Time-dependent vascular actions of cannabidiol in the rat aorta

We have shown that the major active agent of Cannabis sativa, Delta(9)-tetrahydrocannobinol, activates peroxisome proliferator-activated receptor gamma [PPAR gamma, O'Sullivan, S.E., Tarling, E.J., Bennett, AJ., 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. Common. 337, 824-831]. The aim of the present Study was to investigate whether another pharmacologically active phytocannabinoid, cannabidiol, similarly activates PPAR gamma. Functional Vascular Studies were carried Out in rat aortae in vitro by myography. PPAR gamma activation was investigated using reporter gene assays, a PPAR gamma competition-binding assay and an adipogenesis assay. Cannabidiol caused time-dependent (over 2 h) vasorelaxation of preconstricted aortae, sensitive to PPAR gamma antagonism (GW9662, 1 mu M) and super oxide dismutase inhibition. The vascular effects of cannabidiol were not affected by enclothelial denudation, nitric oxide synthase inhibition, pertussis toxin, cannabinoid CB, or cannabinoid CB2 receptor antagonism or capsaicin Pretreatment. When aortae Were contracted with U46619 in a Ca2+-free buffer, vasorelaxation to cannabidiol was substantially reduced. Furthermore, cannabidiol (1 - 30 mu M) inhibited the contractile response to the reintroduction Of Ca2+. in a reporter gene assay, cannabidiol increased the transcriptional activity of PPAR gamma. Cannabidiol was also found to bind to PPAR gamma and stimulate the differentiation of 3T3-L1,1 fibroblasts into adipocytes, a PPAR gamma-mediated response. These results show that cannabidiol binds to and activates PPAR gamma, which partially underlies the time-dependent vascular effects of cannabidiol. However, cannabidiol-inclUced vasorelaxation in the rat isolated aorta appears to be largely due to calcium channel inhibition. (C) 2009 Published by Elsevier B.V.