Novel and As Yet Uncharacterized NonCEI NonCB2 Receptors in the Endothelium

Strong pharmacological and biochemical evidence exists also for non-CB^ non-CB2 AEA receptors in vascular endothelium (Jarai et al., 1999; Wagner et al., 1999). Jarai and co-workers showed that AEA can induce an endothelium-dependent relaxation of rat and mouse mesenteric arteries via novel endothelial sites of action activated by the nonpsychotropic cannabinoid "abnormal cannabidiol," as well as by some of its analogs, and antagonized by the natural cannabinoid, cannabidiol (Jarai et al., 1999) (Figure 6.1). Interestingly, the endothelium-dependent action of both AEA and abnormal cannabidiol on the mesenteric artery was partly antagonized by a rather "selective" concentration (0.5 \\M) of the CE^ antagonist SR141716A. More recent observations showed that the novel endothelial sites of action of AEA are: (1) coupled to G-proteins, as they are blocked by pertussis toxin pretreatment of the rat mesenteric artery, (2) coupled to BK(Ca) calcium channels and to the PI3 kinase/Akt signaling pathway, and (3) selectively blocked by the synthetic cannabidiol analog 0-1918 (Offertaler et al., 2003; Ho and Hiley, 2003a). They do not seem to be involved in the hypotensive effect of systemic AEA as this effect is absent in CB! receptor knockout (as well as in CB/CB^ receptor double-knockout) mice (Jarai et al., 1999), nor in the psychotropic effects of AEA, as abn-cbd exhibits no such effects. Indirect evidence has been recently published for the occurrence of the novel endothelial GPCR in microglial cells, where it might be involved in mediating part of the stimulatory effects of 2-AG on the migration of these cells (Walter et al., 2003). However, the effect of this endocannabinoid on mesenteric artery dilation had been previously described not to be due to interaction with the novel receptors (Jarai et al., 2000).

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