苯二氮革类对尾加压素Ⅱ诱发大鼠大脑皮层切片去甲上腺素释放的影响

背景尾加压素Ⅱ（Urotensin-Ⅱ，UⅡ）及其受体（UT）与精神状态、情绪失调有关（如紧张和焦虑），其作用部分与大脑皮层去甲肾上腺素释放增加有关。苯二氮革类药物产生催眠和抗焦虑作用，减少大脑皮层去甲肾上腺素的释放。因此，我们假设苯二氮革类和UⅡ在大脑皮层存在一定的相互作用。方法本研究中，我们检测苯二氮革类对大鼠大脑皮层切片UⅡ诱发去甲肾上腺素释放的影响以及对大鼠含UT受体的HEK293细胞内（HEK293-rUTcells）Ca2＋（[Ca2＋]i）浓度的影响。结果咪达唑仑、地西泮和氟硝西泮均可浓度依赖地抑制UⅡ诱发去甲肾上腺素的释放，但对[Ca2＋]i浓度无影响。咪达唑仑抑制UⅡ诱发的去甲肾上腺素释放的IC50（0．32CM，P〈0．01），显著低于地西泮（187μM）和氟硝西泮（40μM）。咪达唑仑对UⅡ诱发的去甲肾上腺素释放的抑制作可被苯二氮革类的拮抗剂氟马西尼显著减弱。结论目前研究表明，临床剂量下的咪达唑仑可以显著抑制UII诱发的去甲肾上腺素释放。这种抑制作用，部分地受中枢苯二氮革类受体的调节。

BACKGROUND： Urotensin Ⅱ （UⅡ ） and its receptor （UT） are implicated in mood disorders, such as stress and anxiety, and this may resuk, at least in part, from increased norepinephrine release from the cerebral cortex. Benzodiazepines have been widely used as hypnotics and anxiolytics, producing a decrease in cerebrocortical norepinephrine release. We hypothesized that there was some interaction between benzodiazepines and the UⅡ system in the cerebral cortex. METHODS： In the present study, we have examined the effects of benzodiazepines on UⅡ -increased norepinephrine release from rat cerebrocortical slices and intraceUular Ca2 ＋ concentrations （ [ Ca2＋] i） in HEK293 cells expressing rat UT receptor （HEI（293-rUT cells）. RESULTS： Midazolam, diazepam and flunitrazepam concentration-dependently inhibited U Ⅱ-evoked norepinephrine release but did not affect [ Ca2＋ ] i. The IC50 of midazolam for inhibition of U Ⅱ -evoked norepinephrine release （0. 32 μM, P 〈 0. 01 ） was significantly lower than that of diazepam （187 μM） or flunitrazepam （40 μM）. The inhibitory effects of midazolam on UⅡ -evoked norepinephrine release were significantly attenuated by flumazenil, a benzodiazepine site antagonist. CONCLUSION： The present study suggests that midazolam, at clinically relevant concentration, significantly inhibited U II -evoked norepinephrine release. This inhibitory effect may be partially mediated via central benzodiazepine receptors.