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Effects of Exposure to Intermittent Hypoxia on Oxidative Stress and Acute Hypoxic Ventilatory Response in Humans

¹ Departments of Physiology and Pharmacology, ² Faculty of Medicine, ³ Department of Medicine, ⁴ Hotchkiss Brain Institute, ⁵ Department of Clinical Neurosciences, ⁶ Department of Kinesiology, and ⁷ Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Alberta, Canada

Correspondence and requests for reprints should be addressed to Marc J. Poulin, Ph.D., D.Phil., HMRB-2120, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1. E-mail: poulin{at}ucalgary.ca

Rationale: Periodic occlusion of the upper airway in patients with obstructive sleep apnea leads to chronic intermittent hypoxia, which increases the acute hypoxic ventilatory response (AHVR). Animal studies suggest that oxidative stress may modulate AHVR by increasing carotid body sensitivity to hypoxia. This has not been shown in humans.

Objectives: To determine whether 4 days of exposure to chronic intermittent hypoxia increases AHVR and oxidative stress and to determine the strength of the association between oxidative stress and AHVR.

Methods: After two normoxic control days (Day –4 and Day 0), 10 young healthy men were exposed awake to 4 days (Days 1–4) of intermittent hypoxia for 6 hours per day.

Measurements and Main Results: AHVR, assessed using an isocapnic hypoxia protocol, was determined as the slope of the linear regression between ventilation and oxygen desaturation. Oxidative stress was evaluated by measuring plasma DNA, lipid and protein oxidation, uric acid and antioxidant status by measuring -tocopherol, total vitamin C, and antioxidant enzymatic activities. Between baseline and Day 4, there were significant increases in AHVR, DNA oxidation, uric acid, and vitamin C, whereas antioxidant enzymatic activities and -tocopherol were unchanged. There were strong correlations between the changes in AHVR and DNA oxidation (r = 0.88; P = 0.002).

Conclusions: Chronic intermittent hypoxia increases oxidative stress by increasing production of reactive oxygen species without a compensatory increase in antioxidant activity. This human study shows that reactive oxygen species overproduction modulates increased AHVR. These mechanisms may be responsible for increased AHVR in patients with obstructive sleep apnea.

Key Words: OSA • intermittent hypoxia • ventilation • oxidative stress

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject In patients with obstructive sleep apnea, evaluation of the relationship between intermittent hypoxia and oxidative stress has been hindered by the potential confounding effects of medical comorbidities and obesity. Furthermore, data from animal models of obstructive sleep apnea have suggested that oxidative stress increases the ventilatory sensitivity to acute hypoxia. What This Study Adds to the Field In an experimental human model of intermittent hypoxia, we found that oxidative stress is increased. The changes in oxidative stress are associated with increased ventilatory sensitivity to hypoxia.