Review
Endocannabinoids as cardiovascular modulators

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Abstract

Cannabinoids, the bioactive constituents of the marijuana plant and their synthetic and endogenous analogs cause not only neurobehavioral, but also cardiovascular effects. The most important component of these effects is a profound decrease in blood pressure and heart rate. Although multiple lines of evidence indicate that the hypotensive and bradycardic effects of anandamide and other cannabinoids are mediated by peripherally located CB1 cannabinoid receptors, anandamide can also elicit vasodilation in certain vascular beds, which is independent of CB1 or CB2 receptors. Possible cellular mechanisms underlying these effects and the cellular sources of vasoactive anandamide are discussed.

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.

  • 1.

    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.

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    Present address: Department of Medicine, University of Wuerzburg, Wuerzburg, Germany.

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