Rong Zimei, Cooper Chris E
Centre for English Language Education, University of Nottingham Ningbo China, Ningbo, 315100, China.
School of Biological Sciences, University of Essex, Colchester, CO4 3SQ, UK.
Adv Exp Med Biol. 2016;876:121-127. doi: 10.1007/978-1-4939-3023-4_15.
The brain responds to hypoxia with an increase in cerebral blood flow (CBF). However, such an increase is generally believed to start only after the oxygen tension decreases to a certain threshold level. Although many mechanisms (different vasodilator and different generation and metabolism mechanisms of the vasodilator) have been proposed at the molecular level, none of them has gained universal acceptance. Nitric oxide (NO) has been proposed to play a central role in the regulation of oxygen supply since it is a vasodilator whose production and metabolism are both oxygen dependent. We have used a computational model that simulates blood flow and oxygen metabolism in the brain (BRAINSIGNALS) to test mechanism by which NO may elucidate hypoxic vasodilation. The first model proposed that NO was produced by the enzyme nitric oxide synthase (NOS) and metabolized by the mitochondrial enzyme cytochrome c oxidase (CCO). NO production declined with decreasing oxygen concentration given that oxygen is a substrate for nitric oxide synthase (NOS). However, this was balanced by NO metabolism by CCO, which also declined with decreasing oxygen concentration. However, the NOS effect was dominant; the resulting model profiles of hypoxic vasodilation only approximated the experimental curves when an unfeasibly low K m for oxygen for NOS was input into the model. We therefore modified the model such that NO generation was via the nitrite reductase activity of deoxyhemoglobin instead of NOS, whilst keeping the metabolism of NO by CCO the same. NO production increased with decreasing oxygen concentration, leading to an improved reproduction of the experimental CBF versus PaO2 curve. However, the threshold phenomenon was not perfectly reproduced. In this present work, we incorporated a wider variety of oxygen dependent and independent NO production and removal mechanisms. We found that the addition of NO removal via oxidation to nitrate mediated by oxyhemoglobin resulted in the optimum fit of the threshold phenomenon by the model. Our revised model suggests, but does not prove, that changes in NO concentration can be the primary cause of the relationship between pO2 and cerebral blood flow.
大脑对缺氧的反应是脑血流量（CBF）增加。然而，一般认为这种增加只有在氧张力降至一定阈值水平后才开始。尽管在分子水平上已经提出了许多机制（不同的血管舒张剂以及血管舒张剂的不同生成和代谢机制），但没有一种得到普遍认可。一氧化氮（NO）被认为在氧供应调节中起核心作用，因为它是一种血管舒张剂，其产生和代谢都依赖于氧。我们使用了一个模拟大脑血流和氧代谢的计算模型（BRAINSIGNALS）来测试NO可能阐明缺氧性血管舒张的机制。第一个模型提出NO由一氧化氮合酶（NOS）产生并由线粒体酶细胞色素c氧化酶（CCO）代谢。由于氧是一氧化氮合酶（NOS）的底物，随着氧浓度降低，NO生成减少。然而，这被CCO的NO代谢所平衡，CCO的代谢也随着氧浓度降低而减少。然而，NOS的作用占主导；当将一个低得不合理的NOS氧Km值输入模型时，由此产生的缺氧性血管舒张模型曲线仅近似于实验曲线。因此，我们修改了模型，使NO的生成通过脱氧血红蛋白的亚硝酸还原酶活性而非NOS，同时保持CCO对NO的代谢不变。随着氧浓度降低，NO生成增加，从而使实验性CBF与PaO2曲线得到更好的重现。然而，阈值现象并未得到完美重现。在本研究中，我们纳入了更多种依赖氧和不依赖氧的NO生成及清除机制。我们发现通过氧合血红蛋白介导的氧化为硝酸盐来清除NO，可使模型对阈值现象达到最佳拟合。我们修订后的模型表明，但未证明，NO浓度的变化可能是pO2与脑血流量之间关系的主要原因。
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