Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary & Life Sciences, University of Glasgow, G12 8QQ, UK.
Cell Biology Group, Strathclyde Institute of Pharmacy and Biomedical Science, 161 Cathedral Street, University of Strathclyde, Glasgow G4 0RE, UK.
Eur J Pharmacol. 2019 Jan 5;842:1-9. doi: 10.1016/j.ejphar.2018.10.027. Epub 2018 Oct 23.
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 S1P 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 S1P 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 S1P 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.
在分离的大鼠颈总动脉中，内源性大麻素大麻酰胺通过激活鞘氨醇激酶（SK）诱导内皮依赖性松弛。这会产生鞘氨醇-1-磷酸（S1P），它可以从细胞中释放出来，并激活内皮细胞上的 S1P 受体。在麻醉小鼠中，大麻酰胺对血压具有特征性的三相作用，但 SK 和 S1P 受体在介导血压变化方面的作用从未被研究过。因此，我们在本研究中对此进行了评估。在对照 C57BL/6 小鼠和用 SK1 选择性抑制剂（BML-258，也称为 SK1-I）或 SK2（(R)-FTY720 甲醚（ROMe）预处理的小鼠中测量了 1 和 10mg/kg 大麻酰胺的峰值降压反应，这是一种双重 SK1/2 抑制剂（SKi）或 S1P 受体拮抗剂（W146）。还研究了 S1P 在分离的小鼠主动脉环中的血管舒张反应。BML-258 显著减弱了大麻酰胺的降压反应，但 ROME 没有。用 W146 拮抗 S1P 受体完全阻断了对大麻酰胺的收缩压下降，但没有阻断舒张压下降。W146 阻断了去内皮主动脉环中 S1P 诱导的血管舒张，但在完整内皮环中 S1P 没有引起血管舒张。这项研究提供了证据，表明 SK1/S1P 调节轴是大麻酰胺引起的快速低血压所必需的。大麻酰胺引起的 S1P 的产生可能会激活 S1P，以降低总外周阻力并降低平均动脉压。这些发现对我们理解大麻素的降压和心血管作用具有重要意义。
