title: Cannabidiol improves vasorelaxation in Zucker diabetic fatty rats through cyclooxygenase activation.
abstract: Cannabidiol (CBD) decreases insulitis, inflammation, neuropathic pain, and myocardial dysfunction in preclinical models of diabetes. We recently showed that CBD also improves vasorelaxation in the Zucker diabetic fatty (ZDF) rat, and the objective of the present study was to establish the mechanisms underlying this effect. Femoral arteries from ZDF rats and ZDF lean controls were isolated, mounted on a myograph, and incubated with CBD (10 μM) or vehicle for 2 hours. Subsequent vasorelaxant responses were measured in combination with various interventions. Prostaglandin metabolites were detected using enzyme immunoassay. Direct effects of CBD on cyclooxygenase (COX) enzyme activity were measured by oxygraph assay. CBD enhanced the maximum vasorelaxation to acetylcholine (ACh) in femoral arteries from ZDF lean rats (P < 0.01) and especially ZDF rats (P < 0.0001). In ZDF arteries, this enhancement persisted after cannabinoid receptor (CB) type 1, endothelial CB, or peroxisome proliferator-activated receptor-γ antagonism but was inhibited by CB2 receptor antagonism. CBD also uncovered a vasorelaxant response to a CB2 agonist not previously observed. The CBD-enhanced ACh response was endothelium-, nitric oxide-, and hydrogen peroxide-independent. It was, however, COX-1/2- and superoxide dismutase-dependent, and CBD enhanced the activity of both purified COX-1 and COX-2. The CBD-enhanced ACh response in the arteries was inhibited by a prostanoid EP4 receptor antagonist. Prostaglandin E2 metabolite levels were below the limits of detection, but 6-keto prostaglandin F1 α was decreased after CBD incubation. These data show that CBD exposure enhances the ability of arteries to relax via enhanced production of vasodilator COX-1/2-derived products acting at EP4 receptors.
authors.affiliation: Pharmacology Research Group, School of Life Sciences, University of Nottingham Medical School, Queen's Medical Centre, Nottingham, United Kingdom (A.J.W., M.D.R.); School of Medicine, University of Nottingham Medical School, Royal Derby Hospital, Derby, United Kingdom (S.E.O.); and Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden (M.C., C.J.F.).
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Wheal
authors.affiliation: Pharmacology Research Group, School of Life Sciences, University of Nottingham Medical School, Queen's Medical Centre, Nottingham, United Kingdom (A.J.W., M.D.R.); School of Medicine, University of Nottingham Medical School, Royal Derby Hospital, Derby, United Kingdom (S.E.O.); and Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden (M.C., C.J.F.).
authors.forename: Mariateresa
authors.initials: M
authors.lastname: Cipriano
authors.affiliation: Pharmacology Research Group, School of Life Sciences, University of Nottingham Medical School, Queen's Medical Centre, Nottingham, United Kingdom (A.J.W., M.D.R.); School of Medicine, University of Nottingham Medical School, Royal Derby Hospital, Derby, United Kingdom (S.E.O.); and Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden (M.C., C.J.F.).
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Fowler
authors.affiliation: Pharmacology Research Group, School of Life Sciences, University of Nottingham Medical School, Queen's Medical Centre, Nottingham, United Kingdom (A.J.W., M.D.R.); School of Medicine, University of Nottingham Medical School, Royal Derby Hospital, Derby, United Kingdom (S.E.O.); and Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden (M.C., C.J.F.).
authors.forename: Michael D
authors.initials: MD
authors.lastname: Randall
authors.affiliation: Pharmacology Research Group, School of Life Sciences, University of Nottingham Medical School, Queen's Medical Centre, Nottingham, United Kingdom (A.J.W., M.D.R.); School of Medicine, University of Nottingham Medical School, Royal Derby Hospital, Derby, United Kingdom (S.E.O.); and Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden (M.C., C.J.F.) mbzso@nottingham.ac.uk.
authors.forename: Saoirse Elizabeth
authors.initials: SE
authors.lastname: O'Sullivan
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D002185:Cannabidiol / Q000494:pharmacology*; D051545:Cyclooxygenase 1 / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D005263:Femoral Artery / Q000187:drug effects / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D047495:PPAR gamma; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D058309:Receptors, Prostaglandin E, EP4 Subtype; D014665:Vasodilator Agents; D002185:Cannabidiol; D009569:Nitric Oxide; D006861:Hydrogen Peroxide; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D013482:Superoxide Dismutase; D015232:Dinoprostone; D000109:Acetylcholine