Nitric oxide increases carbon monoxide production by piglet cerebral microvessels
Nitric oxide increases carbon monoxide production by piglet cerebral microvessels
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DOI：
10.1152/ajpheart.00464.2005
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发表时间：
2005-10-01
影响因子：
4.8
通讯作者：
Parfenova, H
中科院分区：
文献类型：
--
作者：
Leffler, CW;Balabanova, L;Parfenova, H
一氧化碳（CO）和一氧化氮（NO）可以参与脑循环的调节。抑制这些气体细胞间信使中的任何一种的产生都会抑制新生猪脑小动脉对兴奋性氨基酸谷氨酸的扩张。谷氨酸可以增加NO的产生。因此，本研究验证了谷氨酸增加的NO刺激大脑微血管产生CO的假设。实验使用刚分离的仅表达血红素氧化酶-2 （HO-2）的仔猪脑微血管。采用气相色谱-质谱联用法测定CO产量。虽然n -omega-硝基- l -精氨酸（L-NNA）抑制一氧化氮合酶（NOS）不会改变基本的HO-2催化活性或CO生成，但L-NNA阻断了谷氨酸对HO-2活性和CO生成的刺激。此外，一氧化氮供体硝普钠模拟谷氨酸对HO-2和CO生成的作用。NO的作用似乎是通过cGMP进行的，因为8-溴-cGMP模拟物和1H-[1,2,4]恶二唑-[4,3-a]喹诺沙林-1-one（ODQ）阻断谷氨酸刺激CO生成和HO-2催化活性。酪蛋白激酶和磷脂酰肌醇3-激酶抑制剂均未改变HO-2的催化活性。相反，氯胺咪唑抑制钙调素阻断了谷氨酸对CO生成的刺激，降低了HO-2的催化活性。这些数据表明，谷氨酸可能通过cgmp依赖性HO-2催化活性的升高激活NOS产生NO，从而导致CO合成。这些结果与体内研究结果一致，即HO或NOS抑制均可阻断仔猪对谷氨酸的脑血管扩张。
Carbon monoxide (CO) and nitric oxide (NO) can be involved in the regulation of cerebral circulation. Inhibition of production of either one of these gaseous intercellular messengers inhibits newborn pig cerebral arteriolar dilation to the excitatory amino acid glutamate. Glutamate can increase NO production. Therefore, the present study tests the hypothesis that NO, which is increased by glutamate, stimulates the production of CO by cerebral microvessels. Experiments used freshly isolated cerebral microvessels from piglets that express only heme oxygenase-2 (HO-2). CO production was measured by gas chromatography-mass spectrometry. Although inhibition of nitric oxide synthase (NOS) with N-omega-nitro-L-arginine (L-NNA) did not alter basal HO-2 catalytic activity or CO production, L-NNA blocked glutamate stimulation of HO-2 activity and CO production. Furthermore, the NO donor sodium nitroprusside mimicked the actions of glutamate on HO-2 and CO production. The action of NO appears to be via cGMP because 8-bromo-cGMP mimics and 1H-[1,2,4] oxadiazole-[4,3-a]quinoxalin-1-one(ODQ) blocks glutamate stimulation of CO production and HO-2 catalytic activity. Inhibitors of neither casein kinase nor phosphotidylinositol 3-kinase altered HO-2 catalytic activity. Conversely, inhibition of calmodulin with calmidazolium chloride blocked glutamate stimulation of CO production and reduced HO-2 catalytic activity. These data suggest that glutamate may activate NOS producing NO that leads to CO synthesis via a cGMP-dependent elevation of HO-2 catalytic activity. These results are consistent with the findings in vivo that either HO or NOS inhibition blocks cerebrovascular dilation to glutamate in piglets.