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首页> 外文期刊>American Journal of Physiology >Extracellular norepinephrine reduces neuronal uptake of norepinephrine by oxidative stress in PC12 cells.
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Extracellular norepinephrine reduces neuronal uptake of norepinephrine by oxidative stress in PC12 cells.

机译：细胞外去甲肾上腺素通过PC12细胞中的氧化应激减少神经元对去甲肾上腺素的摄取。

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摘要

Cardiac norepinephrine (NE) uptake activity is reduced in congestive heart failure. Our studies in intact animals suggest that this effect on the cardiac sympathetic nerve endings is caused by oxidative stress and/or NE toxic metabolites derived from NE. In this study, we investigated the direct effects of NE on neuronal NE uptake activity and NE transporter (NET), using undifferentiated PC12 cells. Cells were incubated with NE (1-500 microM) either alone or in combination of Cu(2+) sulfate (1 microM), which promotes free radical formation by Fenton reaction for 24 h. NE uptake activity was measured using [(3)H]NE. Cell viability was determined with the use of Trypan blue exclusion and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay, and cellular oxidative stress by dichlorodihydrofluorescein fluorescence and the GSH/GSSG ratio. Cell viability was reduced by NE >100 microM. At lower doses, NE produced oxidative stress and a dose-dependent reduction of NE uptake activity without affecting cell viability significantly. Cu(2+), which has no direct effect on NE uptake activity, potentiated oxidative stress and reduction of NE uptake activity produced by NE. This decrease of NE uptake activity was associated with reductions of NE uptake binding sites and NET protein expression by using the radioligand assay and Western blot analysis, but no changes in NET gene expression. In addition, the free-radical scavenger mannitol, and antioxidant enzymes superoxide dismutase and catalase, reduced oxidative stress and attenuated the reductions of NE uptake activity and NET protein produced by NE/Cu. Thus our results support a functional role of oxidative stress in mediating the neuronal NE uptake reducing effect of NE and that this effect of NE on NET is a posttranscriptional event.
机译：充血性心力衰竭时心脏去甲肾上腺素（NE）的摄取活性降低。我们在完整动物中的研究表明，这种对心脏交感神经末梢的作用是由氧化应激和/或源自NE的NE有毒代谢产物引起的。在这项研究中，我们使用未分化的PC12细胞研究了NE对神经元NE摄取活性和NE转运蛋白（NET）的直接影响。将细胞与单独的NE（1-500 microM）或与硫酸铜（2+）（1 microM）组合使用，通过Fenton反应促进自由基形成24小时。使用[（3）H] NE测量NE摄取活性。使用台盼蓝排除法和3-（4,5-二甲基噻唑-2-基）-2,5-二苯基溴化四唑鎓测定法确定细胞活力，并通过二氯二氢荧光素荧光和GSH / GSSG比确定细胞氧化应激。 NE> 100 microM降低了细胞活力。在较低剂量下，NE产生氧化应激，并且NE摄取活性呈剂量依赖性降低，而不会显着影响细胞活力。 Cu（2+），对NE的摄取活性，增强的氧化应激和NE产生的NE摄取活性的降低没有直接影响。通过使用放射性配体测定和蛋白质印迹分析，NE摄取活性的降低与NE摄取结合位点和NET蛋白表达的减少相关，但是NET基因表达没有变化。此外，自由基清除剂甘露醇和抗氧化酶超氧化物歧化酶和过氧化氢酶可降低氧化应激，并减弱NE / Cu产生的NE吸收活性和NET蛋白的降低。因此，我们的结果支持了氧化应激在介导NE的神经元NE摄取减少作用中的功能性作用，并且NE对NET的这种作用是转录后事件。

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