Abstract
AimsThe 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.Methods and resultsUsing 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.ConclusionThis 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.
Highlights
Numerous studies have shown that endogenous, synthetic, and plantderived cannabinoids cause vasorelaxation of a range of animal and human arterial beds.[1,2] The extent of cannabinoid-induced vasorelaxation and the mechanisms involved often differs between the cannabinoid compound studied, the arterial bed used, and the species employed
Other receptor sites implicated in the actions of CBD include the orphan G-protein-coupled receptor GPR55, the putative endothelial cannabinoid receptor (CBe), the transient receptor potential vanilloid 1 (TRPV1) receptor, a1-adrenoceptors, m opioid receptors and 5-HT1A receptors,[4,5] A CBD/THC combination (1 : 1 ratio, Sativex/Nabiximols) is currently licensed internationally in more than 20 countries for the treatment of spasticity in multiple sclerosis, and an as yet unlicensed CBD alone
In the rat isolated aorta, we showed that CBD causes a time-dependant vasorelaxant response that was inhibited by antagonism of the peroxisome proliferator activated receptor gamma (PPARg) receptor and inhibition of superoxide dismutase.[22]
Summary
Numerous studies have shown that endogenous, synthetic, and plantderived cannabinoids cause vasorelaxation of a range of animal and human arterial beds.[1,2] The extent of cannabinoid-induced vasorelaxation and the mechanisms involved often differs between the cannabinoid compound studied, the arterial bed used, and the species employed These mechanisms include activation of cannabinoid receptor one (CB1), cannabinoid receptor two (CB2), transient receptor potential vanilloid one (TRPV1), peroxisome proliferator activated receptor gamma (PPARg), and an as yet unidentified endothelial-bound cannabinoid receptor (CBe).[1,2] Vasorelaxant mediators implicated in cannabinoid-induced vasorelaxation include nitric oxide production, prostaglandin production, metabolite production, and ion channel modulation, some of which have been shown to be coupled to receptor activation.[1,2]. Other receptor sites implicated in the actions of CBD include the orphan G-protein-coupled receptor GPR55, the putative endothelial cannabinoid receptor (CBe), the transient receptor potential vanilloid 1 (TRPV1) receptor, a1-adrenoceptors, m opioid receptors and 5-HT1A receptors,[4,5] A CBD/THC combination (1 : 1 ratio, Sativex/Nabiximols) is currently licensed internationally in more than 20 countries for the treatment of spasticity in multiple sclerosis, and an as yet unlicensed CBD alone
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