Mechanisms of vasorelaxation induced by the cannabidiol analogue compound O-1602 in the rat small mesenteric artery

Atypical cannabinoid O-1602 (5-Methyl-4-[(1R,6R)-3-methyl-6-(1-cyclohexen-1-yl]-1,3-benzenediol) induces vasorelaxation and activates the orphan G protein-coupled receptor GPR55 in human endothelial cells. This study investigates the underlying mechanisms of vasorelaxation induced by this compound. The vasodilator activity was assessed in the rat third order branch of the superior mesenteric artery using a wire myograph. The vasorelaxation was partially endothelium-dependent (pEC_50%=5.8±0.3). The endothelial component was antagonized by the putative endothelial receptor antagonists rimonabant (3 μM; pEC_50%=5.1±0.2) and O-1918 (10 μM; pEC_50%=5.3±0.2) but not by the CB₁ and CB₂ receptors antagonists AM 251 (10 μM) and AM 630 (10 μM), respectively. The vasorelaxation was not pertussis toxin-sensitive and not mediated through TRPVI receptors or by the release of NO, but was reduced by inhibition of Ca²⁺ sensitive K⁺ channels (K_Ca). In endothelium-denuded vessels, O-1602 abolished CaCl₂-induced contraction and the inhibition was apparently reversed by O-1918. O-1602 mediates its vasorelaxant effects partly by an endothelium-dependent pathway involving rimonabant- and O-1918-sensitive targets that are distinct from the classical CB₁ and CB₂ cannabinoid receptors and might involve activation of K_Ca. The endothelium-independent relaxation might involve interfering with Ca²⁺ entry.