Sakashita N, Ando Y, Yonehara T, Tanaka Y, Sato K, Uchino M, Ando M
First Department of Internal Medicine, Kumamoto University School of Medicine, Japan.
Biochim Biophys Acta. 1994 Oct 21;1227(1-2):67-73. doi: 10.1016/0925-4439(94)90108-2.
To elucidate the critical role of superoxide dismutase (SOD) and nitric oxide in brain injury and systemic circulation during brain ischemia, we performed bilateral carotid artery ligation (BCAL) on rats and evaluated the effects of NG-monomethyl-L-arginine (L-NMMA) and a long-acting SOD derivative (SMA-SOD). After administration of L-NMMA, specific inhibitor against nitric oxide synthase (NOS), most of BCAL rats died within 6 h while no BCAL rats without L-NMMA died at all. Administration of SMA-SOD exhibited no effect on the life span of BCAL rats. Magnetic resonance imaging (MRI) and microscopic analysis for the ischemic brain revealed that, although administration of L-NMMA showed no significant effect on the ischemic brain of BCAL rats, SMA-SOD effectively prevented the ischemic changes based on permeability edema in the frontal lobe. Measurement of changes in the blood flow of the ischemic brain revealed that administration of L-NMMA decreased the blood flow in the BCAL rats while no remarkable changes were seen after administration of SMA-SOD. Urinary secretion of NO2-/NO3-, the metabolites of nitric oxide, was increased by challenging BCAL, and the presence of L-NMMA or SMA-SOD diminished this elevation. Blood pressure was increased by performing BCAL to rats, and administration of L-NMMA showed further elevation of the blood pressure. On the contrary, administration of SMA-SOD decreased post-ischemic hypertension. These results suggest that SOD may play a protective role for brain ischemia by suppressing increased vascular permeability, while nitric oxide showed beneficial effect on the ischemic brain by increasing the blood flow in the ischemic brain.
为阐明超氧化物歧化酶（SOD）和一氧化氮在脑缺血期间脑损伤及全身循环中的关键作用，我们对大鼠进行双侧颈动脉结扎（BCAL），并评估了N-单甲基-L-精氨酸（L-NMMA）和一种长效SOD衍生物（SMA-SOD）的作用。给予一氧化氮合酶（NOS）特异性抑制剂L-NMMA后，大多数BCAL大鼠在6小时内死亡，而未给予L-NMMA的BCAL大鼠无一死亡。给予SMA-SOD对BCAL大鼠的寿命无影响。对缺血脑进行磁共振成像（MRI）和显微镜分析显示，虽然给予L-NMMA对BCAL大鼠的缺血脑无显著影响，但SMA-SOD有效预防了基于额叶通透性水肿的缺血性变化。测量缺血脑血流变化发现，给予L-NMMA可使BCAL大鼠的血流减少，而给予SMA-SOD后未见明显变化。BCAL可使一氧化氮代谢产物NO2-/NO3-的尿分泌增加，而L-NMMA或SMA-SOD的存在可减轻这种升高。对大鼠进行BCAL可使血压升高，给予L-NMMA可使血压进一步升高。相反，给予SMA-SOD可降低缺血后高血压。这些结果表明，SOD可能通过抑制血管通透性增加对脑缺血发挥保护作用，而一氧化氮通过增加缺血脑血流对缺血脑产生有益影响。
