title: Cannabinoid and lipid-mediated vasorelaxation in retinal microvasculature.
abstract: The endocannabinoid system plays a role in regulation of vasoactivity in the peripheral vasculature; however, little is known about its role in regulation of the CNS microvasculature. This study investigated the pharmacology of cannabinoids and cannabimimetic lipids in the retinal microvasculature, a CNS vascular bed that is autoregulated. Vessel diameter (edge detector) and calcium transients (fura-2) were recorded from segments of retinal microvasculature isolated from adult, male Fischer 344 rats. Results showed that abnormal cannabidiol (Abn-CBD), an agonist at the putative endothelial cannabinoid receptor, CBe, inhibited endothelin 1 (ET-1) induced vasoconstriction in retinal arterioles. These actions of Abn-CBD were independent of CB1/CB2 receptors and were not mediated by agonists for GPR55 or affected by nitric oxide synthase (NOS) inhibition. However, the vasorelaxant effects of Abn-CBD were abolished when the endothelium was removed and were inhibited by the small Ca(2+)-sensitive K channel (SKCa) blocker, apamin. The effects of the endogenous endocannabinoid metabolite, N-arachidonyl glycine (NAGly), a putative agonist for GPR18, were virtually identical to those of Abn-CBD. GPR18 mRNA and protein were present in the retina, and immunohistochemistry demonstrated that GPR18 was localized to the endothelium of retinal vessels. These findings demonstrate that Abn-CBD and NAGly inhibit ET-1 induced vasoconstriction in retinal arterioles by an endothelium-dependent signaling mechanism that involves SKCa channels. The endothelial localization of GPR18 suggests that GPR18 could contribute to cannabinoid and lipid-mediated retinal vasoactivity.
authors.affiliation: Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4R2.
authors.forename: Jessica
authors.initials: J
authors.lastname: MacIntyre
authors.affiliation: Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4R2.
authors.forename: Alex
authors.initials: A
authors.lastname: Dong
authors.affiliation: Department of Psychological and Brain Sciences, Gill Center for Biomolecular Science, Indiana University, Bloomington, IN, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Straiker
authors.affiliation: Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4R2.
authors.forename: Jiequan
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4R2.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Howlett
authors.affiliation: Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4R2.
authors.forename: Amina
authors.initials: A
authors.lastname: Bagher
authors.affiliation: Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4R2.
authors.forename: Eileen
authors.initials: E
authors.lastname: Denovan-Wright
authors.affiliation: Department of Ophthalmology and Visual Sciences, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4R2; Centre for Ophthalmology and Visual Science and the ARC Centre of Excellence in Vision Science, The University of Western Australia, Nedlands, Western Australia.
authors.forename: Dao-Yi
authors.initials: DY
authors.lastname: Yu
authors.affiliation: Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4R2; Department of Ophthalmology and Visual Sciences, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4R2. Electronic address: mkelly@dal.ca.
authors.forename: Melanie E M
authors.initials: ME
authors.lastname: Kelly
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D002186:Cannabinoids; D019332:Endothelin-1 / Q000494:pharmacology*; D005625:Frontal Lobe / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008055:Lipids; D008297:Male; D055806:Microvessels; D012333:RNA, Messenger / Q000378:metabolism; D011916:Rats, Inbred F344; D043882:Receptors, Cannabinoid / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D012118:Resorcinols / Q000494:pharmacology*; D012160:Retina / Q000187:drug effects / Q000502:physiology; D012171:Retinal Vessels / Q000187:drug effects* / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects*
chemical_list: C479832:4-(3-3,4-p-menthadien-(1,8)-yl)olivetol; D001095:Arachidonic Acids; D002186:Cannabinoids; D019332:Endothelin-1; C588261:GPR18 protein, rat; C568825:GPR55 protein, rat; D008055:Lipids; C465623:N-arachidonylglycine; D012333:RNA, Messenger; D043882:Receptors, Cannabinoid; D043562:Receptors, G-Protein-Coupled; D012118:Resorcinols; D005998:Glycine
keywords: Cannabinoid; GPR18; Microvasculature; Retina