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Time-Dependent Vascular Actions of Cannabidiol in the Rat Aorta

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Time-Dependent Vascular Actions of Cannabidiol in the Rat Aorta European Journal of Pharmacology 612 (2009) 61–68 Contents lists available at ScienceDirect European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar Cardiovascular Pharmacology Time-dependent vascular actions of cannabidiol in the rat aorta Saoirse E. O'Sullivan a,⁎, Yan Sun b, Andrew J. Bennett b, Michael D. Randall b, David A. Kendall b a School of Graduate Entry Medicine and Health, Derby City General Hospital, University of Nottingham, Derby DE22 3DT, United Kingdom b School of Biomedical Sciences, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, United Kingdom article info abstract Article history: We have shown that the major active agent of Cannabis sativa, Δ9-tetrahydrocannabinol, activates Received 31 October 2008 peroxisome proliferator-activated receptor gamma [PPARγ, O'Sullivan, S.E., Tarling, E.J., Bennett, A.J., Kendall, Received in revised form 18 February 2009 D.A., Randall, M.D., 2005c. Novel time-dependent vascular actions of delta9-tetrahydrocannabinol mediated Accepted 3 March 2009 by peroxisome proliferator-activated receptor gamma. Biochem. Biophys. Res. Commun. 337, 824–831]. The Available online 11 March 2009 aim of the present study was to investigate whether another pharmacologically active phytocannabinoid, cannabidiol, similarly activates PPAR . Functional vascular studies were carried out in rat aortae in vitro by Keywords: γ Cannabinoid myography. PPARγ activation was investigated using reporter gene assays, a PPARγ competition-binding Cannabidiol assay and an adipogenesis assay. Cannabidiol caused time-dependent (over 2 h) vasorelaxation of pre- Aorta constricted aortae, sensitive to PPARγ antagonism (GW9662, 1 µM) and super oxide dismutase inhibition. Vasorelaxation The vascular effects of cannabidiol were not affected by endothelial denudation, nitric oxide synthase Peroxisome proliferator-activated receptor inhibition, pertussis toxin, cannabinoid CB1 or cannabinoid CB2 receptor antagonism, or capsaicin pre- gamma treatment. When aortae were contracted with U46619 in a Ca2+-free buffer, vasorelaxation to cannabidiol Calcium channel was substantially reduced. Furthermore, cannabidiol (1–30 µM) inhibited the contractile response to the re- introduction of Ca2+. In a reporter gene assay, cannabidiol increased the transcriptional activity of PPARγ. Cannabidiol was also found to bind to PPARγ and stimulate the differentiation of 3T3-L1 fibroblasts into adipocytes, a PPARγ-mediated response. These results show that cannabidiol binds to and activates PPARγ, 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. © 2009 Published by Elsevier B.V. 1. Introduction and cannabinoid CB2 (McPartland et al., 2007), although it has been shown to antagonise both cannabinoid CB1 and cannabinoid CB2 Cannabidiol is a major component of the cannabis plant, Cannabis receptors in the low nanomolar range (Thomas et al., 2007). sativa, but lacks the psychotropic effects of the better known active Cannabidiol is also suggested to be an antagonist of the GPR55 9 agent, Δ -tetrahydrocannabinol (THC). Cannabidiol is anxiolytic receptor (Ryberg et al., 2007). (Moreira et al., 2006; Zuardi et al., 2006; Resstel et al., 2006) and Peroxisome proliferator-activated receptors (PPARs) belong to a may antagonise the psychotropic effects of THC in the clinically family of nuclear receptors of which there are three isotypes: α, δ and available cannabis-based medicine, Sativex (Russo and Guy, 2006). In γ (Ferré, 2004). PPARs heterodimerise with the retinoid X receptor, addition to its behavioural effects, cannabidiol has been shown to be and bind to DNA sequences called PPAR response elements (PPREs), anti-inflammatory (Costa et al., 2007; Esposito et al., 2007), anti- which lead to the transcription of target genes upon ligand activation. oxidant (García-Arencibia et al., 2007), neuroprotective (El-Remessy PPARs are primarily involved in the regulation of metabolism and et al., 2006), a potent inhibitor of cancer cell growth (Ligresti et al., energy homeostasis. For example, agonists of the PPARγ isoform 2006) and is beneficial in diabetes (El-Remessy et al., 2006; Weiss improve insulin sensitivity and are used in the management of type 2 et al., 2006). However, the molecular targets for cannabidiol are still diabetes (Ferré, 2004; Rangwala and Lazar, 2004). In addition, PPARγ unclear. Cannabidiol is reported to have a low affinity for both of the agonists have been shown to have positive cardiovascular effects, ‘ ’ classical G-protein-coupled cannabinoid receptors, cannabinoid CB1 which include increased availability of