Phillis J W, Smith-Barbour M, Perkins L M, O'Regan M H
Department of Physiology, School of Medicine, Wayne State University, Detroit, MI 48201.
Brain Res Bull. 1994;34(5):457-66. doi: 10.1016/0361-9230(94)90019-1.
The purpose of this study was to evaluate potential mechanisms of ischemia-evoked amino acid transmitter release. Changes in extracellular levels of transmitter amino acids and lactic acid dehydrogenase (LDH) in rat cerebral cortex during and following four-vessel occlusion elicited global cerebral ischemia were examined using a cortical cup technique. Ischemia-evoked release of glutamate, aspartate and gamma-amino-butyric acid (GABA) was compared in control vs. drug-treated animals. Tetrodotoxin and antagonists of glutamate receptors (DNQX, MK-801, and AP-3) depressed the initial rate of increase in extracellular glutamate and aspartate without altering the total amount of these amino acids collected in the cortical superfusates. Cobalt, a calcium channel antagonist, failed to alter efflux. Acidic amino acid transport inhibitors (dihydrokainate, L-trans-PDC) depressed the rate of onset of glutamate and aspartate release and dihydrokainate depressed total release by 44%. PD 81723, an allosteric enhancer at the A1 adenosine receptor, depressed glutamate efflux, as did L-NAME, an inhibitor of nitric oxide synthase. Extracellular increases in GABA levels were depressed by tetrodotoxin and L-trans-PDC. The GABA transport inhibitor, nipecotic acid, increased the initial rate of onset of GABA release. Increases in LDH levels in the extracellular fluid became apparent during the period of ischemia and continued to increase during the subsequent 90 min of reperfusion. These results suggest that ischemia evokes a release of neurotransmitter amino acids that is only partially dependent upon Ca2+ influx activation or the reversal of amino acid transporters. Nonselective mechanisms, resulting from the disruption of plasma membrane integrity, may contribute significantly to the total ischemia-evoked release of excitatory amino acids.
本研究的目的是评估缺血诱发氨基酸递质释放的潜在机制。采用皮质杯技术，检测了四动脉闭塞诱发全脑缺血期间及之后大鼠大脑皮质中递质氨基酸和乳酸脱氢酶（LDH）细胞外水平的变化。比较了对照动物与药物处理动物中缺血诱发的谷氨酸、天冬氨酸和γ-氨基丁酸（GABA）的释放情况。河豚毒素和谷氨酸受体拮抗剂（DNQX、MK-801和AP-3）可降低细胞外谷氨酸和天冬氨酸的初始增加速率，但不改变皮质灌流液中收集的这些氨基酸的总量。钙通道拮抗剂钴未能改变流出。酸性氨基酸转运抑制剂（二氢海因酸、L-反式-2,4-二氨基丁酸）降低了谷氨酸和天冬氨酸释放的起始速率，二氢海因酸使总释放量降低了44%。A1腺苷受体的变构增强剂PD 81723以及一氧化氮合酶抑制剂L-NAME均可降低谷氨酸流出。河豚毒素和L-反式-2,4-二氨基丁酸可降低细胞外GABA水平的升高。GABA转运抑制剂尼克酸增加了GABA释放的初始起始速率。细胞外液中LDH水平的升高在缺血期间变得明显，并在随后的90分钟再灌注期间持续升高。这些结果表明，缺血诱发神经递质氨基酸的释放，该释放仅部分依赖于Ca2+内流激活或氨基酸转运体的逆转。由质膜完整性破坏导致的非选择性机制可能对兴奋性氨基酸的总缺血诱发释放有显著贡献。
