Vasorelaxant effect of Win 55,212-2 in rat aorta: New mechanisms involved

R(+)-[2,3-dihydro-5-methyl-3-[(moroholinyl)methyl] pyrrolo [1,2,3-de]-1,4benzoxazinyl]-1(1-naphthalenyl) methanone mesylate (Win 55,212-2) is a synthetic cannabinoid classically classified as a potent CB1 and CB2 agonist with high stereoselectivity and a slight preference for CB2 cannabinoid receptors. Its vascular actions are not always explained by its binding to these cannabinoid receptors and new targets are being proposed. The aim of this study was to further assess the vascular actions of Win 55,212-2. Isometric tension changes in response to a cumulative concentration–response curve of Win 55,212-2 (10− 9 M–10− 4 M) were recorded in aortic rings from male Wistar rats. The involvement of the endothelium, cannabinoid receptors, vanilloid receptors, and the release of calcitonin gene related peptide (CGRP) was tested. Win 55,212-2 caused a concentration-dependent vasorelaxation in rat aorta. This vascular effect was significantly inhibited by endothelial denudation, inhibition of nitric oxide synthesis, a CB1 receptor antagonist, a transient receptor potential vanilloid-1 antagonist, capsaicin desensibilization, and a CGRP receptor antagonist (P < 0.001). CB2 and non-CB1/non-CB2 receptor antagonists only caused a slight inhibitory effect in vasorelaxation to Win 55,212-2. The present findings indicate that endothelium and nitric oxide-dependent vasorelaxation induced by Win 55,212-2 mainly involves vanilloid receptors while CB1, CB2 and nonCB1/nonCB2 cannabinoid receptors have a minor participation in its vascular effect.