Role of Endothelium in Abnormal Cannabidiol-Induced Vasoactivity in Retinal Arterioles.
Role of Endothelium in Abnormal Cannabidiol-Induced Vasoactivity in Retinal Arterioles.
复制标题
DOI：
10.1167/iovs.14-14879
复制
发表时间：
2015-06
影响因子：
4.4
通讯作者：
E. Su;M. Kelly;S. Cringle;Dao-Yi Yu
中科院分区：
文献类型：
--
作者：
E. Su;M. Kelly;S. Cringle;Dao-Yi Yu
大麻素类化合物通过内皮受体靶点介导血管阻力的变化。我们研究了视网膜阻力小动脉中大麻素介导的血管活性反应中内皮的参与。方法在内皮完整和内皮剥脱的离体灌注猪视网膜小动脉中，在内皮素-1（ET-1）预收缩和无内皮素-1（ET-1）预收缩的情况下，研究了非典型大麻素，异常大麻二酚（abn-CBD），非CB 1/CB 2内皮大麻素受体（CBeR）的原型激动剂，管腔内（IL）和管腔外（EL）给药的血管反应。还研究了CB 1受体拮抗剂AM 251和据报道拮抗CBeR的CBD类似物O-1918的作用。结果在无预收缩的情况下，IL和EL给药abn-CBD均诱导剂量依赖性血管收缩反应。与EL给药相比，IL给药abn-CBD诱导了显著更大的血管收缩。相反，在ET-1预收缩的视网膜小动脉中仅观察到abn-CBD的血管舒张。当使用IL时，内皮去除显着降低了abn-CBD诱导的血管活性，但当使用EL时则不然。IL abn-CBD诱导的血管活性可被O-1918和AM 251拮抗。结论：大麻素在离体灌注的视网膜小动脉中表现出复杂的血管活性作用。仅在预收缩的视网膜血管中观察到abn-CBD介导的血管舒张的事实表明，abn-CBD诱导的血管活性反应高度依赖于血管张力。此外，IL和EL给药产生了不同的反应，去除内皮细胞减弱了abn-CBD血管活性，突出了内皮细胞在abn-CBD血管活性中的关键作用。AM 251和O-1918对abn-CBD诱导的血管活性的抑制表明了调节abn-CBD诱导的血管活性的可能性。
PURPOSE Cannabinoids have been reported to mediate changes in vascular resistance through endothelial receptor targets. We examined involvement of the endothelium in cannabinoid-mediated vasoactive responses in resistance arterioles of the retina. METHODS Vascular responses to both intraluminal (IL) and extraluminal (EL) administration of the atypical cannabinoid, abnormal cannabidiol (abn-CBD), a prototypical agonist at the non-CB1/CB2 endothelial cannabinoid receptor (CBeR), were studied in endothelial intact and endothelial denuded, isolated perfused porcine retinal arterioles with and without endothelin-1 (ET-1) precontraction. The effects of AM251, a CB1 receptor antagonist, and O-1918, an analog of CBD reported to antagonize CBeR, were also studied. RESULTS Dose-dependent vasocontractile responses were induced by both IL and EL administration of abn-CBD in the absence of precontraction. Significantly greater vasoconstriction was induced by IL administration of abn-CBD than with EL administration. In contrast, only vasodilation to abn-CBD was observed in ET-1 precontracted retinal arterioles. Endothelium removal significantly reduced abn-CBD-induced vasoactivity when abn-CBD was used IL but not when applied EL. IL abn-CBD-induced vasoactivity was antagonized by O-1918 and AM251. CONCLUSIONS Cannabinoids show complex vasoactive actions in isolated perfused retinal arterioles. The fact that abn-CBD-mediated vasorelaxation was seen only in precontracted retinal vessels indicates that the abn-CBD-induced vasoactive response is highly dependent on vascular tone. Furthermore, IL and EL administration produced differential responses, and removal of endothelium blunted abn-CBD vasoactivity, highlighting the critical role of endothelium in abn-CBD vasoactivity. AM251 and O-1918 inhibition of abn-CBD-induced vasoactivity suggests the possibility of modulating abn-CBD-induced vasoactivity.