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Central (brainstem) and peripheral (carotid body) respiratory chemoreflexes act in concert to modulate breathing during sleep, maintaining blood gases (PCO2 and PO2) within narrow limits. Increases in both central and peripheral chemoreflex gain have been reported in clinical populations that experience central sleep apnoea and likely underlie the pathophysiology of this disorder. However, how central-peripheral chemoreceptor interaction affects the apparent gain of each chemoreflex is controversial. Data from our laboratory demonstrate that there is a negative interaction between central and peripheral chemoreceptors in the rat, such that brainstem hypocapnia augments peripheral chemoreflex gain in response to both carotid body PCO2 and PO2. We note that a negative interaction may also occur in humans, especially relevant in those experiencing chronic hypocapnia. Interestingly, chronic hypocapnia occurs in populations prone to central sleep apnea, such as congestive heart failure (CHF) patients and individuals sleeping at high altitude. These observations lead us to propose the novel hypothesis that a negative interaction between chemoreceptors results in an augmented peripheral chemoreceptor gain when the central chemoreceptors are hypocapnic, thereby contributing directly to breathing instability during sleep.

Reactive oxygen species (ROS) likely play a role in the hypoxic ventilatory response. We determined whether hypoxic responses were influenced by alterations in cellular redox status induced by reductions in superoxide dismutase-1 (SOD-1) activity, a cytosolic anti-oxidant enzyme. Using whole-body, continuous-flow plethysmography, we compared ventilatory responses to moderate hypoxia (10% inspired O2) of Sod1+/+, +/- and -/- postnatal day 4 (P4) littermates. Sod1+/- neonates exhibited a consistently lower breathing frequency than their wild-type littermates, regardless of inspired O2 level. While SOD-1 deficiency had no effect on the magnitude of the ventilatory response during hypoxia, it did compromise stability of breathing in the post-hypoxic period. Our results suggest SOD-1 stimulates ventilation and helps stabilize breathing after a hypoxic perturbation.