Brain mitochondrial nitric oxide synthase: in vitro and in vivo inhibition by chlorpromazine
Brain mitochondrial nitric oxide synthase: in vitro and in vivo inhibition by chlorpromazine
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DOI：
10.1016/j.abb.2004.07.012
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发表时间：
2004-10-15
影响因子：
3.9
通讯作者：
Boveris, A
中科院分区：
文献类型：
--
作者：
Lores-Arnaiz, S;D'Amico, G;Boveris, A
小鼠脑线粒体有一个147 kDa的一氧化氮合酶(MtNOS)，可与抗nNOS抗体反应，其酶活性为0.31-0.48nmolNO/min mg蛋白。脑亚线粒体膜加入氯丙嗪可抑制线粒体一氧化氮合酶活性(IC50=2.0+/-0.1um)。氯丙嗪(10 mg/kg，ip)小鼠脑线粒体分离线粒体一氧化氮合酶活性显著抑制(48%)，状态3呼吸显著增加(分别为40%和29%，以苹果酸-谷氨酸和琥珀酸为底物)。对照组小鼠线粒体呼吸被精氨酸抑制16%，而被N-奥米伽-硝基-L-精氨酸(N-omega-nitro-L-Arinine，N-omega-nitro-Negro-Arinine)增加，表明线粒体呼吸受线粒体一氧化氮合酶和一氧化氮的调节作用。同样，NNA可使线粒体H_2O_2生成量减少55%。在加入氯丙嗪的小鼠线粒体中，NNA对线粒体呼吸和过氧化氢产生的影响明显较低，而在氯丙嗪处理的小鼠分离的线粒体中，NNA对线粒体呼吸和过氧化氢产生的影响不明显。结果表明，氯丙嗪在体外可抑制脑线粒体一氧化氮合酶的活性，在体内可起到同样的作用。(C)2004 Elsevier Inc.保留所有权利。
Mouse brain mitochondria have a nitric oxide synthase (mtNOS) of 147kDa that reacts with anti-nNOS antibodies and that shows an enzymatic activity of 0.31-0.48nmol NO/min mg protein. Addition of chlorpromazine to brain submitochondrial membranes inhibited mtNOS activity (IC50 = 2.0 +/- 0.1 muM). Brain mitochondria isolated from chlorpromazine-treated mice (10mg/kg, i.p.) show a marked (48%) inhibition of mtNOS activity and a markedly increased state 3 respiration (40 and 29% with malate-glutamate and succinate as substrates, respectively). Respiration of mitochondria isolated from control mice was 16% decreased by arginine and 56%, increased by NNA (N-omega-nitro-L-arginine) indicating a regulatory activity of mtNOS and NO on mitochondrial respiration. Similarly, mitochondrial H2O2 production was 55% decreased by NNA. The effect of NNA on mitochondrial respiration and H2O2 production was significantly lower in chlorpromazine-added mitochondria and absent in mitochondria isolated from chlorpromazine-treated mice. Results indicate that chlorpromazine inhibits brain mtNOS activity in vitro and can exert the same action in vivo. (C) 2004 Elsevier Inc. All rights reserved.