Zygmunt P M, Petersson J, Andersson D A, Chuang H, Sørgård M, Di Marzo V, Julius D, Högestätt E D
Department of Clinical Pharmacology, Institute of Laboratory Medicine, University of Lund, Sweden.
Nature. 1999 Jul 29;400(6743):452-7. doi: 10.1038/22761.
The endogenous cannabinoid receptor agonist anandamide is a powerful vasodilator of isolated vascular preparations, but its mechanism of action is unclear. Here we show that the vasodilator response to anandamide in isolated arteries is capsaicin-sensitive and accompanied by release of calcitonin-gene-related peptide (CGRP). The selective CGRP-receptor antagonist 8-37 CGRP, but not the cannabinoid CB1 receptor blocker SR141716A, inhibited the vasodilator effect of anandamide. Other endogenous (2-arachidonylglycerol, palmitylethanolamide) and synthetic (HU 210, WIN 55,212-2, CP 55,940) CB1 and CB2 receptor agonists could not mimic the action of anandamide. The selective 'vanilloid receptor' antagonist capsazepine inhibited anandamide-induced vasodilation and release of CGRP. In patch-clamp experiments on cells expressing the cloned vanilloid receptor (VR1), anandamide induced a capsazepine-sensitive current in whole cells and isolated membrane patches. Our results indicate that anandamide induces vasodilation by activating vanilloid receptors on perivascular sensory nerves and causing release of CGRP. The vanilloid receptor may thus be another molecular target for endogenous anandamide, besides cannabinoid receptors, in the nervous and cardiovascular systems.
内源性大麻素受体激动剂花生四烯乙醇胺是离体血管制剂的一种强效血管舒张剂，但其作用机制尚不清楚。在此我们表明，离体动脉对花生四烯乙醇胺的血管舒张反应对辣椒素敏感，并伴有降钙素基因相关肽（CGRP）的释放。选择性CGRP受体拮抗剂8-37 CGRP，而非大麻素CB1受体阻断剂SR141716A，抑制了花生四烯乙醇胺的血管舒张作用。其他内源性（2-花生四烯酸甘油酯、棕榈酰乙醇胺）和合成的（HU 210、WIN 55,212-2、CP 55,940）CB1和CB2受体激动剂无法模拟花生四烯乙醇胺的作用。选择性“香草酸受体”拮抗剂辣椒平抑制了花生四烯乙醇胺诱导的血管舒张和CGRP的释放。在对表达克隆香草酸受体（VR1）的细胞进行的膜片钳实验中，花生四烯乙醇胺在全细胞和分离的膜片中诱导出一种对辣椒平敏感的电流。我们的结果表明，花生四烯乙醇胺通过激活血管周围感觉神经上的香草酸受体并导致CGRP的释放来诱导血管舒张。因此，除了大麻素受体外，香草酸受体可能是内源性花生四烯乙醇胺在神经和心血管系统中的另一个分子靶点。
