ANTIISCHEMIC EFFICACY OF A NITRIC-OXIDE SYNTHASE INHIBITOR AND A N-METHYL-D-ASPARTATE RECEPTOR ANTAGONIST IN MODELS OF TRANSIENT AND PERMANENT FOCAL CEREBRAL-ISCHEMIA
ANTIISCHEMIC EFFICACY OF A NITRIC-OXIDE SYNTHASE INHIBITOR AND A N-METHYL-D-ASPARTATE RECEPTOR ANTAGONIST IN MODELS OF TRANSIENT AND PERMANENT FOCAL CEREBRAL-ISCHEMIA
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DOI：
10.1111/j.1476-5381.1994.tb16201.x
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发表时间：
1994-09-01
影响因子：
7.3
通讯作者：
MACRAE, IM
中科院分区：
文献类型：
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作者：
DAWSON, DA;GRAHAM, DI;MACRAE, IM
1 我们最近通过在左侧大脑中动脉 (MCA) 局部应用内皮素-1，开发了一种新的大鼠短暂性局灶性缺血模型。为了验证这种方法，本研究评估了 NMDA 受体拮抗剂地佐西平 (MK-801) 在内皮素-1 模型中的神经保护功效。随后评估一氧化氮 (NO) 合酶抑制剂 N-G-硝基-L-精氨酸甲酯 (L-NAME) 的抗缺血功效，并与其对抗永久性局灶性缺血的功效进行对比，以确定内皮素-1 模型在识别新型药物保护剂方面的效用。2 MK-801（0.12 mg kg(-1) 推注，108 mu g kg(-1)h(-1) 输注）静脉注射，短暂性 MCA 闭塞 (MCAO) 前 1 或 2.5 小时引起的低血压持续约 1.5 小时，因此 1 小时组中 MCAO 时的平均动脉血压 (MABP) 显着低于对照组（MABP：生理盐水为 86 +/- 11、68 +/- 6 和 84 +/- 4 mmHg（平均值 +/- s.d.），分别为 1 小时 MK-801 和 2.5 小时 MK-801 组）。 2.5 小时预处理方案导致半球损伤体积显着减少 (71%)（缺血发作 4 小时后评估），而 1 小时预处理方案则没有（半球损伤体积：生理盐水、1 小时和 2.5 小时 MK-801 组为 59 +/- 38、51 +/- 51 和 17 +/- 28 mm(3)）3。 MK-801 在短暂性局灶性脑缺血的内皮素-1 模型中具有显着的神经保护作用，对药物引起的低血压高度敏感。这一结果与之前对永久性 MCAO 的研究形成鲜明对比，其中 MK-801 诱导的低血压并未损害其神经保护作用。4 L-NAME（3 mg kg(-1)，MCAO 前 30 分钟静脉注射）适度但显着地减少了永久性 MCA 闭塞后 4 小时的缺血损伤体积 (16%)，而在短暂性局灶性缺血模型中实现的损伤体积减少 29% 并未达到显着效果。由于与该模型相关的更大的可变性。 L-NAME 在任一模型中均未显着改变 MABP。5 通过抑制 NO 合酶实现的适度神经保护表明，NO 作为永久性局灶性脑缺血后神经毒性的介质，其重要性相对较小。此外，L-NAME 对短暂性局灶性缺血的类似功效表明，再灌注的存在不会增强 NO 对局灶性缺血损伤后急性期（4 小时）神经元损伤的贡献。
1 We have recently developed a new model of transient focal ischaemia in the rat utilising topical application of endothelin-1 to the left middle cerebral artery (MCA). In order to validate this approach the present study assessed the neuroprotective efficacy of the NMDA receptor antagonist dizocilpine (MK-801) in the endothelin-1 model. The anti-ischaemic efficacy of the nitric oxide (NO) synthase inhibitor N-G-nitro-L-arginine methyl ester (L-NAME) was subsequently evaluated, and contrasted with its efficacy against permanent focal ischaemia, to determine the utility of the endothelin-1 model for identification of novel pharmacoprotective agents.2 MK-801 (0.12 mg kg(-1) bolus, 108 mu g kg(-1)h(-1) infusion i.v., either 1 or 2.5 h pre-transient MCA occlusion (MCAO)) induced hypotension that persisted for approximately 1.5 h so that mean arterial blood pressure (MABP) at the time of MCAO was significantly lower in the 1 h group compared with control (MABP: 86 +/- 11, 68 +/- 6 and 84 +/- 4 mmHg (mean +/- s.d.) for saline, 1 h MK-801 and 2.5 h MK-801 groups respectively). The 2.5 h pretreatment schedule resulted in significant reduction (71%) in the volume of hemispheric damage (assessed 4 h post onset of ischaemia) while the 1 h pretreatment schedule did not (volumes of hemispheric damage: 59 +/- 38, 51 +/- 51 and 17 +/- 28 mm(3) for saline, 1 h and 2.5 h MK-801 groups).3 Thus the considerable neuroprotective effect of MK-801 in the endothelin-1 model of transient focal cerebral ischaemia was highly sensitive to drug-induced hypotension. This result is in contrast to previous studies of permanent MCAO where MK-801-induced hypotension did not compromise its neuroprotective action.4 L-NAME (3 mg kg(-1), i.v. 30 min pre-MCAO) moderately, but significantly, reduced (16%) the volume of ischaemic damage 4 h post-permanent MCA occlusion, whereas the 29% reduction in volume of damage achieved in the model of transient focal ischaemia did not attain significance due to the greater variability associated with this model. L-NAME did not significantly alter MABP in either model.5 The modest neuroprotection achieved with NO synthase inhibition suggests NO is of relatively minor importance as a mediator of neurotoxicity following permanent focal cerebral ischaemia. In addition the comparable efficacy of L-NAME against transient focal ischaemia suggests the presence of reperfusion does not enhance the contribution of NO to neuronal injury in the acute (4 h) phase following a focal ischaemic insult.