Kline D D, Yang T, Premkumar D R, Thomas A J, Prabhakar N R
Department, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, USA.
J Appl Physiol (1985). 2000 Apr;88(4):1496-508. doi: 10.1152/jappl.2000.88.4.1496.
In the present study, the role of nitric oxide (NO) generated by endothelial nitric oxide synthase (NOS-3) in the control of respiration during hypoxia and hypercapnia was assessed using mutant mice deficient in NOS-3. Experiments were performed on awake and anesthetized mutant and wild-type (WT) control mice. Respiratory responses to 100, 21, and 12% O(2) and 3 and 5% CO(2)-balance O(2) were analyzed. In awake animals, respiration was monitored by body plethysmography along with O(2) consumption (VO(2)) and CO(2) production (VCO(2)). In anesthetized, spontaneously breathing mice, integrated efferent phrenic nerve activity was monitored as an index of neural respiration along with arterial blood pressure and blood gases. Under both experimental conditions, WT mice responded with greater increases in respiration during 12% O(2) than mutant mice. Respiratory responses to hyperoxic hypercapnia were comparable between both groups of mice. Arterial blood gases, changes in blood pressure, VO(2), and VCO(2) during hypoxia were comparable between both groups of mice. Respiratory responses to cyanide and brief hyperoxia were attenuated in mutant compared with WT mice, indicating reduced peripheral chemoreceptor sensitivity. cGMP levels in the brain stem during 12% O(2), taken as an index of NO production, were greater in mutant compared with WT mice. These observations demonstrate that NOS-3 mutant mice exhibit selective blunting of the respiratory responses to hypoxia but not to hypercapnia, which in part is due to reduced peripheral chemosensitivity. These results support the idea that NO generated by NOS-3 is an important physiological modulator of respiration during hypoxia.
在本研究中，利用缺乏内皮型一氧化氮合酶（NOS-3）的突变小鼠，评估了由内皮型一氧化氮合酶产生的一氧化氮（NO）在低氧和高碳酸血症期间对呼吸控制中的作用。对清醒和麻醉的突变型及野生型（WT）对照小鼠进行了实验。分析了对100%、21%和12%氧气以及3%和5%二氧化碳-平衡氧气的呼吸反应。在清醒动物中，通过体容积描记法监测呼吸，并同时监测氧气消耗（VO₂）和二氧化碳产生（VCO₂）。在麻醉的自主呼吸小鼠中，监测整合的膈神经传出活动作为神经呼吸指标，并同时监测动脉血压和血气。在两种实验条件下，WT小鼠在12%氧气时呼吸增加幅度均大于突变小鼠。两组小鼠对高氧高碳酸血症的呼吸反应相当。两组小鼠在低氧期间的动脉血气、血压变化、VO₂和VCO₂相当。与WT小鼠相比，突变小鼠对氰化物和短暂高氧的呼吸反应减弱，表明外周化学感受器敏感性降低。以12%氧气时脑干中的cGMP水平作为NO产生的指标，突变小鼠中的该水平高于WT小鼠。这些观察结果表明，NOS-3突变小鼠对低氧的呼吸反应表现出选择性减弱，但对高碳酸血症的反应未减弱，这部分是由于外周化学敏感性降低所致。这些结果支持了以下观点，即NOS-3产生的NO是低氧期间呼吸的重要生理调节因子。
