Sustaining Excessive Nitric Oxide Upregulates Protein Expression of Nitric Oxide Synthase via Soluble Guanylyl Cyclase: An In Vivo Study in Rats
Sustaining Excessive Nitric Oxide Upregulates Protein Expression of Nitric Oxide Synthase via Soluble Guanylyl Cyclase: An In Vivo Study in Rats
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DOI：
10.1097/00005344-200407000-00006
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发表时间：
2004-07
影响因子：
3
通讯作者：
S. Kagota;Y. Yamaguchi;Kazuki Nakamura;K. Shinozuka;M. Kunitomo
中科院分区：
文献类型：
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作者：
S. Kagota;Y. Yamaguchi;Kazuki Nakamura;K. Shinozuka;M. Kunitomo
本研究的目的是阐明是否上调内皮NO合酶（eNOS）/一氧化氮（NO）途径与下调NO/可溶性鸟苷酸环化酶（sGC）途径。为了产生急性或慢性过量的NO，将脂多糖（LPS）以4 mg/kg的单次剂量（LPS-单次组）或以0.5、1.0和2.0mg/kg的每隔一天的逐步剂量（LPS-重复组）腹腔内给予大鼠。在治疗后24小时，在来自LPS单一组的胸主动脉中，响应于硝普钠侧（SNP）（NO供体）和乙酰胆碱（ACh）的舒张以及sGC和eNOS的蛋白水平保持不变。与此相反，在LPS重复组中，SNP诱导的舒张和sGC蛋白表达显著降低，而ACh诱导的舒张和eNOS蛋白表达显著增加。用NO清除剂NOX-100处理后，所有这些舒张和蛋白水平的变化都得到了恢复。此外，在LPS重复组中观察到的血管功能的类似改变发生在使用渗透泵（0.4 mg/h）通过皮下接受SNP的大鼠中。这些结果表明，持续过量的NO暴露诱导内皮中eNOS/NO途径的上调以及NO/sGC途径的下调。
The aim of this study was to elucidate whether upregulation of the endothelial NO synthase (eNOS)/nitric oxide (NO) pathway is associated with downregulation of the NO/soluble guanylyl cyclase (sGC) pathway. To produce acutely or chronically excessive NO, lipopolysaccharide (LPS) was administered intraperitoneally to rats in a single dose of 4 mg/kg (LPS-single group) or in stepwise doses of 0.5, 1.0, and 2.0 mg/kg every other day (LPS-repeated group). At 24 hours after the treatment, in the thoracic aorta from the LPS-single group, both relaxations in response to sodium nitroprus-side (SNP), an NO donor, and acetylcholine (ACh) and protein levels of sGC and eNOS remained unchanged. In contrast, in the LPS-repeated group, the SNP-induced relaxation and sGC protein expression significantly decreased, while the ACh-induced relaxation and eNOS protein expression significantly increased compared with the non-treated control. All these changes in the relaxations and protein levels were restored by treatment with NOX-100, an NO scavenger. Furthermore, similar alteration in vascular function observed in the LPS-repeated group occurred in rats receiving SNP via subcutaneous using osmotic pumps (0.4 mg/h). These results indicate that persistent excessive NO exposure induces upregulation of the eNOS/NO pathway in the endothelium together with downregulation of the NO/sGC pathway.