Vascular actions of endocannabinoids

Anandamide was first shown to be a vasodilator in the rat cerebral vasculature, but these effects were sensitive to indomethacin, suggesting that cannabinoids may cause relaxation through the stimulation of the metabolism of arachidonic acid (Ellis etal., 1995). Dependence on prostanoids was also found for the vasorelaxant effects of A9-tetrahydrocannabinol. In the rat isolated mesenteric and coronary vasculatures, anandamide is a vasodilator (Randall et al., 1996; Randall and Kendall, 1997; Figure 20.2). In mesenteric arterial vessels (Randall et al., 1996; Randall et al., 1997; Plane et al., 1997; White and Hiley, 1997), and the coronary vasculature (Randall and Kendall, 1997), anandamide induces relaxation in the presence of blockers of both nitric oxide synthase and cyclooxygenase, and also in the absence of the endothelium (Randall et al., 1996; White and Hiley, 1997; Figure 20.2). Accordingly in these vessels it acts independently of endothelial autacoids. Early studies reported that responses to anandamide were abolished by high extracellular potassium, and proposed that endocannabinoids might act via hyper-polarization (Randall et al., 1996).

The relaxant effects of anandamide show tissue selectivity, as it does not relax conduit vessels such as rat carotid arteries (Holland et al., 1999) or the rat aorta

Concentration of anandamide (|l VII

Concentration of anandamide (|l VII

Figure 20.2 Shows that in the rat isolated perfused mesenteric arterial bed that vasorelaxation to anandamide is unaffected by inhibition of nitric oxide synthesis (with 300 |J,M L-NAME), inhibition of cyclooxygenase (with 10 |J,M indomethacin) or removal of the endothelium. Data shown as mean ± S.E.M.

(Darker et al., 1998). Indeed, it may be that the actions of endocannabinoids are localized to the resistance vasculature.

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