ROLE OF NITRIC OXIDE IN PATHOGENESIS UNDERLYING ISCHEMIC BRAIN DAMAGE

本研究旨在探讨缺血性脑损伤是否可能通过脑组织中一氧化氮的过度产生而发生。首先，使用新设计的微型传感器直接测量大鼠脑内一氧化氮的浓度。在MCAO后15-20分钟，患侧大脑半球出现大量的一氧化氮产生(约2-3个摩尔)，然后恢复到基线水平。MCAO后3小时，一氧化氮水平再次高于基线水平。缺血前给予LNA(Nomega-Nitro-L-Arg，1 mg/kg，已有报道该剂量可有效预防大鼠大脑中动脉闭塞后的缺血性脑水肿)可抑制上述两种现象，并显著阻断缺血性脑水肿。其次，通过对大脑中动脉阻塞大鼠大脑半球MVs钙离子依赖性和非依赖性一氧化氮合酶活性的时序学研究，发现钙离子依赖性一氧化氮合酶首次被激活，是其…活性的10倍。MCAO后即刻有更多的基线值。在MCAO后4小时，钙离子非依赖性一氧化氮合酶被显著激活(为基线值的9倍，P&lt；0.01vs.对照组)。在MCAO后48,168小时，钙依赖的一氧化氮合酶被再次激活(是基础值的3倍，P<0.01，与对照组相比)。第三，LNA对大脑中动脉阻塞后脑含水量的影响。结果表明，在MCAO后72小时，反复腹腔注射0.01~1 mg/kg的LNA可有效地防止脑含水量的增加。本研究提示，脑缺血后MVS产生高浓度的一氧化氮，LNA对脑MVS中这两种类型的一氧化氮合酶均有抑制作用，可能有助于预防缺血性脑水肿的发生。本研究首次提供了两种不同类型的一氧化氮合酶被激活并参与缺血性脑损伤发病机制的证据，证明一氧化氮合酶的完全抑制是不必要的。较少

The present study aimed at examining whether ischemic brain damage might develop mediated via a postischemic overproduction of nitric oxide in the brain tissue.First, concentration of nitric oxide in the rat brain was directly measured, using newly devised microsensor. The exaggerated production (ca. 2-3 mumol) of nitric oxide was appeared in the affected hemisphere 15-20 minutes after MCAo and then reversed to the baseline. Three hours after MCAo, nitric oxide was yielded again over the baseline. The preischemic administration of LNA (Nomega-nitro-L-arginine, 1mg/kg, It is already reported that this dose is effective for prevention of ischemic brain edema following MCAo in rats) inhibited both of the above phenomena and ischemic brain edema was significantly blocked. Second, from the chronological study of Ca2^+-dependent and -independent NOS activity of cerebral MVs obtained from the affected hemisphere of the MCAo rats, Ca2^+-dependent NOS was first activated 10 times more than its … More baseline value immediately after MCAo. At 4 hours after MCAo, Ca2^+-independent NOS (9 times of the baseline value, p<0.01 vs.control) was siginifcantly activated (p<0.01 vs.control). At 48,168 hr after MCAo, in place of Ca2^+-independent, Ca2^+-dependent NOS was activated again (3 times of the baseline value, p<0.01 vs.control).Third, effects of LNA on brain water content subjected to MCAo was examined. it was elucidated that repeated intraperitoneal injection of 0.01 to 1mg/kg LNA found to be effective for prevention of increase in brain water content, 72 hours after MCAo.The present study suggested that the ischemic brain is always subjected to high-concentrated nitric oxide, yielded from cerebral MVs and that adequate inhibition of both type of NOS in cerebral MVs by LNA might be beneficial for prevention of ischemic brain edema. The present study provided the first evidence that two distinct types of NOSs were activated and involved in the pathogenesis of ischemic brain damage and that a total inhibition of NOS is not required. Less