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 CB(1) and CB(2) agonist with high stereoselectivity and a slight preference for CB(2) 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 CB(1) receptor antagonist, a transient receptor potential vanilloid-1 antagonist, capsaicin desensibilization, and a CGRP receptor antagonist (P<0.001). CB(2) and non-CB(1)/non-CB(2) 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 CB(1), CB(2) and nonCB(1)/nonCB(2) cannabinoid receptors have a minor participation in its vascular effect.
Dannert
M T
MT
Universidad Complutense de Madrid, Facultad de Medicina, Dpto Farmacología, Avda Complutense s/n 28040 Madrid, Spain.
Alsasua
A
A
Herradon
E
E
Martín
M I
MI
López-Miranda
V
V
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000378:metabolism; D048588:Benzoxazines; D001685:Biological Factors / Q000378:metabolism; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009025:Morpholines / Q000494:pharmacology*; D009281:Naphthalenes / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D011453:Prostaglandins / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D043882:Receptors, Cannabinoid / Q000187:drug effects; D050916:TRPV Cation Channels / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
D048588:Benzoxazines; D001685:Biological Factors; D009025:Morpholines; D009281:Naphthalenes; D011453:Prostaglandins; D043882:Receptors, Cannabinoid; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D014665:Vasodilator Agents; C067410:endothelium-dependent hyperpolarization factor; D009569:Nitric Oxide; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D015740:Calcitonin Gene-Related Peptide