Overexpression of inducible nitric oxide synthase in rostral ventrolateral medulla causes hypertension and sympathoexcitation via an increase in oxidative stress
Overexpression of inducible nitric oxide synthase in rostral ventrolateral medulla causes hypertension and sympathoexcitation via an increase in oxidative stress
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DOI：
10.1161/01.res.0000152965.75127.9d
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发表时间：
2005-02-04
影响因子：
20.1
通讯作者：
Sunagawa, K
中科院分区：
文献类型：
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作者：
Kimura, Y;Hirooka, Y;Sunagawa, K
本研究探讨了诱导型一氧化氮合酶（iNOS）的作用，在头端腹外侧延髓（RVLM）的脑干，血管中枢所在地，在控制血压和交感神经活动。将编码iNOS（AdiNOS）或β-半乳糖苷酶（Adbetagal）的腺病毒载体转染到Wistar-Kyoto（WKY）大鼠的RVLM中。使用无线电遥测系统监测血压和心率。通过免疫组织化学染色或蛋白质印迹分析证实RVLM中的iNOS表达。AdiNOS转染后第6天至第11天，平均动脉压显著升高，但Adbetagal转染后无变化。AdiNOS转染大鼠尿去甲肾上腺素排泄量显著高于Adbetagal转染大鼠。微量注射氨基胍或S-甲基异硫脲，iNOS抑制剂，或tempol，一种抗氧化剂，显着减弱诱导型一氧化氮合酶基因转移引起的升压反应。硫代巴比妥酸反应物质的水平，氧化应激的标志物，在AdiNOS转染大鼠比Adbetagal转染大鼠显着更大。在AdiNOS转染的大鼠中，RVLM中的二氢乙锭荧光增加。此外，仅在AdiNOS转染大鼠的RVLM中观察到硝基酪氨酸阳性细胞。脑池内灌注tempol显著减弱了AdiNOS转染引起的升压反应和硫代巴比妥酸反应物质水平的增加。这些结果表明，RVLM中iNOS的过表达通过交感神经系统的激活而增加血压，这是由氧化应激的增加介导的。
The present study examined the role of inducible nitric oxide synthase (iNOS) in the rostral ventrolateral medulla (RVLM) of the brain stem, where the vasomotor center is located, in the control of blood pressure and sympathetic nerve activity. Adenovirus vectors encoding iNOS (AdiNOS) or beta-galactosidase (Adbetagal) were transfected into the RVLM in Wistar-Kyoto (WKY) rats. Blood pressure and heart rate were monitored using a radiotelemetry system. iNOS expression in the RVLM was confirmed by immunohistochemical staining or Western blot analysis. Mean arterial pressure significantly increased from day 6 to day 11 after AdiNOS transfection, but did not change after Adbetagal transfection. Urinary norepinephrine excretion was significantly higher in AdiNOS-transfected rats than in Adbetagal-transfected rats. Microinjection of aminoguanidine or S-methylisothiourea, iNOS inhibitors, or tempol, an antioxidant, significantly attenuated the pressor response evoked by iNOS gene transfer. The levels of thiobarbituric acid-reactive substances, a marker of oxidative stress, were significantly greater in AdiNOS-transfected rats than in Adbetagal-transfected rats. Dihydroethidium fluorescence in the RVLM was increased in AdiNOS-transfected rats. In addition, nitrotyrosine-positive cells were observed in the RVLM only in AdiNOS-transfected rats. Intracisternal infusion of tempol significantly attenuated the pressor response and the increase in the levels of thiobarbituric acid-reactive substances induced by AdiNOS transfection. These results suggest that overexpression of iNOS in the RVLM increases blood pressure via activation of the sympathetic nervous system, which is mediated by an increase in oxidative stress.