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Chronic Intermittent Hypoxia Increases Apnoea Index in Sleeping Rats

  • Deirdre EdgeEmail author
  • Aidan Bradford
  • Ken D. O’Halloran
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 758)

Abstract

Intermittent hypoxia (IH) is the dominant feature of sleep-disordered breathing which is very common. It is recognized that IH elicits plasticity in the respiratory control system. Recently it was reported in humans that IH destabilizes breathing during sleep increasing the susceptibility to apnoea. Many forms of respiratory plasticity are dependent upon reactive oxygen species (ROS), and NADPH oxidase has been identified as an important source of ROS necessary for IH-induced plasticity. In the present study, we sought to examine the effects of chronic IH (CIH) on the propensity for spontaneous apnoea during sleep. Adult male Wistar rats were exposed to 20 cycles of normoxia and hypoxia (5% O2 at nadir; SaO2 ∼ 80%) per hour, 8 h a day for 7 consecutive days (CIH group, N = 6). The sham group (N = 6) were subject to alternating cycles of air under identical experimental conditions in parallel. Two additional groups of CIH-treated rats were given either the superoxide dismutase mimetic – tempol (1 mM, N = 8), or the NAPDH oxidase inhibitor – apocynin (2 mM, N = 8) in their drinking water throughout the study. Following gas exposures, breathing during sleep was assessed in unrestrained animals using the technique of whole-body plethysmography. CIH significantly increased apnoea index during sleep (4.7 ± 0.8 vs. 11.3 ± 1.6 events/h; mean ± SEM, sham vs. CIH, Student’s t test, p = 0.0035). Apnoea duration was unaffected by CIH treatment. The CIH-induced increase in the occurrence of apnoea was completely reversed by antioxidant supplementation (4.9 ± 0.9 events/h for CIH + tempol and 5.6 ± 0.9 events/h for CIH + apocynin). CIH-induced increase in the propensity for apnoea may have clinical relevance and may explain the phenomenon of ‘complex’ apnoea in sleep apnoea patients. Our results suggest that oxidative stress is implicated in CIH-induced respiratory disturbance during sleep. We conclude that antioxidants may be a realistic adjunct therapy in the treatment of sleep-disordered breathing.

Keywords

Chronic intermittent hypoxia Sleep disordered breathing Animal model Plasticity Apnoea index Reactive oxygen species Oxidative stress Respiratory neurons NADPH-oxidase Antioxidants 

Notes

Acknowledgements

Supported by the Health Research Board, Ireland (RP/2007/29). DE is enrolled in the School of Medicine and Medical Science Translational Medicine PhD training programme.

