Adenosine modulates N-methyl-D-aspartate-stimulated hippocampal nitric oxide production in vivo.
Adenosine modulates N-methyl-D-aspartate-stimulated hippocampal nitric oxide production in vivo.
复制标题
DOI：
10.1161/01.str.26.9.1627
复制
发表时间：
1995-09
期刊：
影响因子：
8.3
通讯作者：
A. Bhardwaj;F. Northington;R. Koehler;Theodore H. Stiefel;D. Hanley;R. Traystman
中科院分区：
文献类型：
--
作者：
A. Bhardwaj;F. Northington;R. Koehler;Theodore H. Stiefel;D. Hanley;R. Traystman
背景和目的腺苷在突触前抑制兴奋性氨基酸（EAA）的释放，因此被认为是神经保护性的。由于EAA刺激的一氧化氮（NO）的合成可能在长时程增强和兴奋性毒性介导的损伤中发挥重要作用，我们测试了腺苷激动剂在体内减弱基础和EAA诱导的海马NO产生以及腺苷A1受体介导这种反应的假设。方法在戊巴比妥钠麻醉下，将微透析探针置于成年SD大鼠海马CA 3区。用含3 μ mol/L [14 C] L-精氨酸的人工脑脊液灌注探针5小时。回收的[14 C] L-瓜氨酸在流出物中被用作NO生产的标志。在10组大鼠中，比较了用N-甲基-D-天冬氨酸（NMDA）、腺苷激动剂、腺苷拮抗剂和NO合成酶抑制剂N ω-硝基-L-精氨酸甲酯（L-NAME）的各种组合灌注的右侧和左侧探针之间[14 C] L-瓜氨酸恢复的时间依赖性增加。结果：在人工脑脊液灌注期间，[14 C] L-瓜氨酸的回收率在5小时内逐渐增加至141 +/- 27 fmol/min（+/- SEM）。用1 mmol/L NMDA灌注侧外侧可使[14 C] L-瓜氨酸的恢复增加到317 +/- 62 fmol/min。与单独使用NMDA相比，用1 mmol/L L-NAME灌注NMDA可抑制[14 C] L-瓜氨酸的恢复。用0.1 mmol/L 2-氯腺苷灌注减弱了基础和NMDA增强的[14 C] L-瓜氨酸恢复。2-氯腺苷的这种作用可被0.1mmol/L的A1受体拮抗剂8-环戊基-1，3-二丙基黄嘌呤逆转。输注0.1 mmol/L（2S）-N6-[2-endo-norboryl]腺苷（一种特异性A1受体激动剂）也减弱了0.1 mmol/L和1 mmol/L NMDA增强的[14 C] L-瓜氨酸恢复。结论：使用间接方法评估体内NO产生，这些数据与体外结果一致，表明NMDA受体刺激增强NO产生。此外，我们得出的结论是，刺激A1受体可以减弱基础NO和NMDA诱导的NO产生。由于NMDA受体刺激会放大谷氨酸释放，因此我们的数据与突触前A1受体介导的EAA释放抑制以及随后的NO产生下调是一致的。
BACKGROUND AND PURPOSE Adenosine acts presynaptically to inhibit release of excitatory amino acids (EAAs) and is thus considered to be neuroprotective. Because EAA-stimulated synthesis of nitric oxide (NO) may play an important role in long-term potentiation and excitotoxic-mediated injury, we tested the hypotheses that adenosine agonists attenuate basal and EAA-induced NO production in the hippocampus in vivo and that adenosine A1 receptors mediate this response. METHODS Microdialysis probes were placed bilaterally into the CA3 region of the hippocampus of adult Sprague-Dawley rats under pentobarbital anesthesia. Probes were perfused for 5 hours with artificial cerebrospinal fluid containing 3 mumol/L [14C]L-arginine. Recovery of [14C]L-citrulline in the effluent was used as a marker of NO production. In 10 groups of rats, time-dependent increases in [14C]L-citrulline recovery were compared between right- and left-sided probes perfused with various combinations of N-methyl-D-aspartate (NMDA), adenosine agonists, adenosine antagonists, and the NO synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME). RESULTS Recovery of [14C]L-citrulline during perfusion with artificial cerebrospinal fluid progressively increased to 141 +/- 27 fmol/min (+/- SEM) over 5 hours. Contralateral perfusion with 1 mmol/L NMDA augmented [14C]L-citrulline recovery to 317 +/- 62 fmol/min. Perfusion of 1 mmol/L L-NAME with NMDA inhibited [14C]L-citrulline recovery compared with NMDA alone. Perfusion with 0.1 mmol/L 2-chloroadenosine attenuated basal as well as NMDA-enhanced [14C]L-citrulline recovery. This action of 2-chloroadenosine was reversed by infusion of 0.1 mmol/L 8-cyclopentyl-1,3-dipropylxanthine, a specific A1 receptor antagonist. Infusion of 0.1 mmol/L (2S)-N6-[2-endo-norboryl]adenosine, a specific A1 receptor agonist, also attenuated the 0.1 mmol/L and 1 mmol/L NMDA-enhanced [14C]L-citrulline recovery. CONCLUSIONS Using an indirect method of assessing NO production in vivo, these data are consistent with in vitro results showing that NMDA receptor stimulation enhances NO production. Furthermore, we conclude that stimulation of A1 receptors can attenuate the basal as well as NMDA-induced production of NO. Because NMDA receptor stimulation amplifies glutamate release, our data are consistent with presynaptic A1 receptor-mediated inhibition of EAA release and consequent downregulation of NO production.