Jiang Min Hai, Hada Junichi
Department of Neurology, Hangzhou First People's Hospital, 261, Huansha Road, Hangzhou, Zhejiang, 310006, China.
Eur J Pharmacol. 2007 Jul 12;567(1-2):83-8. doi: 10.1016/j.ejphar.2007.03.014. Epub 2007 Mar 24.
This study was designed to characterize nitric oxide (NO) production and anoxic depolarization in the rat hippocampus during transient forebrain ischemia using two NO synthase (NOS) inhibitors, L-N(5)-(1-iminoethyl)ornithine (L-NIO), a relatively selective endothelial NOS (eNOS) inhibitor, and 7-nitroindazole, a relatively selective neuronal NOS (nNOS) inhibitor, and an NO scavenger, [2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide] (carboxy-PTIO). We measured the mean arterial blood pressure, hippocampal blood flow, NO concentration and direct current potential before, during and after transient forebrain ischemia, which was induced by 4-vessel occlusion for 10 min. Saline, L-NIO (20 mg/kg), 7-nitroindazole (25 mg/kg), L-NIO (20 mg/kg)+7-nitroindazole (25 mg/kg) or carboxy-PTIO (1 mg/kg) was administered intraperitoneally 20 min before the onset of ischemia. We observed early and sharp NO production in the hippocampus during ischemia in the saline group. This NO increase during ischemia was significantly reduced by L-NIO (20 mg/kg)+7-nitroindazole (25 mg/kg) or carboxy-PTIO (1 mg/kg), but not L-NIO (20 mg/kg) or 7-nitroindazole (25 mg/kg). On the other hand, NO production after ischemia was significantly reduced by 7-nitroindazole (25 mg/kg), L-NIO (20 mg/kg)+7-nitroindazole (25 mg/kg) or carboxy-PTIO (1 mg/kg), but not L-NIO (20 mg/kg). The peak latency of NO production during ischemia always preceded the onset latency of anoxic depolarization in both the saline group and the carboxy-PTIO group. In the carboxy-PTIO group, the onset latency of anoxic depolarization was significantly longer than that in the saline group. Moreover, carboxy-PTIO significantly reduced the anoxic depolarization amplitude, compared with that of the saline group. These results suggest that both NOS-dependent and-independent NO formation contributes to early and sharp NO production during ischemia, and that this NO increase is, at least in part, related to the triggering of anoxic depolarization.
本研究旨在利用两种一氧化氮合酶（NOS）抑制剂，即相对选择性的内皮型 NOS（eNOS）抑制剂 L-N(5)-(1-亚氨基乙基)鸟氨酸（L-NIO）和相对选择性的神经元型 NOS（nNOS）抑制剂 7-硝基吲唑，以及一种 NO 清除剂[2-(4-羧基苯基)-4,4,5,5-四甲基咪唑啉-1-氧基-3-氧化物]（羧基-PTIO），来表征短暂性前脑缺血期间大鼠海马体中一氧化氮（NO）的产生及缺氧去极化情况。我们在由四动脉闭塞 10 分钟诱导的短暂性前脑缺血之前、期间和之后，测量了平均动脉血压、海马体血流量、NO 浓度和直流电位。在缺血发作前 20 分钟腹腔注射生理盐水、L-NIO（20 毫克/千克）、7-硝基吲唑（25 毫克/千克）、L-NIO（20 毫克/千克）+7-硝基吲唑（25 毫克/千克）或羧基-PTIO（1 毫克/千克）。我们观察到在生理盐水组缺血期间海马体中早期且急剧的 NO 产生。缺血期间这种 NO 的增加被 L-NIO（20 毫克/千克）+7-硝基吲唑（25 毫克/千克）或羧基-PTIO（1 毫克/千克）显著降低，但未被 L-NIO（20 毫克/千克）或 7-硝基吲唑（25 毫克/千克）降低。另一方面，缺血后 NO 的产生被 7-硝基吲唑（25 毫克/千克）、L-NIO（20 毫克/千克）+7-硝基吲唑（25 毫克/千克）或羧基-PTIO（1 毫克/千克）显著降低，但未被 L-NIO（20 毫克/千克）降低。在生理盐水组和羧基-PTIO 组中，缺血期间 NO 产生的峰值潜伏期总是先于缺氧去极化的起始潜伏期。在羧基-PTIO 组中，缺氧去极化的起始潜伏期明显长于生理盐水组。此外，与生理盐水组相比，羧基-PTIO 显著降低了缺氧去极化幅度。这些结果表明，依赖 NOS 和不依赖 NOS 的 NO 形成均有助于缺血期间早期且急剧的 NO 产生，并且这种 NO 的增加至少部分与缺氧去极化的触发有关。
