Zhang Z G, Reif D, Macdonald J, Tang W X, Kamp D K, Gentile R J, Shakespeare W C, Murray R J, Chopp M
Department of Neurology, Henry Ford Hospital, Detroit, MI 48202, USA.
J Cereb Blood Flow Metab. 1996 Jul;16(4):599-604. doi: 10.1097/00004647-199607000-00009.
We tested the effects of administration of a selective neuronal nitric oxide synthase (nNOS) inhibitor, ARL 17477, on ischemic cell damage and regional cerebral blood flow (rCBF), in rats subjected to transient (2 h) middle cerebral artery (MCA) occlusion and 166 h of reperfusion (n = 48) and in rats without MCA occlusion (n = 25), respectively. Animals were administered ARL 17477 (i.v.): 10 mg/kg; 1 mg/kg; 3mg/kg; N-nitro-L-arginine (L-NA) 10 mg/kg L-NA 1 mg/kg; and Vehicle. Administration of ARL 17477 1 mg/kg, 3 mg/kg and 10 mg/kg reduced ischemic infarct volume by 53 (p < 0.05), 23, and 6.5%, respectively. L-NA 1 mg/kg and 10 mg/kg increased infarct volume by 2 and 15%, respectively (p > 0.05). Administration of ARL 17477 (10 mg/kg) significantly (p < 0.05) decreased rCBF by 27 +/- 5.3 and 24 +/- 14.08% and cortical NOS activity by 86 +/- 14.9 and 91 +/- 8.9% at 10 min or 3 h, respectively, and did not alter mean arterial blood pressure (MABP). L-NA (10 mg/kg) significantly reduced rCBF by 23 +/- 9.8% and NOS activity by 81 +/- 7% and significantly (p < 0.05) increased MABP. Treatment with 3 mg/kg and 1 mg/kg ARL 17477 reduced rCBF by only 2.4 +/- 4.5 and 0%, respectively, even when NOS activity was reduced by 63 +/- 13.4 and 45 +/- 15.7% at 3 h, respectively, (p < 0.05). The data demonstrate that ARL 17477 inhibits nNOS in the rat brain and causes a dose-dependent reduction in infarct volume after transient MCA occlusion.
我们分别测试了给予选择性神经元型一氧化氮合酶（nNOS）抑制剂ARL 17477对短暂（2小时）大脑中动脉（MCA）闭塞并再灌注166小时的大鼠（n = 48）以及未进行MCA闭塞的大鼠（n = 25）的缺血性细胞损伤和局部脑血流量（rCBF）的影响。动物静脉注射ARL 17477：10毫克/千克；1毫克/千克；3毫克/千克；N-硝基-L-精氨酸（L-NA）10毫克/千克、L-NA 1毫克/千克以及溶剂。给予1毫克/千克、3毫克/千克和10毫克/千克的ARL 17477分别使缺血梗死体积减少了53%（p < 0.05）、23%和6.5%。1毫克/千克和10毫克/千克的L-NA分别使梗死体积增加了2%和15%（p > 0.05）。给予ARL 17477（10毫克/千克）在10分钟或3小时时分别使rCBF显著（p < 0.05）降低了27±5.3%和24±14.08%，使皮质NOS活性分别降低了86±14.9%和91±8.9%，并且未改变平均动脉血压（MABP）。L-NA（10毫克/千克）使rCBF显著降低了23±9.8%，使NOS活性降低了81±7%，并使MABP显著（p < 0.05）升高。即使在3小时时3毫克/千克和1毫克/千克的ARL 17477分别使NOS活性降低了63±13.4%和45±15.7%（p < 0.05），它们也仅分别使rCBF降低了2.4±4.5%和0%。数据表明，ARL 17477可抑制大鼠脑中的nNOS，并在短暂MCA闭塞后导致梗死体积呈剂量依赖性减少。
