed by immune cells (Munro et al., 1993). Through the use of a selective cannabinoid CB1 receptor antagonist, SR141716A (N-{piperidin-1-yl}-5-{4-chlorophenyl}-1-{2,4-dichlorophenyl}-4-methyl-1H-pyrazole-3-carboxamide HCl; Rinaldi-Carmona et al., 1994), the hypotensive and bradycardic effects of cannabinoids in rodents could be attributed to activation of peripheral cannabinoid CB1 receptors Varga et al., 1995, Járai et al., 1999. This conclusion has been confirmed by the absence of such effects in cannabinoid CB1 receptor-knockout mice Járai et al., 1999, Ledent et al., 1999.
Recent findings implicate endogenous cannabinoids in cardiovascular regulation. Circulating macrophages and platelets activated by hemorrhage or by bacterial endotoxin synthesize anandamide and another endogenous cannabinoid, 2-arachidonoyl glycerol (2-AG), and these endocannabinoids contribute to the hypotension of hemorrhagic and septic shock via the activation of peripheral cannabinoid CB1 receptors Wagner et al., 1997, Varga et al., 1998. Vascular endothelial cells also contain anandamide (Deutsch et al., 1997) and 2-AG Mechoulam et al., 1998, Sugiura et al., 1998, and functional cannabinoid CB1 receptors are present on cerebrovascular smooth muscle cells (Gebremedhin et al., 1999). It has been proposed that the endothelium-derived hyperpolarizing factor (EDHF) released by various vasodilators may be an endocannabinoid (Randall et al., 1996), although this has been contested Plane et al., 1997, Pratt et al., 1998.
There is evidence that various cannabinoids produce strong vasodilation in vitro Chataigneau et al., 1998, Deutsch et al., 1997, Ellis et al., 1995, Wagner et al., 1999, but the underlying mechanisms are unclear (Pratt et al., 1998). However, there is a lack of information on the in vivo effects of cannabinoids on blood flow to various organs, and on the hemodynamic changes underlying their hypotensive action. In a study of the cardiovascular effects of a series of cannabinoids in anesthetized rats, the synthetic cannabinoid HU-210 ({−}-11-OH-Δ9-tetrahydrocannabinol dimethylheptyl) was found to be the most potent analog in producing hypotension and bradycardia with ED50's (doses producing half-maximal effects) of 2 and 90 μg/kg, respectively (Lake et al., 1997a). Moreover, at a maximally effective i.v. dose, HU-210 lowered blood pressure by 75–80 mm Hg for up to 2 h, whereas a maximal hypotensive dose of anandamide lowered blood pressure transiently (∼15 min) by no more than 45 mm Hg (Lake et al., 1997a). The way this different degree of blood pressure reduction is achieved, e.g. reduction of cardiac output or of systemic vascular resistance, is unknown. Our aim was to analyze and compare the regional and systemic hemodynamic changes in response to anandamide, its metabolically stable analog R-methanandamide (Abadji et al., 1994), and HU-210, and the sensitivity of these changes to inhibition by SR141716A in urethane-anesthetized rats. The results indicate that cannabinoids differently decrease cardiac output and total peripheral resistance, and that all three cannabinoids are strong vasodilators in the heart and the brain via the activation of vascular cannabinoid CB1 receptors. Furthermore, anandamide and R-methanandamide cause mesenteric vasodilation that does not appear to involve activation of cannabinoid CB1 receptors.
Section snippets
Drugs, chemicals
The source of the cannabinoids used has been provided elsewhere Lake et al., 1997a, Járai et al., 1999. Hexamethonium, arginine vasopressin, and urethane were from Sigma (St. Louis, MO). 46Scandium and 57Cobalt-labeled microspheres (diameter 15.5±0.1 μm) were from NEN Dupont (Boston, MA).
Animals, surgery
A total of 80 male Sprague–Dawley rats (300–380 g) were used, according to procedures approved by the Institutional Animal Care and Use Committee. The rats were anesthetized with urethane, 0.7 g/kg i.v.+0.3
Basal cardiovascular parameters
Fig. 1 contains the basal cardiovascular parameters in urethane-anesthetized controls and rats treated with 3 mg/kg SR141716A i.v. 30 min prior to the measurements. Of note, basal mean blood pressure and heart rate were not different from values we reported in conscious, chronically cannulated rats (Lake et al., 1997b). The well-documented hypotension following intraperitoneal administration of urethane can be avoided by the treatment protocol described by Maggi and Meli (1986) and employed
Discussion
The profound and long lasting hypotension elicited via activation of peripheral cannabinoid CB1 receptors is unsurpassed by hypotension triggered through any other mechanism (Lake et al., 1997a). Known ligands for these receptors include not only plant-derived and synthetic cannabinoids, but also endogenous substances such as anandamide (Devane et al., 1992). Both anandamide and the synthetic agonist HU-210 elicit hypotension, and although anandamide is less efficacious and its effect is much
Acknowledgements
This work was supported by grants R01-HL59257 and R01-HL49938 from the National Institutes of Health (to G.K.), a fellowship (to J.A.W.) from the Deutsche Forschungsgemeinschaft, a fellowship (to Z.J.) from Sanofi Recherche (Montpellier, France), and a Martin Rodbell Visiting Scientist award sponsored by Philip Morris (to S.B.). We thank Dr. Jerry Hirsch for help with the gamma spectrometry.
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- 1
Current address: Department of Medicine, University of Würzburg, Würzburg, Germany.
- 2
Current address: St. Emery Municipal Hospital, Budapest, Hungary.
- 3
Current address: National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.