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首页> 外文期刊>American Journal of Physiology >Cerebral microvascular nNOS responds to lowered oxygen tension through a bumetanide-sensitive cotransporter and sodium-calcium exchanger
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Cerebral microvascular nNOS responds to lowered oxygen tension through a bumetanide-sensitive cotransporter and sodium-calcium exchanger

机译：脑微血管nNOS通过对布美他尼敏感的共转运蛋白和钠钙交换剂对降低的氧张力作出反应

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Na~+ cotransporters have a substantial role in neuronal damage during brain hypoxia. We proposed these cotransporters have beneficial roles in oxygen-sensing mechanisms that increase periarteriolar nitric oxide (NO) concentration ([NO]) during mild to moderate oxygen deprivation. Our prior studies have shown that cerebral neuronal NO synthase (nNOS) is essential for [NO] responses to decreased oxygen tension and that endothelial NO synthase (eNOS) is of little consequence. In this study, we explored the mechanisms of three specific cotransporters known to play a role in the hypoxic state: KB-R7943 for blockade of the Na~+/Ca~(2+) exchanger, bumetanide for the Na~+-K~+-2Cl~- cotransporter, and amiloride for Na~+/H~+ cotransporters. In vivo measurements of arteriolar diameter and [NO] at normal and locally reduced oxygen tension in the rat parietal cortex provided the functional analysis. As previously found for intestinal arterioles, bumetanide-sensitive cotransporters are primarily responsible for sensing reduced oxygen because the increased [NO] and dilation were suppressed. The Na~+/Ca~(2+) exchanger facilitated increased NO formation because blockade also suppressed [NO] and dilatory responses to decreased oxygen. Amiloride-sensitive Na~+/H~+ cotransporters did not significantly contribute to the microvascular regulation. To confirm that nNOS rather than eNOS was primarily responsible for NO generation, eNOS was suppressed with the fusion protein cavtratin for the caveolaedomain of eNOS. Although the resting [NO] decreased and arterioles constricted as eNOS was suppressed, most of the increased NO and dilatory response to oxygen were preserved because nNOS was functional: Therefore, nNOS activation secondary to Na~+-K~+-2C1~ cotransporter and Na~+/Ca~(2+) exchanger functions are key to cerebral vascular oxygen responses.
机译：Na +协同转运蛋白在脑缺氧期间在神经元损伤中起重要作用。我们提出这些辅助转运蛋白在轻度至中度缺氧期间增加小动脉周围一氧化氮（NO）浓度（[NO]）的氧传感机制中具有有益作用。我们先前的研究表明，大脑神经元一氧化氮合酶（nNOS）对于[NO]对氧张力降低的反应至关重要，而内皮一氧化氮合酶（eNOS）的影响很小。在这项研究中，我们探索了已知在缺氧状态中发挥作用的三种特定的共转运蛋白的机制：KB-R7943用于阻断Na〜+ / Ca〜（2+）交换子，布美他尼用于Na〜+ -K〜 + -2Cl〜-协同转运蛋白，阿米洛利用于Na〜+ / H〜+协同转运蛋白。在正常和局部降低的大鼠顶叶皮层中的氧气张力下的小动脉直径和[NO]的体内测量提供了功能分析。如先前在肠小动脉中发现的那样，布美他尼敏感的共转运蛋白主要负责感测还原的氧气，因为[NO]和扩张的增加受到抑制。 Na + / Ca〜（2+）交换剂促进了NO的形成，因为封锁也抑制了[NO]和对减少的氧气的扩张反应。阿米洛利敏感的Na〜+ / H〜+共转运蛋白对微血管调节没有显着贡献。为了确认nNOS而非eNOS是NO产生的主要原因，eNOS的海绵状结构域的融合蛋白cavtratin抑制了eNOS。尽管由于eNOS被抑制，静止的[NO]减少并且小动脉收缩，但由于nNOS起作用，大多数NO的增加和对氧气的扩张反应得以保留：因此，nNOS活化继发于Na〜+ -K〜+ -2C1〜共转运蛋白和Na〜+ / Ca〜（2+）交换子功能是脑血管氧反应的关键。

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