Effects of exposure to intermittent hypoxia on oxidative stress and acute hypoxic ventilatory response in humans

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 carotidbodysensitivity to hypoxia. This has not beenshown 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 24 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 a-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 a-tocopherol were unchanged. There were strong correlations between the changes in AHVR and DNA oxidation (r 5 0.88; P 5 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.