nitric oxide, reductions in blood pressure and attenuation of atherosclerosis (Bishop-Bailey, 2000; Hsueh and Bruemmer, 2004). Some of the beneficial effects of PPARγ ligands are brought about by anti-inflammatory actions, fl ⁎ Corresponding author. Tel.: +44 1332724643. including inhibition of pro-in ammatory cytokines, increasing anti- E-mail address: [email protected] (S.E. O'Sullivan). inflammatory cytokines, and inhibition of inducible nitric oxide 0014-2999/$ – see front matter © 2009 Published by Elsevier B.V. doi:10.1016/j.ejphar.2009.03.010 62 S.E. O'Sullivan et al. / European Journal of Pharmacology 612 (2009) 61–68 synthase (iNOS) expression (see Széles et al., 2007 for a recent vasorelaxant effect of a single concentration of cannabidiol or review). vehicle control (0.1% ethanol) on induced tone was assessed as the PPARs have a large ligand binding pocket and are pharmacologi- reduction in tone over time. For each experimental protocol, vehicle cally promiscuous, being activated by a number of natural and control and cannabidiol-treated experiments were performed in synthetic ligands including, as reported recently, cannabinoids (see adjacent segments of the same artery. Net relaxation was calculated O'Sullivan, 2007 for a recent review). Specifically, it has been reported as the vasorelaxant effect of cannabidiol minus the vasorelaxant that ajulemic acid, an analogue of a THC metabolite, binds to and effect of vehicle (in adjacent aortic segments) over time. In some increases the transcriptional activity of PPARγ with anti-inflammatory experiments, the vascular effects of cannabidiol were investigated actions (Liu et al., 2003). Similarly, the endocannabinoids anandamide in un-contracted vessels. and 2-arachidonoylglycerol (2-AG) have anti-inflammatory actions To assess the contribution of PPARγ activation, some experi- sensitive to PPARγ antagonism (Rockwell and Kaminski, 2004; ments were performed in the presence of the PPARγ antagonist Rockwell et al., 2006). Anandamide has also been shown to directly GW9662 (1 µM) added 10 min prior to pre-contraction. To bind to PPARγ (Bouaboula et al., 2005; Gasperi et al., 2007). We investigate the role of endothelium-derived relaxing factors in recently showed that THC increases the transcriptional activity of the time-dependent vasorelaxation to cannabidiol, some vessels PPARγ and leads to vascular responses that are inhibited by a PPARγ were denuded of their endothelium by abrasion with a human hair. antagonist (O'Sullivan et al., 2005c, 2006). As many of the effects of The role of endothelium-derived nitric oxide (NO) was investigated G cannabidiol treatment are consistent with those of PPARγ activation, using the nitric oxide synthase inhibitor, N -nitro-L-arginine and since other cannabinoid compounds have been shown to activate methyl ester (L-NAME, 300 µM, present throughout, O'Sullivan PPARγ, the possibility exists that PPARγ activation might underlie et al., 2005c). To establish a potential role for superoxide dismutase some of the pharmacological effects of cannabidiol. (SOD) activity, some experiments were performed in the presence In vitro, abnormal cannabidiol, a synthetic analogue of cannabidiol, of the SOD inhibitor diethyldithiocarbamate (DETCA, 3 mM), added causes vasorelaxation of rat isolated mesenteric arteries via the 30 min prior to pre-contraction of arteries (O'Sullivan et al., putative ‘endothelial’ cannabinoid receptor, potassium channel acti- 2005c). vation and calcium channel blockade (Offertáler et al., 2003; Ho and To assess any possible contribution of cannabinoid receptor Hiley, 2003). In vivo, abnormal cannabidiol causes hypotension and activation, some experiments were performed in the presence of the mesenteric vasodilatation in wild-type mice and in mice lacking both cannabinoid CB1 receptor antagonist, AM251 (1 µM), or the cannabi- cannabinoid CB1 and cannabinoid CB2 receptors (Járai et al., 1999). noid CB2 receptor antagonist, AM630 (1 µM), both added 10 min before However, to date, the vascular responses to cannabidiol (as opposed to contracting vessels. To assess if cannabidiol acts at a G(i/o)-protein- abnormal cannabidiol) remain uninvestigated. We have previously coupled receptor, some vessels were incubated for 2 h with 200 ng/ml shown that THC causes time-dependent, endothelium-dependent, pertussis toxin (PTX, O'Sullivan et al., 2005b), and vasorelaxation to PPARγ-mediated vasorelaxation of the rat isolated aorta (O'Sullivan cannabidiol or vehicle assessed. The involvement of TRPV1 receptors on et al., 2005c). Therefore, the aim of the present study was to sensory nerves was assessed by incubating vessels for 1 h with the investigate whether similar time-dependent, PPARγ-mediated vasor- TRPV1 agonist capsaicin
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