Abstract
In the isolated rat carotid artery, the endocannabinoid anandamide induces endothelium-dependent relaxation via activation of the enzyme sphingosine kinase (SK). This generates sphingosine-1-phosphate (S1P) which can be released from the cell and activates S1P receptors on the endothelium. In anaesthetised mice, anandamide has a well-characterised triphasic effect on blood pressure but the contribution of SK and S1P receptors in mediating changes in blood pressure has never been studied. Therefore, we assessed this in the current study.The peak hypotensive response to 1 and 10 mg/kg anandamide was measured in control C57BL/6 mice and in mice pretreated with selective inhibitors of SK1 (BML-258, also known as SK1-I) or SK2 ((R)-FTY720 methylether (ROMe), a dual SK1/2 inhibitor (SKi) or an S1P1 receptor antagonist (W146). Vasodilator responses to S1P were also studied in isolated mouse aortic rings.The hypotensive response to anandamide was significantly attenuated by BML-258 but not by ROMe. Antagonising S1P1 receptors with W146 completely blocked the fall in systolic but not diastolic blood pressure in response to anandamide. S1P induced vasodilation in denuded aortic rings was blocked by W146 but caused no vasodilation in endothelium-intact rings.This study provides evidence that the SK1/S1P regulatory-axis is necessary for the rapid hypotension induced by anandamide. Generation of S1P in response to anandamide likely activates S1P1 to reduce total peripheral resistance and lower mean arterial pressure. These findings have important implications in our understanding of the hypotensive and cardiovascular actions of cannabinoids.
Highlights
In a previous study (Mair et al, 2010), we identified a novel pathway which may underlie the endothelium-dependent vasodilator effects of anandamide in the rat coronary artery
Baseline mean arterial blood pressure (MAP) was 92.6 ± 3.0 mmHg in vehicle-treated mice (n = 12) which was not significantly different from animals injected with the dual sphingosine kinase 1 (SK1)/2 inhibitor, SKi (75 mg/kg) 24 h previously (91.6 ± 2.6 mmHg; n = 12, Fig., 2A)
It is possible that are involved.Anandamide (AEA) employs a signalling pathway that induces phosphorylation and activation of SK1 via extracellular signal-regulated kinases-1/2, and we previously demonstrated this effect in isolated rat coronary arteries in vitro (Mair et al, 2010)
Summary
In a previous study (Mair et al, 2010), we identified a novel pathway which may underlie the endothelium-dependent vasodilator effects of anandamide in the rat coronary artery. Anandamide (AEA) is an endogenously-generated cannabinoid which activates the endocannabinoid receptors CB1 and CB2 and the vanilloid transient receptor potential channels of V1 type (TRPV1) receptor (Stanley and O'Sullivan, 2014) These endocannabinoids might activate as yet uncharacterised receptors within the cardiovascular system, such as the orphan G protein-coupled receptors (GPCRs), GPR55 (Ryberg et al, 2007; Johns et al, 2007) and GPR119 (Overton et al, 2006). Both GPR55 and GPR119 have been demonstrated to bind endocannabinoids and evidence exists for a non-CB1/non-CB2 endothelial receptor, CBx (Offertaler et al, 2003; Zakrzeska et al, 2010) this is controversial and requires further investigation. Based on our in vitro data in the rat coronary artery (Mair et al, 2010), we hypothesised that generation of S1P in response to i.v. administration of AEA may underlie the phase I hypotensive response in the mouse
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