Carbon monoxide induces vasodilation and nitric oxide release but suppresses endothelial NOS
Carbon monoxide induces vasodilation and nitric oxide release but suppresses endothelial NOS
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DOI：
10.1152/ajprenal.1999.277.6.f882
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发表时间：
1999-12-01
影响因子：
4.2
通讯作者：
Goligorsky, MS
中科院分区：
文献类型：
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作者：
Thorup, C;Jones, CL;Goligorsky, MS
一氧化碳（CO）的血管效应类似于一氧化氮（NO），但尚不清楚这两种信使是否收敛或表现出相互反馈调节。这些问题进行了检查，在显微解剖灌注肾阻力动脉（RRA）研究使用NO敏感的微电极。灌注RRA与缓冲液含有浓度增加的CO导致在一个双相释放NO。NO响应峰值在100 nM CO，然后下降到几乎为零，在10 μ M当一系列的50秒脉冲的100 nM CO重复应用（150秒的间隔），连续的NO响应的幅度减小。NO释放对L-精氨酸有依赖性，而对D-精氨酸无依赖性; NO合成酶（NOS）抑制剂N（G）-硝基-L-精氨酸甲酯（L-NAME）预处理可抑制NO释放。CO（100 nM）也抑制NO释放诱导的100 μ M：卡巴胆碱，一种有效的内皮NOS（eNOS）激动剂。RRA从大鼠内源性CO生产诱导HO升高（氯化钴12小时前的研究）也表现出抑制反应卡巴胆碱。此外，在体外灌注的延髓传入小动脉中获得了与这些结果一致的反应，其中对CO的血管舒张反应是双相的，对乙酰胆碱的反应是钝的。总的来说，这些数据表明，CO诱导的NO释放可以归因于eNOS的刺激或NO从细胞存储池的位移。为了解决这个问题，直接在体外测量NO选择性电极的NO生产重组eNOS显示，CO剂量依赖性抑制NO的合成。总之，上述数据表明，尽管高水平的CO抑制NOS活性和NO产生，但较低浓度的CO诱导NO从大的细胞内池中释放，因此可以模拟NO的血管效应。
The vascular effects of carbon monoxide (CO) resemble those of nitric oxide (NO), but it is unknown whether the two messengers converge or exhibit reciprocal feedback regulation. These questions were examined in microdissected perfused renal resistance arteries (RRA) studied using NO-sensitive microelectrodes. Perfusion of RRA with buffers containing increasing concentrations of CO resulted in a biphasic release of NO. The NO response peaked at 100 nM CO and then declined to virtually zero at 10 mu M When a series of 50-s pulses of 100 nM CO were applied repeatedly (150 s interval), the amplitude of consecutive NO responses was diminished. NO release from RRA showed dependence on L-arginine but not D-arginine, and the responses to CO were inhibited by pretreatment with N(G)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthases (NOS). CO (100 nM) also suppressed NO release induced by 100 mu M: carbachol, a potent agonist for endothelial NOS (eNOS). RRA from rats in which endogenous CO production from inducible HO was elevated (cobalt chloride 12 h prior to study) also showed suppressed responses to carbachol. Furthermore, responses consistent with these findings were obtained in juxtamedullary afferent arterioles perfused in vitro, where the vasodilatory response to CO was biphasic and the response to acetylcholine was blunted. Collectively, these data suggest that the CO-induced NO release could be attributed to either stimulation of eNOS or to NO displacement from a cellular storage pool. To address this, direct in vitro measurements with an NO-selective electrode of NO production by recombinant eNOS revealed that CO dose-dependently inhibits NO synthesis. Together, the above data demonstrate that, whereas high levels of CO inhibit NOS activity and NO generation, lower concentrations of CO induce release of NO from a large intracellular pool and, therefore, may mimic the vascular effects of NO.