Wagner J A, Járai Z, Bátkai S, Kunos G
Department of Pharmacology and Toxicology, Medical College of Virginia, Richmond, VA 23298, USA.
Eur J Pharmacol. 2001 Jul 6;423(2-3):203-10. doi: 10.1016/s0014-2999(01)01112-8.
Activation of peripheral cannabinoid CB(1) receptors elicits hypotension. Using the radioactive microsphere technique, we examined the effects of cannabinoids on systemic hemodynamics in anesthetized rats. The potent cannabinoid CB(1) receptor agonist HU-210 ([-]-11-OH-Delta(9) tetrahydrocannabinol dimethylheptyl, 10 microg/kg i.v.) reduced mean blood pressure by 57+/-5 mm Hg by decreasing cardiac index from 37+/-1 to 23+/-2 ml/min/100 g (P<0.05) without significantly affecting systemic vascular resistance index. HU-210 elicited a similar decrease in blood pressure following ganglionic blockade and vasopressin infusion. The endogenous cannabinoid anandamide (arachidonyl ethanolamide, 4 mg/kg i.v.) decreased blood pressure by 40+/-7 mm Hg by reducing systemic vascular resistance index from 3.3+/-0.1 to 2.3+/-0.1 mm Hg min/ml/100 g (P<0.05), leaving cardiac index and stroke volume index unchanged. HU-210, anandamide, and its metabolically stable analog, R-methanandamide, lowered vascular resistance primarily in the coronaries and the brain. These vasodilator effects remained unchanged when autoregulation was prevented by maintaining blood pressure through volume replacement, but were prevented by pretreatment with the cannabinoid CB(1) receptor antagonist SR141716A (N-[piperidin-1-yl]-5-[4-chlorophenyl]-1-[2,4-dichlorophenyl]-4-methyl-1H-pyrazole-3-carboxamide HCl; 3 mg/kg i.v.). Only anandamide and R-methanandamide were vasodilators in the mesentery. We conclude that cannabinoids elicit profound coronary and cerebral vasodilation in vivo by direct activation of vascular cannabinoid CB(1) receptors, rather than via autoregulation, a decrease in sympathetic tone or, in the case of anandamide, the action of a non-cannabinoid metabolite. Differences between the hemodynamic profile of various cannabinoids may reflect quantitative differences in cannabinoid CB(1) receptor expression in different tissues and/or the involvement of as-yet-unidentified receptors.
外周大麻素CB(1)受体的激活会引发低血压。我们使用放射性微球技术，研究了大麻素对麻醉大鼠全身血流动力学的影响。强效大麻素CB(1)受体激动剂HU-210（[-]-11-羟基-Δ(9)四氢大麻酚二甲基庚基，静脉注射10微克/千克）通过将心脏指数从37±1降至23±2毫升/分钟/100克，使平均血压降低了57±5毫米汞柱（P<0.05），而对全身血管阻力指数没有显著影响。在进行神经节阻断和输注血管加压素后，HU-210引起了类似的血压下降。内源性大麻素花生四烯酸乙醇胺（静脉注射4毫克/千克）通过将全身血管阻力指数从3.3±0.1降至2.3±0.1毫米汞柱·分钟/毫升/100克，使血压降低了40±7毫米汞柱（P<0.05），而心脏指数和每搏量指数保持不变。HU-210、花生四烯酸乙醇胺及其代谢稳定类似物R-甲酰基花生四烯酸乙醇胺主要使冠状动脉和脑血管阻力降低。当通过补液维持血压来防止自身调节时，这些血管舒张作用保持不变，但在预先使用大麻素CB(1)受体拮抗剂SR141716A（N-[哌啶-1-基]-5-[4-氯苯基]-1-[2,4-二氯苯基]-4-甲基-1H-吡唑-3-甲酰胺盐酸盐；静脉注射3毫克/千克）后，这些作用被阻止。只有花生四烯酸乙醇胺和R-甲酰基花生四烯酸乙醇胺在肠系膜中是血管舒张剂。我们得出结论，大麻素通过直接激活血管大麻素CB(1)受体在体内引起深刻的冠状动脉和脑血管舒张，而不是通过自身调节、交感神经张力降低，或者就花生四烯酸乙醇胺而言，不是通过非大麻素代谢物的作用。各种大麻素血流动力学特征的差异可能反映了不同组织中大麻素CB(1)受体表达的定量差异和/或尚未确定的受体的参与。
