If endocannabinoids are to be significant regulators of vascular function then they must be produced in areas associated with the cardiovascular system. The proposal that endocannabinoids might be endothelium-derived autacoids was supported by the finding that cultured rat renal endothelial cells contain anandamide, together with synthase and amidase activities (Deutsch et al., 1997). In addition, cultured human umbilical vein endothelial cells release the endocannabinoid, 2-arachidonylglycerol, on stimulation with a calcium ionophore (Sugiura et al., 1998). However, bovine coronary endothelial cells do not produce endocannabinoids, and furthermore, these cells metabolize exogenous anandamide, possibility via a cytochrome P450 monooxygenase to vasoactive metabolites (Pratt et al., 1998).
Sensory nerves have been proposed as another potential site of production and release. In this respect Ishioka and Bukoski (1999) demonstrated that nerve-dependent calcium-induced relaxation of rat mesenteric vessels was blocked by SR141716A, with the suggestion that an endocannabinoid was released from the nerves, and mediated the vasorelaxation.
In the context of pathophysiology, Wagner et al. (1997) demonstrated in a rat model of hemorrhagic shock that activated macrophages released anandamide. Similarly in endotoxic shock the synthesis of 2-AG in platelets is increased and anandamide is only detectable in macrophages after exposure to lipopolysaccharide (Varga et al., 1998). In vitro, mouse J774 macrophages also release both 2-AG and anandamide, and participate in their degradation (Di Marzo et al., 1999). These findings certainly point to the genesis of endocannabinoids in blood cells, which is enhanced in shock, and contributes towards the cardiovascular sequelae.
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