References

  1. Chowdhuri S, Shanidze I, Pierchala L, Belen D, Mateika JH, Badr MS (2010) Effect of episodic hypoxia on the susceptibility to hypocapnic central apnea during NREM sleep. J Appl Physiol 108:369–377PubMedCrossRefGoogle Scholar
  2. del Rio R, Moya EA, Iturriaga R (2010) Carotid body and cardiorespiratory alterations in intermittent hypoxia: the oxidative link. Eur Respir J 36:143–150PubMedCrossRefGoogle Scholar
  3. Dunleavy M, Bradford A, O’Halloran KD (2008) Oxidative stress impairs upper airway muscle endurance in an animal model of sleep-disordered breathing. Adv Exp Med Biol 605:458–462PubMedCrossRefGoogle Scholar
  4. Fuller DD, Bach KB, Baker TL, Kinkead R, Mitchell GS (2000) Long term facilitation of phrenic motor output. Respir Physiol 121:135–146PubMedCrossRefGoogle Scholar
  5. Hougee S, Hartog A, Sanders A, Graus YM, Hoijer MA, Garssen J, van den Berg WB, van Beuningen HM, Smit HF (2006) Oral administration of the NADPH-oxidase inhibitor apocynin partially restores diminished cartilage proteoglycan synthesis and reduces inflammation in mice. Eur J Pharmacol 531:264–269PubMedCrossRefGoogle Scholar
  6. Iturriaga R, Rey S, Alcayaga J, del Rio R (2006) Chronic intermittent hypoxia enhances carotid body chemosensory responses to acute hypoxia. Adv Exp Med Biol 580:227–232, discussion 351–9PubMedCrossRefGoogle Scholar
  7. Julien C, Bairam A, Joseph V (2008) Chronic intermittent hypoxia reduces ventilatory long-term facilitation and enhances apnea frequency in newborn rats. Am J Physiol Regul Integr Comp Physiol 294:R1356–R1366PubMedCrossRefGoogle Scholar
  8. Lavie L (2009) Oxidative stress – a unifying paradigm in obstructive sleep apnea and comorbidities. Prog Cardiovasc Dis 51:303–312PubMedCrossRefGoogle Scholar
  9. Macfarlane PM, Mitchell GS (2008) Respiratory long-term facilitation following intermittent hypoxia requires reactive oxygen species formation. Neuroscience 152:189–197PubMedCrossRefGoogle Scholar
  10. Macfarlane PM, Satriotomo I, Windelborn JA, Mitchell GS (2009) NADPH oxidase activity is necessary for acute intermittent hypoxia-induced phrenic long-term facilitation. J Physiol 587:1931–1942PubMedCrossRefGoogle Scholar
  11. McKay LC, Feldman JL (2008) Unilateral ablation of pre-botzinger complex disrupts breathing during sleep but not wakefulness. Am J Respir Crit Care Med 178:89–95PubMedCrossRefGoogle Scholar
  12. Mendelson WB, Martin JV, Perlis M, Giesen H, Wagner R, Rapoport SI (1988) Periodic cessation of respiratory effort during sleep in adult rats. Physiol Behav 43:229–234PubMedCrossRefGoogle Scholar
  13. Morgenthaler TI, Kagramanov V, Hanak V, Decker PA (2006) Complex sleep apnea syndrome: is it a unique clinical syndrome? Sleep 29:1203–1209PubMedGoogle Scholar
  14. Peng YJ, Overholt JL, Kline D, Kumar GK, Prabhakar NR (2003) Induction of sensory long-term facilitation in the carotid body by intermittent hypoxia: implications for recurrent apneas. Proc Natl Acad Sci U S A 100:10073–10078PubMedCrossRefGoogle Scholar
  15. Peng YJ, Nanduri J, Yuan G, Wang N, Deneris E, Pendyala S, Natarajan V, Kumar GK, Prabhakar NR (2009) NADPH oxidase is required for the sensory plasticity of the carotid body by chronic intermittent hypoxia. J Neurosci 29:4903–4910PubMedCrossRefGoogle Scholar
  16. Prabhakar NR, Kumar GK, Nanduri J, Semenza GL (2007) ROS signaling in systemic and cellular responses to chronic intermittent hypoxia. Antioxid Redox Signal 9:1397–1403PubMedCrossRefGoogle Scholar
  17. Row BW, Liu R, Xu W, Kheirandish L, Gozal D (2003) Intermittent hypoxia is associated with oxidative stress and spatial learning deficits in the rat. Am J Respir Crit Care Med 167:1548–1553PubMedCrossRefGoogle Scholar
  18. Salloum A, Rowley JA, Mateika JH, Chowdhuri S, Omran Q, Badr MS (2009) Increased propensity for central apnea in patients with obstructive sleep apnea: effect of nasal continuous positive airway pressure. Am J Respir Crit Care Med 181:189–193PubMedCrossRefGoogle Scholar
  19. Skelly JR, Edge D, Shortt CM, Jones JFX, Bradford A, O’Halloran KD (2012) Tempol ameliorates pharyngeal dilator muscle dysfunction in a rodent model of chronic intermittent hypoxia. Am J Respir Cell Mol Biol 46:139–148Google Scholar
  20. Veasey SC, Davis CW, Fenik P, Zhan G, Hsu YJ, Pratico D, Gow A (2004a) Long-term intermittent hypoxia in mice: protracted hypersomnolence with oxidative injury to sleep-wake brain regions. Sleep 27:194–201PubMedGoogle Scholar
  21. Veasey SC, Zhan G, Fenik P, Pratico D (2004b) Long-term intermittent hypoxia: reduced excitatory hypoglossal nerve output. Am J Respir Crit Care Med 170:665–672PubMedCrossRefGoogle Scholar
  22. Xu W, Chi L, Row BW, Xu R, Ke Y, Xu B, Luo C, Kheirandish L, Gozal D, Liu R (2004) Increased oxidative stress is associated with chronic intermittent hypoxia-mediated brain cortical neuronal cell apoptosis in a mouse model of sleep apnea. Neuroscience 126:313–323PubMedCrossRefGoogle Scholar
  23. Zhang JH, Fung SJ, Xi M, Sampogna S, Chase MH (2010) Apnea produces neuronal degeneration in the Pons and medulla of guinea pigs. Neurobiol Dis 40:251–264PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2012

Authors and Affiliations

  • Deirdre Edge
    • 1
    Email author
  • Aidan Bradford
    • 2
  • Ken D. O’Halloran
    • 1
  1. 1.UCD School of Medicine and Medical ScienceUniversity College DublinDublin 4Ireland
  2. 2.Department of Physiology and Medical PhysicsRoyal College of Surgeons in IrelandDublin 2Ireland

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