Hemodynamic effects of cannabinoids: coronary and cerebral vasodilation mediated by cannabinoid CB₁ receptors

Abstract

Activation of peripheral cannabinoid CB₁ receptors elicits hypotension. Using the radioactive microsphere technique, we examined the effects of cannabinoids on systemic hemodynamics in anesthetized rats. The potent cannabinoid CB₁ receptor agonist HU-210 ({−}-11-OH-Δ⁹ tetrahydrocannabinol dimethylheptyl, 10 μg/kg i.v.) reduced mean blood pressure by 57±5 mm Hg by decreasing cardiac index from 37±1 to 23±2 ml/min/100 g (P<0.05) without significantly affecting systemic vascular resistance index. HU-210 elicited a similar decrease in blood pressure following ganglionic blockade and vasopressin infusion. The endogenous cannabinoid anandamide (arachidonyl ethanolamide, 4 mg/kg i.v.) decreased blood pressure by 40±7 mm Hg by reducing systemic vascular resistance index from 3.3±0.1 to 2.3±0.1 mm Hg min/ml/100 g (P<0.05), leaving cardiac index and stroke volume index unchanged. HU-210, anandamide, and its metabolically stable analog, R-methanandamide, lowered vascular resistance primarily in the coronaries and the brain. These vasodilator effects remained unchanged when autoregulation was prevented by maintaining blood pressure through volume replacement, but were prevented by pretreatment with the cannabinoid CB₁ receptor antagonist SR141716A (N-{piperidin-1-yl}-5-{4-chlorophenyl}-1-{2,4-dichlorophenyl}-4-methyl-1H-pyrazole-3-carboxamide HCl; 3 mg/kg i.v.). Only anandamide and R-methanandamide were vasodilators in the mesentery. We conclude that cannabinoids elicit profound coronary and cerebral vasodilation in vivo by direct activation of vascular cannabinoid CB₁ receptors, rather than via autoregulation, a decrease in sympathetic tone or, in the case of anandamide, the action of a non-cannabinoid metabolite. Differences between the hemodynamic profile of various cannabinoids may reflect quantitative differences in cannabinoid CB₁ receptor expression in different tissues and/or the involvement of as-yet-unidentified 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.