Zhang F, Iadecola C
Department of Neurology, University of Minnesota, Minneapolis 55455, USA.
Brain Res. 1998 Aug 17;802(1-2):104-10. doi: 10.1016/s0006-8993(98)00557-5.
We investigated the temporal profile of the reduction in focal cerebral ischemic damage exerted by aminoguanidine (AG), an inhibitor of inducible nitric oxide synthase (iNOS). In anesthetized spontaneously hypertensive rats, the middle cerebral artery (MCA) was occluded distal to the origin of the lenticulostriate arteries. Rats were treated with vehicle (saline) or AG (100 mg kg-1, i.p.) immediately after MCA occlusion and, thereafter, two times per day. Rats were sacrificed 1(n = 7), 2(n = 8), 3 (n = 6) or 4 days (n = 5) after MCA occlusion. Injury volume (mm3) was determined in thionin-stained sections using an image analyzer. Volumes were corrected for ischemic swelling. Administration of AG up to 2 days after MCA occlusion did not reduce cerebral ischemic damage (p < 0.05 from vehicle; t-test). Treatment for a longer period decreased injury volume, the reduction averaging 21 +/- 5% at 3 days (p < 0.05) and 30 +/- 9% at 4 days (p < 0.05). Aminoguanidine did not affect ischemic brain swelling (p > 0.05). Administration of AG did not substantially modify arterial pressure, arterial blood gases, pH, hematocrit, plasma glucose and rectal temperature. We conclude that the protective effect of AG is time-dependent and occurs only when the drug is administered for longer than 2 days, starting after induction of ischemia. Because iNOS enzymatic activity develops more than 24 h after MCA occlusion [C. Iadecola, X. Xu, F. Zhang, E.E. El-Fakahany, M.E. Ross, Marked induction of calcium-independent nitric oxide synthase activity after focal cerebral ischemia, J. Cereb. Blood Flow, Metab. 14 (1995) 52-59; C. Iadecola, F. Zhang, X. Xu, R. Casey, M.E. Ross, Inducible nitric oxide synthase gene expression in brain following cerebral ischemia, J. Cereb. Blood Flow Metab. 15 (1995) 378-384.], the data support the hypothesis that the protective effect of AG is medicated by inhibition of iNOS in the post-ischemic brain.
我们研究了诱导型一氧化氮合酶（iNOS）抑制剂氨基胍（AG）减轻局灶性脑缺血损伤的时间进程。在麻醉的自发性高血压大鼠中，大脑中动脉（MCA）在豆纹动脉起始部远端被阻断。MCA阻断后立即用溶剂（生理盐水）或AG（100 mg/kg，腹腔注射）处理大鼠，此后每天两次。MCA阻断后1天（n = 7）、2天（n = 8）、3天（n = 6）或4天（n = 5）处死大鼠。使用图像分析仪在硫堇染色切片中测定损伤体积（mm³）。对体积进行缺血性肿胀校正。MCA阻断后2天内给予AG并未减轻脑缺血损伤（与溶剂相比，p < 0.05；t检验）。较长时间的治疗可减少损伤体积，3天时平均减少21±5%（p < 0.05），4天时平均减少30±9%（p < 0.05）。氨基胍不影响缺血性脑肿胀（p > 0.05）。给予AG对动脉血压、动脉血气、pH、血细胞比容、血浆葡萄糖和直肠温度无显著影响。我们得出结论，AG的保护作用具有时间依赖性，且仅在缺血诱导后给药超过2天时才会出现。因为iNOS酶活性在MCA阻断后24小时以上才出现[C. Iadecola，X. Xu，F. Zhang，E.E. El-Fakahany，M.E. Ross，局灶性脑缺血后钙非依赖性一氧化氮合酶活性的显著诱导，《脑血流与代谢杂志》14（1995）52 - 59；C. Iadecola，F. Zhang，X. Xu，R. Casey，M.E. Ross，脑缺血后诱导型一氧化氮合酶基因在脑中的表达，《脑血流与代谢杂志》15（1995）378 - 384。]，这些数据支持了AG的保护作用是通过抑制缺血后脑中的iNOS介导的这一假说。
