Delaney S M, Shepel P N, Geiger J D
Department of Pharmacology and Therapeutics, University of Manitoba Faculty of Medicine, Winnipeg, Canada.
J Pharmacol Exp Ther. 1998 May;285(2):561-7.
Glutamate release after ischemia, hypoxia and seizure activity plays an important role in stimulating adenosine production and release. We characterized the ionotropic glutamate receptor subtype that regulates adenosine levels in vivo and investigated the role of nitric oxide and free radicals in mediating N-methyl-D-aspartate (NMDA)-induced increases in adenosine levels. Rats received unilateral intrastriatal injections and were sacrificed 15 min postinjection by high-energy focused microwave irradiation (10 kW, 1.25 s). Adenosine levels were measured by high-performance liquid chromatography in ipsilateral and contralateral striata. NMDA and kainic acid dose-dependently increased levels of adenosine whereas (+/-)-alpha-amino-3-hydroxy-5-methyl-4-isoxazol proprionic acid had no effect. The NMDA- and kainic acid-induced increases were blocked by dizocilpine, and the kainic acid response was decreased by 6-cyano-7-nitroquinoxaline-2,3-dione. The effects of NMDA and kainic acid on levels of adenosine were not additive. Intrastriatal L-arginine decreased, and the nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester, increased basal adenosine levels. Coadministration of NMDA with L-arginine or NG-nitro-L-arginine methyl ester did not significantly affect NMDA-induced increases in levels of adenosine. N-Tert-butyl-phenylnitrone, a free radical scavenger, reversed L-arginine-induced decreases and NMDA-induced increases in levels of adenosine. Together, these results indicate that NMDA-type ionotropic receptors play an important role in regulating in vivo levels of adenosine in rat striatum and that free radicals, but not nitric oxide, apparently are involved in NMDA-induced increases in levels of adenosine. Conversely, nitric oxide, but not free radicals, apparently exert tonic control over basal levels of endogenous adenosine.
缺血、缺氧及癫痫活动后谷氨酸的释放，在刺激腺苷生成和释放过程中发挥重要作用。我们对体内调节腺苷水平的离子型谷氨酸受体亚型进行了特性分析，并研究了一氧化氮和自由基在介导N-甲基-D-天冬氨酸（NMDA）诱导的腺苷水平升高过程中的作用。给大鼠进行单侧纹状体内注射，注射后15分钟通过高能聚焦微波辐射（10千瓦，1.25秒）处死大鼠。采用高效液相色谱法测定同侧和对侧纹状体中的腺苷水平。NMDA和 kainic 酸剂量依赖性地增加腺苷水平，而（±）-α-氨基-3-羟基-5-甲基-4-异恶唑丙酸则无此作用。地卓西平可阻断NMDA和 kainic 酸诱导的升高，6-氰基-7-硝基喹喔啉-2,3-二酮可降低 kainic 酸反应。NMDA和 kainic 酸对腺苷水平的影响并非相加性的。纹状体内注射L-精氨酸可降低腺苷水平，而一氧化氮合酶抑制剂N-硝基-L-精氨酸甲酯则可提高基础腺苷水平。NMDA与L-精氨酸或N-硝基-L-精氨酸甲酯共同给药，对NMDA诱导的腺苷水平升高无显著影响。自由基清除剂N-叔丁基苯硝酮可逆转L-精氨酸诱导的腺苷水平降低以及NMDA诱导的腺苷水平升高。这些结果共同表明，NMDA型离子型受体在调节大鼠纹状体中腺苷的体内水平方面发挥重要作用，并且自由基而非一氧化氮显然参与了NMDA诱导的腺苷水平升高。相反，一氧化氮而非自由基显然对内源性腺苷的基础水平发挥着紧张性控制作用。
