Alpha-2 Adrenoceptor Agonists Decrease Cyclic Guanosine 3',5'-Monophosphate in the Mouse Brain
Alpha-2 Adrenoceptor Agonists Decrease Cyclic Guanosine 3',5'-Monophosphate in the Mouse Brain
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DOI：
10.1097/00000542-199609000-00013
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发表时间：
1996-09
期刊：
影响因子：
8.8
通讯作者：
Y. Vulliemoz;Hong Shen;L. Virág
中科院分区：
文献类型：
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作者：
Y. Vulliemoz;Hong Shen;L. Virág
背景 在中枢神经系统神经递质中，兴奋的药物或条件会增加环鸟苷 3',5'-单磷酸 (cGMP)，这是由神经调节剂一氧化氮介导的作用，而镇静的药物或条件会降低 cGMP。挥发性麻醉剂被证明会降低小脑 cGMP，这种作用与其麻醉和抗惊厥作用相关。由于α-2肾上腺素受体激动剂具有麻醉特性，因此研究了一氧化氮-cGMP途径在α-2肾上腺素受体激动剂可乐定和右美托咪定的作用中的作用。方法 给小鼠各组腹腔注射一剂 30-600 微克/公斤可乐定，或 3-300 微克/公斤 D-美托咪定（右美托咪定）或 L-美托咪定。 α-2 肾上腺素受体拮抗剂，0.3-5 mg/kg 育亨宾或 1 mg/kg 阿替美唑，1 mg/kg α-1 拮抗剂哌唑嗪，以及 10-300 mg/kg 一氧化氮合酶抑制剂 N omega-硝基-l-精氨酸甲酯和 N omega-硝基-l-精氨酸，在治疗前 10-20 分钟给予激动剂。老鼠被聚焦到头部的微波辐射杀死。通过放射免疫测定法对不同脑区的脱蛋白提取物中的环化 GMP 进行测量。结果 可乐定和右美托咪定在镇静剂量下，剂量依赖性地降低小脑 cGMP（ED50：可乐定和右美托咪定分别为 100 和 50 微克/千克）。这种效应被育亨宾和阿替美唑抑制，但不被哌唑嗪抑制，证实了对激动剂的反应的α2性质。 L-美托咪定没有镇静/催眠作用，不会降低 cGMP。用最大剂量为 100 mg/kg 的一氧化氮合酶拮抗剂对小鼠进行预处理，消除了对激动剂的 cGMP 反应。在大脑皮层、海马和尾状核中也获得了类似的结果。结论 结果表明一氧化氮-cGMP 途径是与介导镇静作用的 α-2 肾上腺素受体耦合的效应系统。
Background In the central nervous system neurotransmitters, drugs or conditions that excite increase cyclic guanosine 3',5'-monophosphate (cGMP), an effect mediated by the neuromodulator nitric oxide, whereas those that sedate decrease cGMP. Volatile anesthetics were shown to decrease cerebellar cGMP, an effect that correlates with their anesthetic and anticonvulsant effect. Because alpha-2 adrenoceptor agonists have anesthetic properties, the role of the nitric oxide-cGMP pathway in the action of the alpha-2 adrenoceptor agonists clonidine and dexmedetomidine was investigated. Methods Groups of mice were given, intraperitoneally, one dose of either 30-600 micro gram/kg clonidine, or 3-300 micro gram/kg D-medetomidine (dexmedetomidine) or L-medetomidine. The alpha-2 adrenoceptor antagonists, 0.3-5 mg/kg yohimbine or 1 mg/kg atipamezole, 1 mg/kg of the alpha-1 antagonist prazosin, and 10-300 mg/kg of the nitric oxide synthase inhibitors, N omega-nitro-l-arginine methylester and N omega-nitro-l-arginine, were given 10-20 min before the agonist. The mice were killed by microwave radiation focused to the head. Cyclic GMP was measured by radioimmunoassay in deproteinized extracts from different brain areas. Results Clonidine and dexmedetomidine, at sedative doses, dose-dependently decreased cerebellar cGMP (ED50: 100 and 50 micro gram/kg for clonidine and dexmedetomidine, respectively). This effect was inhibited by yohimbine and atipamezole, but not by prazosin, confirming the alpha-2 nature of the response to the agonists. L-medetomidine, which has no sedative/hypnotic effect, did not decrease cGMP. Pretreatment of the mice with a maximum dose of 100 mg/kg of a nitric oxide synthase antagonist abolished the cGMP response to the agonists. Similar results were obtained in the cerebral cortex, hippocampus and caudate nucleus. Conclusions The results suggest that the nitric oxide-cGMP pathway is an effector system coupled to the alpha-2 adrenoceptor mediating sedation.