title: Cannabidiol causes endothelium-dependent vasorelaxation of human mesenteric arteries via CB1 activation.
abstract: OBJECTIVE
  The protective effects of cannabidiol (CBD) have been widely shown in preclinical models and have translated into medicines for the treatment of multiple sclerosis and epilepsy. However, the direct vascular effects of CBD in humans are unknown.
  
  
  RESULTS
  Using wire myography, the vascular effects of CBD were assessed in human mesenteric arteries, and the mechanisms of action probed pharmacologically. CBD-induced intracellular signalling was characterized using human aortic endothelial cells (HAECs). CBD caused acute, non-recoverable vasorelaxation of human mesenteric arteries with an Rmax of ∼ 40%. This was inhibited by cannabinoid receptor 1 (CB1) receptor antagonists, desensitization of transient receptor potential channels using capsaicin, removal of the endothelium, and inhibition of potassium efflux. There was no role for cannabinoid receptor-2 (CB2) receptor, peroxisome proliferator activated receptor (PPAR)γ, the novel endothelial cannabinoid receptor (CBe), or cyclooxygenase. CBD-induced vasorelaxation was blunted in males, and in patients with type 2 diabetes or hypercholesterolemia. In HAECs, CBD significantly reduced phosphorylated JNK, NFκB, p70s6 K and STAT5, and significantly increased phosphorylated CREB, ERK1/2, and Akt levels. CBD also increased phosphorylated eNOS (ser1177), which was correlated with increased levels of ERK1/2 and Akt levels. CB1 receptor antagonism prevented the increase in eNOS phosphorylation.
  
  
  CONCLUSIONS
  This study shows, for the first time, that CBD causes vasorelaxation of human mesenteric arteries via activation of CB1 and TRP channels, and is endothelium- and nitric oxide-dependent.
authors.affiliation: School of Medicine, University of Nottingham, Royal Derby Hospital, Derby DE22 3DT, UK.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Stanley
authors.affiliation: School of Medicine, University of Nottingham, Royal Derby Hospital, Derby DE22 3DT, UK.
authors.forename: William H
authors.initials: WH
authors.lastname: Hind
authors.affiliation: School of Medicine, University of Nottingham, Royal Derby Hospital, Derby DE22 3DT, UK.
authors.forename: Cristina
authors.initials: C
authors.lastname: Tufarelli
authors.affiliation: School of Medicine, University of Nottingham, Royal Derby Hospital, Derby DE22 3DT, UK mbzso@nottingham.ac.uk.
authors.forename: Saoirse E
authors.initials: SE
authors.lastname: O'Sullivan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002185:Cannabidiol / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects*; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000188:drug therapy; D009569:Nitric Oxide / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D043884:Receptor, Cannabinoid, CB1; D014665:Vasodilator Agents; D002185:Cannabidiol; D009569:Nitric Oxide
keywords: Cannabidiol; Cannabinoid; Endothelium; Human; Vasorelaxation