Exogenous NO suppresses flow-induced endothelium-derived NO production because of depletion of tetrahydrobiopterin
Exogenous NO suppresses flow-induced endothelium-derived NO production because of depletion of tetrahydrobiopterin
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DOI：
10.1152/ajpheart.00408.2004
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发表时间：
2005-02-01
影响因子：
4.8
通讯作者：
Kajiya, F
中科院分区：
文献类型：
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作者：
Mochizuki, S;Sipkema, P;Kajiya, F
外源性一氧化氮（NO）抑制内皮源性NO的产生。我们感兴趣的是确定在血流诱导的内皮源性NO生成中是否也是如此。如果是这样，那么机制是由于细胞内四氢生物蝶呤的耗竭[BH4；NO合成酶（NOS）的一种辅助因子]，它通过不偶联的NOS产生超氧化物。分离的犬股动脉灌注100 muM s -亚硝基-n -乙酰青霉胺（SNAP； NO供体）和/或64 muM BH4。灌注SNAP抑制了血流诱导的NO生成，通过灌注率与NO生成率线性关系斜率的变化来评价（P < 0.02 vs对照组；n = 7）。随后BH4灌注使坡度恢复到对照水平。同时灌注SNAP和BH4可保持对照水平的NO生成（n = 7）。同时灌注SNAP和4,5-二羟基-1,3-苯二磺酸（Tiron; 1 mM；一种膜透性超氧化物清除剂）也保持了对照水平的NO产量（n = 7），而在SNAP后灌注Tiron不能使NO产量恢复到对照水平（P < 0.02与对照组相比，n = 7）。我们还发现SNAP灌注后内皮细胞中BH4浓度明显降低。综上所述，这些结果表明外源性NO抑制了细胞内BH4耗竭导致的非偶联NOS释放的超氧化物引起的血流诱导的内皮源性NO生成。
Exogenous nitric oxide (NO) suppresses endothelium-derived NO production. We were interested in determining whether this is also the case in flow-induced endothelium-derived NO production. If so, then is the mechanism because of intracellular depletion of tetrahydrobiopterin [BH4; a cofactor of NO synthase (NOS)], which results in superoxide production by uncoupled NOS? Isolated canine femoral arteries were perfused with 100 muM S-nitroso-N-acetylpenicillamine (SNAP; an NO donor) and/or 64 muM BH4. Perfusion of SNAP suppressed flow-induced NO production, which was evaluated as a change in the slope of the linear relationship between perfusion rate and NO production rate ( P < 0.02 vs. control; n = 7). Subsequent BH4 perfusion returned the slope to the control level. Concomitant perfusion of SNAP and BH4 retained the control-level NO production ( n = 7). Concomitant perfusion of SNAP and 4,5-dihydroxy-1,3-benzene disulfonic acid ( Tiron; 1 mM; a membrane-permeable superoxide scavenger) also retained the control-level NO production ( n = 7), whereas perfusion of Tiron after SNAP could not return the NO production to the control level ( P < 0.02 vs. control; n = 7). We also found a significant decrease in BH4 concentration in the endothelial cells after SNAP perfusion. In conclusion, these results indicate that exogenous NO suppresses the flow-induced, endothelium-derived NO production by superoxide released from uncoupled NOS because of intracellular BH4 depletion.