Blunted respiratory responses to hypoxia in mutant mice deficient in nitric oxide synthase-3

• Published in: Journal of applied physiology (1985) 2000-04, Vol.88 (4), p.1496-1508
• Main Authors: Kline, David D, Yang, Tianen, Premkumar, Daniel R. D, Thomas, Agnes J, Prabhakar, Nanduri R
• Format: Article
• Language: English
• Subjects: Anatomy & physiology; Animals; Biological and medical sciences; Cardiorespiratory control. Arterial mecano- and chemoreceptor; Carotid Body - pathology; Carotid Body - physiology; Carotid Body - physiopathology; Efferent Pathways - physiology; Efferent Pathways - physiopathology; Female; Fundamental and applied biological sciences. Psychology; Hypoxia - physiopathology; Male; Mice; Mice, Knockout; Mutation; Nitric Oxide Synthase - deficiency; Nitric Oxide Synthase - genetics; Nitric Oxide Synthase - metabolism; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Oxygen Consumption; Phrenic Nerve - physiology; Phrenic Nerve - physiopathology; Reference Values; Respiratory Physiological Phenomena; Respiratory system; Rodents; Space life sciences; Vertebrates: respiratory system
• ISSN: 8750-7587; 1522-1601
• DOI: 10.1152/jappl.2000.88.4.1496

Department of 1  Physiology and Biophysics and 2  Medicine, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106 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 ( O 2 ) and CO 2 production ( CO 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, O 2 , and CO 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. nitric oxide; nitric oxide synthase enzyme; nitric oxide synthase deficiency; carotid body