Time-dependent vascular actions of cannabidiol in the rat aorta.
We have shown that the major active agent of Cannabis sativa, Delta(9)-tetrahydrocannabinol, activates peroxisome proliferator-activated receptor gamma [PPARgamma, O'Sullivan, S.E., Tarling, E.J., Bennett, A.J., Kendall, D.A., Randall, M.D., 2005c. Novel time-dependent vascular actions of delta9-tetrahydrocannabinol mediated by peroxisome proliferator-activated receptor gamma. Biochem. Biophys. Res. Commun. 337, 824-831]. The aim of the present study was to investigate whether another pharmacologically active phytocannabinoid, cannabidiol, similarly activates PPARgamma. Functional vascular studies were carried out in rat aortae in vitro by myography. PPARgamma activation was investigated using reporter gene assays, a PPARgamma competition-binding assay and an adipogenesis assay. Cannabidiol caused time-dependent (over 2 h) vasorelaxation of pre-constricted aortae, sensitive to PPARgamma antagonism (GW9662, 1 microM) and super oxide dismutase inhibition. The vascular effects of cannabidiol were not affected by endothelial denudation, nitric oxide synthase inhibition, pertussis toxin, cannabinoid CB1 or cannabinoid CB2 receptor antagonism, or capsaicin pre-treatment. When aortae were contracted with U46619 in a Ca2+-free buffer, vasorelaxation to cannabidiol was substantially reduced. Furthermore, cannabidiol (1-30 microM) inhibited the contractile response to the re-introduction of Ca2+. In a reporter gene assay, cannabidiol increased the transcriptional activity of PPARgamma. Cannabidiol was also found to bind to PPARgamma and stimulate the differentiation of 3T3-L1 fibroblasts into adipocytes, a PPARgamma-mediated response. These results show that cannabidiol binds to and activates PPARgamma, which partially underlies the time-dependent vascular effects of cannabidiol. However, cannabidiol-induced vasorelaxation in the rat isolated aorta appears to be largely due to calcium channel inhibition.
O'Sullivan
Saoirse E
SE
School of Graduate Entry Medicine and Health, Derby City General Hospital, University of Nottingham, Derby DE223DT, United Kingdom. Saoirse.osullivan@nottingham.ac.uk
Sun
Yan
Y
Bennett
Andrew J
AJ
Randall
Michael D
MD
Kendall
David A
DA
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D041721:3T3-L1 Cells; D050156:Adipogenesis / Q000187:drug effects; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000502:physiology; D001667:Binding, Competitive / Q000187:drug effects; D002185:Cannabidiol / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects; D017930:Genes, Reporter; D008156:Luciferases / Q000378:metabolism; D008297:Male; D051379:Mice; D009213:Myography; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013482:Superoxide Dismutase / Q000378:metabolism; D013997:Time Factors; D015533:Transcriptional Activation / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology
C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D047495:PPAR gamma; D014662:Vasoconstrictor Agents; D002185:Cannabidiol; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D008156:Luciferases; D013482:Superoxide Dismutase