title: 2-Arachidonylglyceryl ether and abnormal cannabidiol-induced vascular smooth muscle relaxation in rabbit pulmonary arteries via receptor-pertussis toxin sensitive G proteins-ERK1/2 signaling.
abstract: The receptor(s) used by cannabinoids to relax vascular smooth muscle is unknown. Here, we investigated the effects of 2-arachidonylglyceryl ether (2-AG ether), a metabolically stable endocannabinoid, and abnormal cannabidiol (abn-CBD) on relaxation of permeabilized pulmonary arterial strips monitored with force, and on extracellular signal-regulated mitogen-activated protein kinases (ERK1/2) phosphorylation in permeabilized vascular smooth muscle cells using immunoblotting. We found that 2-AG ether and abn-CBD caused relaxation and increased phosphorylation of ERK1/2. 2-AG ether effects were completely abolished by N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251), and N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716A), and partially blocked by (-)-1.3-dimethoxy-2-(3-3,4-trans-p-menthadien-(1,8)-yl)-orcinol (O-1918). In contrast, abn-CBD effects were completely abolished by O-1918, and only partially blocked by AM251, and SR141716A. Both 2-AG ether and abn-CBD effects were partially blocked by pertussis toxin, an inhibitor of Gi/o proteins. PD98059, an inhibitor of mitogen activated protein kinase kinase (MEK), completely abolished the relaxation, but only partially blocked the increased phosphorylation of ERK1/2 by 2-AG ether. In contrast, abn-CBD-induced relaxation was partially blocked and the increased phosphorylation of ERK1/2 was abolished by PD98059. These findings suggest that 2-AG ether and abn-CBD-induced vascular smooth muscle relaxation are mediated by the cannabinoid CB1 receptor, and the abn-CBD receptor, respectively, and are modulated by cross-talk between the receptors. These responses occur mainly by coupling to pertussis toxin sensitive G proteins, but also, in part independent of these G proteins, which have been classically thought to initiate MEK/ERK1/2 signaling to relax vascular smooth muscle.
authors.affiliation: Department of Anesthesiology, University of Washington, Box 356540, Seattle, WA 98195, USA. jsu@u.washington.edu
authors.forename: Judy Y
authors.initials: JY
authors.lastname: Su
authors.forename: Anhkiet C
authors.initials: AC
authors.lastname: Vo
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005419:Flavonoids / Q000494:pharmacology; D005989:Glycerides / Q000494:pharmacology*; D066298:In Vitro Techniques; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D037342:Pertussis Toxin / Q000494:pharmacology*; D010766:Phosphorylation; D010880:Piperidines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D011817:Rabbits; D020239:Receptor Cross-Talk; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects* / Q000378:metabolism; D012118:Resorcinols / Q000494:pharmacology*; D000077285:Rimonabant; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: C485531:((-)-4-(3-3,4-trans-p-menthadien-(1,8)-yl)-orcinol); C479832:4-(3-3,4-p-menthadien-(1,8)-yl)olivetol; D005419:Flavonoids; D005989:Glycerides; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D043562:Receptors, G-Protein-Coupled; D012118:Resorcinols; D014665:Vasodilator Agents; C424442:noladin ether; C103505:AM 251; D037342:Pertussis Toxin; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D000077285:Rimonabant; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one