Selective Ligands and Cellular Effectors of a G Protein-Coupled Endothelial Cannabinoid Receptor

Abstract

The cannabinoid analog abnormal cannabidiol [abn-cbd; (Ϫ)-4-(3-3,4-trans-p-menthadien-[1,8]-yl)-olivetol] does not bind to CB 1 or CB 2 receptors, yet it acts as a full agonist in relaxing rat isolated mesenteric artery segments. Vasorelaxation by abncbd is endothelium-dependent, pertussis toxin-sensitive, and is inhibited by the BK Ca channel inhibitor charybdotoxin, but not by the nitric-oxide synthase inhibitor N -nitro-L-arginine methyl ester or by the vanilloid VR1 receptor antagonist capsazepine. The cannabidiol analog O-1918 does not bind to CB 1 or CB 2 receptors and does not cause vasorelaxation at concentrations up to 30 M, but it does cause concentration-dependent (1-30 M) inhibition of the vasorelaxant effects of abn-cbd and anandamide. In anesthetized mice, O-1918 dose-dependently inhibits the hypotensive effect of abn-cbd but not the hypotensive effect of the CB 1 receptor agonist (Ϫ)-11-OH-⌬ 9 -tetrahydrocannabinol dimethylheptyl. In human umbilical vein endothelial cells, abn-cbd induces phosphorylation of p42/44 mitogenactivated protein kinase and protein kinase B/Akt, which is inhibited by O-1918, by pertussis toxin or by phosphatidylinositol 3 (PI3) kinase inhibitors. These findings indicate that abncbd is a selective agonist and that O-1918 is a selective, silent antagonist of an endothelial "anandamide receptor", which is distinct from CB 1 or CB 2 receptors and is coupled through G i /G o to the PI3 kinase/Akt signaling pathway.

Endocannabinoids Acting at Cannabinoid-1 Receptors Regulate Cardiovascular Function in Hypertension

“…Anandamide can elicit vasodilation 13,[32][33][34] and decreased cardiac contractility 35 through an additional G i /G o -coupled receptor distinct from CB 1 or CB 2 , which is inhibited by SR141716 13 but not by other CB 1 antagonists such as AM251. 35,36 In the present experiments, AM251 and SR141716 were equally effective in eliciting pressor and cardiostimulatory responses and in blocking the depressor effects of URB597 in hypertensive rats.…”

The endocannabinoid system: a general view and latest additions

“…Finally, a different GPCR for AEA and the nonpsychtropic cannabinoid, abnormal-cannabidiol, has been described in vascular endothelial cells. This putative receptor mediates the local vasodilatory, but not the systemic hypotensive, effects of AEA, and is blocked by both cannabidiol and a synthetic analogue O-1981O- (Ja´rai et al, 1999Offertaler et al, 2003). It appears to be coupled to guanylyl cyclase or to p42/44 mitogen-activated protein kinase and protein kinase B/Akt.…”

Blood pressure regulation by endocannabinoids and their receptors

“…Apart from their well-known neurobehavioral and immunological actions, cannabinoids also elicit potent cardiovascular effects, such as profound hypotension (Lake et al, 1997a;Hillard, 2000;Kunos et al, 2002;Randall et al, 2002;Ralevic et al, 2002). Although several lines of evidence indicate that the cardiovascular depressive effects of cannabinoids are mediated by peripherally localized CB 1 receptors, recent studies also suggest the existence of as yet undefined endothelial and cardiac receptor(s) that mediate certain endocannabinoid-induced cardiovascular effects Járai et al, 1999;Ford et al, 2002;Ho and Hiley, 2003;Kunos et al, 2002;Offertáler et al, 2003;O'Sullivan et al, 2004), however, the discussion of the latter is beyond the main scope of this summary. It has been established that the endocannabinergic system plays a pivotal role in cardiovascular regulation under various pathophysiological conditions associated with hypotension including hemorrhagic (Wagner et al, 1997), endotoxic (Varga et al, 1998) and cardiogenic shock (Wagner et al, 2001a, and advanced liver cirrhosis (Bátkai et al, 2001;Ros et al, 2002).…”