title: Role of Endothelium in Abnormal Cannabidiol-Induced Vasoactivity in Retinal Arterioles.
abstract: OBJECTIVE
  Cannabinoids have been reported to mediate changes in vascular resistance through endothelial receptor targets. We examined involvement of the endothelium in cannabinoid-mediated vasoactive responses in resistance arterioles of the retina.
  
  
  METHODS
  Vascular responses to both intraluminal (IL) and extraluminal (EL) administration of the atypical cannabinoid, abnormal cannabidiol (abn-CBD), a prototypical agonist at the non-CB1/CB2 endothelial cannabinoid receptor (CBeR), were studied in endothelial intact and endothelial denuded, isolated perfused porcine retinal arterioles with and without endothelin-1 (ET-1) precontraction. The effects of AM251, a CB1 receptor antagonist, and O-1918, an analog of CBD reported to antagonize CBeR, were also studied.
  
  
  RESULTS
  Dose-dependent vasocontractile responses were induced by both IL and EL administration of abn-CBD in the absence of precontraction. Significantly greater vasoconstriction was induced by IL administration of abn-CBD than with EL administration. In contrast, only vasodilation to abn-CBD was observed in ET-1 precontracted retinal arterioles. Endothelium removal significantly reduced abn-CBD-induced vasoactivity when abn-CBD was used IL but not when applied EL. IL abn-CBD-induced vasoactivity was antagonized by O-1918 and AM251.
  
  
  CONCLUSIONS
  Cannabinoids show complex vasoactive actions in isolated perfused retinal arterioles. The fact that abn-CBD-mediated vasorelaxation was seen only in precontracted retinal vessels indicates that the abn-CBD-induced vasoactive response is highly dependent on vascular tone. Furthermore, IL and EL administration produced differential responses, and removal of endothelium blunted abn-CBD vasoactivity, highlighting the critical role of endothelium in abn-CBD vasoactivity. AM251 and O-1918 inhibition of abn-CBD-induced vasoactivity suggests the possibility of modulating abn-CBD-induced vasoactivity.
authors.affiliation: Centre for Ophthalmology and Visual Science, University of Western Australia, Perth, Australia 2Lions Eye Institute, University of Western Australia, Perth, Australia.
authors.forename: Er-Ning
authors.initials: EN
authors.lastname: Su
authors.affiliation: Laboratory for Retina and Optic Nerve Research, Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Melanie E
authors.initials: ME
authors.lastname: Kelly
authors.affiliation: Centre for Ophthalmology and Visual Science, University of Western Australia, Perth, Australia 2Lions Eye Institute, University of Western Australia, Perth, Australia.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Cringle
authors.affiliation: Centre for Ophthalmology and Visual Science, University of Western Australia, Perth, Australia 2Lions Eye Institute, University of Western Australia, Perth, Australia.
authors.forename: Dao-Yi
authors.initials: DY
authors.lastname: Yu
mesh_terms: D000818:Animals; D001160:Arterioles / Q000187:drug effects*; D002185:Cannabidiol / Q000031:analogs & derivatives / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000502:physiology*; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors; D012118:Resorcinols / Q000494:pharmacology*; D012171:Retinal Vessels / Q000187:drug effects*; D013552:Swine; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology
chemical_list: C479832:4-(3-3,4-p-menthadien-(1,8)-yl)olivetol; D019332:Endothelin-1; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D012118:Resorcinols; D002185:Cannabidiol; C103505:AM 251