Wagner J A, Varga K, Ellis E F, Rzigalinski B A, Martin B R, Kunos G
Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298, USA.
Nature. 1997 Dec 4;390(6659):518-21. doi: 10.1038/37371.
Anandamide, an endogenous cannabinoid ligand, binds to CB1 cannabinoid receptors in the brain and mimics the neurobehavioural actions of marijuana. Cannabinoids and anandamide also elicit hypotension mediated by peripheral CB1 receptors. Here we report that a selective CB1 receptor antagonist, SR141716A, elicits an increase in blood pressure in rats subjected to haemorrhagic shock, whereas similar treatment of normotensive rats or intracerebroventricular administration of the antagonist during shock do not affect blood pressure. Blood from haemorrhaged rats causes hypotension in normal rats, which can be prevented by SR141716A but not by inhibition of nitric oxide synthase in the recipient. Macrophages and platelets from haemorrhaged rats elicit CB1 receptor-mediated hypotension in normotensive recipients, and incorporate arachidonic acid or ethanolamine into a product that co-elutes with anandamide on reverse-phase high-performance liquid chromatography. Also, macrophages from control rats stimulated with ionomycin or bacterial phospholipase D produce anandamide, as identified by gas chromatography and mass spectrometry. These findings indicate that activation of peripheral CB1 cannabinoid receptors contributes to haemorrhagic hypotension, and anandamide produced by macrophages may be a mediator of this effect.
花生四烯乙醇胺，一种内源性大麻素配体，与大脑中的CB1大麻素受体结合，并模拟大麻的神经行为作用。大麻素和花生四烯乙醇胺还会引发由外周CB1受体介导的低血压。在此我们报告，一种选择性CB1受体拮抗剂SR141716A可使失血性休克大鼠的血压升高，而对正常血压大鼠进行类似处理或在休克期间向脑室内注射该拮抗剂则不会影响血压。失血性休克大鼠的血液会使正常大鼠出现低血压，这种情况可被SR141716A预防，但不能通过抑制受体大鼠的一氧化氮合酶来预防。失血性休克大鼠的巨噬细胞和血小板可在正常血压受体中引发CB1受体介导的低血压，并将花生四烯酸或乙醇胺整合到一种在反相高效液相色谱上与花生四烯乙醇胺共洗脱的产物中。此外，经离子霉素或细菌磷脂酶D刺激的对照大鼠巨噬细胞会产生花生四烯乙醇胺，这已通过气相色谱和质谱鉴定。这些发现表明，外周CB1大麻素受体的激活会导致失血性低血压，巨噬细胞产生的花生四烯乙醇胺可能是这种效应的介质。
