Shimizu Takahiro, Tanaka Kenjiro, Nakamura Kumiko, Taniuchi Keisuke, Yawata Toshio, Higashi Youichirou, Ueba Tetsuya, Dimitriadis Fotios, Shimizu Shogo, Yokotani Kunihiko, Saito Motoaki
Department of Pharmacology, Kochi University School of Medicine, Nankoku, Kochi 783-8505, Japan.
Department of Pharmacology, Kochi University School of Medicine, Nankoku, Kochi 783-8505, Japan.
Neuropharmacology. 2014 Jul;82:19-27. doi: 10.1016/j.neuropharm.2014.03.005. Epub 2014 Mar 19.
We recently reported that intracerebroventricularly administered 2-arachidonoylglycerol elevated plasma noradrenaline and adrenaline by brain monoacylglycerol lipase- (MGL) and cyclooxygenase-mediated mechanisms in the rat. These results suggest that 2-arachidonoylglycerol is hydrolyzed by MGL to free arachidonic acid, which is further metabolized to prostaglandins (PGs) by cyclooxygenase in the brain, thereby elevating plasma noradrenaline and adrenaline. On the other hand, 2-arachidonoylglycerol can be also metabolized by cyclooxygenase to PG glycerol esters (PG-Gs), which seems to be hydrolyzed by MGL to free PGs. Here, we examined the involvement of brain PG-Gs in the elevation of plasma noradrenaline and adrenaline regarding PGE2-G and prostanoid EP receptors using anesthetized male Wistar rats. Intracerebroventricularly administered PGE2-G (1.5 and 3 nmol/animal) dose-dependently elevated plasma noradrenaline but not adrenaline. PGE2-G also elevated systolic, mean and diastolic blood pressure and heart rate. The PGE2-G-induced elevation of plasma noradrenaline was attenuated by JZL184 (MGL inhibitor). Intracerebroventricularly administered PGE2 (0.3 and 1.5 nmol/animal) and sulprostone (0.1 and 0.3 nmol/animal) (EP1/EP3 agonist) also elevated plasma noradrenaline but not adrenaline in a dose-dependent manner. The sulprostone-induced elevation was attenuated by L-798,106 (EP3 antagonist), but not by SC-51322 (EP1 antagonist). L-798,106 also attenuated the PGE2-G- and PGE2-induced elevation of plasma noradrenaline, while PF-04418948 (EP2 antagonist) and L-161,982 (EP4 antagonist) had no effect on the PGE2-G-induced response. These results suggest a possibility that brain PGE2-G produced from 2-arachidonoylglycerol can be hydrolyzed to free PGE2, thereby activating central sympathetic outflow by brain prostanoid EP3 receptor-mediated mechanisms in the rat.
我们最近报道，在大鼠中，脑室内注射2-花生四烯酸甘油酯可通过脑单酰甘油脂肪酶（MGL）和环氧化酶介导的机制升高血浆去甲肾上腺素和肾上腺素。这些结果表明，2-花生四烯酸甘油酯被MGL水解为游离花生四烯酸，后者在脑中被环氧化酶进一步代谢为前列腺素（PGs），从而升高血浆去甲肾上腺素和肾上腺素。另一方面，2-花生四烯酸甘油酯也可被环氧化酶代谢为PG甘油酯（PG-Gs），而PG-Gs似乎被MGL水解为游离PGs。在此，我们使用麻醉的雄性Wistar大鼠，研究了脑PG-Gs在PGE2-G和前列腺素EP受体介导的血浆去甲肾上腺素和肾上腺素升高过程中的作用。脑室内注射PGE2-G（1.5和3 nmol/只动物）剂量依赖性地升高血浆去甲肾上腺素，但不升高肾上腺素。PGE2-G还升高收缩压、平均血压和舒张压以及心率。JZL184（MGL抑制剂）可减弱PGE2-G诱导的血浆去甲肾上腺素升高。脑室内注射PGE2（0.3和1.5 nmol/只动物）和舒前列素（0.1和0.3 nmol/只动物）（EP1/EP3激动剂）也剂量依赖性地升高血浆去甲肾上腺素，但不升高肾上腺素。L-798,106（EP3拮抗剂）可减弱舒前列素诱导的升高，但SC-51322（EP1拮抗剂）则无此作用。L-798,106也可减弱PGE2-G和PGE2诱导的血浆去甲肾上腺素升高，而PF-04418948（EP2拮抗剂）和L-161,982（EP4拮抗剂）对PGE2-G诱导的反应无影响。这些结果提示，2-花生四烯酸甘油酯产生的脑PGE2-G可能被水解为游离PGE2，从而通过大鼠脑中前列腺素EP3受体介导的机制激活中枢交感神经输出。
