Up-regulation of noradrenaline transporter in response to prolonged exposure to ketamine
Up-regulation of noradrenaline transporter in response to prolonged exposure to ketamine
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DOI：
10.1007/s00210-002-0534-1
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发表时间：
2002-05-01
影响因子：
3.6
通讯作者：
Yanagihara, N
中科院分区：
文献类型：
--
作者：
Hara, K;Minami, K;Yanagihara, N
我们以前报道过，静脉麻醉剂氯胺酮通过作用于部分重叠地帕明结合位点的位置而强烈地抑制去甲肾上腺素转运体(NAT)的活性。在这里，我们报道了长期暴露于氯胺酮对培养的牛肾上腺髓质细胞的功能活性和NAT及其mRNA数量的影响。用氯胺酮(10-1000微米)处理细胞1-24小时，细胞对[H-3]去甲肾上腺素(NA)的摄取一过性减少，随后增加。饱和分析显示，氯胺酮(100微米，12h)可使[H-3]NA摄取的V-max增加，而K值无明显变化。氯胺酮还增加了[H-3]尼索西汀与细胞质膜的特异性结合。[H-3]Nisoxetine结合的Scatchard分析表明，氯胺酮增加了质膜上NAT的数目，但不改变K-d值，但增加了B-max。蛋白质合成抑制剂放线菌酮可阻断氯胺酮对[H-3]NA摄取的刺激作用。氯胺酮处理细胞12~24 h后，NAT基因表达增强。本研究结果表明，长期暴露于氯胺酮可增加NAT及其mRNA的功能活性。这可能暗示，氯胺酮在长时间麻醉期间通过上调NAT来负向调节交感神经活动。
We previously reported that the intravenous anaesthetic ketamine acutely inhibits the activity of the noradrenaline transporter (NAT) by acting on a site partly overlapping the desipramine binding site. Here we report the effects of a prolonged exposure to ketamine on the functional activity and number of NAT and its mRNA in cultured bovine adrenal medullary cells. Treatment of cells with ketamine (10-1000 muM) for 1-24 h resulted in a transient decrease and subsequent increase in [H-3]noradrenaline (NA) uptake by the cells. Saturation analysis showed that ketamine (100 muM, 12 h) increased the V-max value of [H-3]NA uptake without any change in the K value. Ketamine also increased the specific binding of [H-3]nisoxetine to plasma membranes isolated from the cells. Scatchard analysis of [H-3]nisoxetine binding revealed that ketamine increased the B-max value without altering the K-d value, suggesting an increase in the number of NAT in the plasma membrane. The stimulatory effect of ketamine on [H-3]NA uptake was blocked by cycloheximide, an inhibitor of protein synthesis. Treatment of cells with ketamine for 12-24 h enhanced the expression of NAT mRNA. The present findings demonstrated that prolonged exposure to ketamine increases the functional activity of NAT and its mRNA. This may imply that ketamine negatively modulates sympathetic nervous activity through an up-regulation of NAT during long anaesthesia.