Obstructive sleep apnea is a common disorder affecting 2% of adults with a strong male predominance. We believe obstructive sleep apnea to be primarily a product of deficient pharyngeal anatomy. During wakefulness, thre is compensation for a small airway by reflex-driven activation of pharyngeal dilator muscles. During sleep, the reflex mechanism is diminished or lost leading to collapse of the airway. In this application, we propose to study normal subjects and apnea patients to better define the mechanisms controlling pharyngeal muscle activity. We propose four groups of studies. 1. Neural Reflexes: We believe that the upper airway negative pressure reflex is critical in activating pharyngeal muscles in the apnea patient during wakefulness compensating for deficient anatomy. We propose to evaluate this reflex: a) during sleep onset (alpha-theta transition) and b) during stable REM sleep when apneas is more frequent). We also propose a series of studies to better define the mechanism driving this augmented muscle activity during wakefulness. 2. Chemical Influences: Unlike the reflex mechanisms that are lost during sleep, we hypothesize that CO2 influences on pharyngeal muscle activity is maintained. Therefore, we propose to determine in normal humans: a) the response of two pharyngeal dilator muscles to increasing PCO2 during wakefulness and sleep and b) the integrated relationship between CO2 influences and the negative pressure reflex on these muscle awake and asleep. 3. Hormonal Influences: Sleep apnea is more common in men than women. We hypothesize that female hormones (estrogen and progesterone) produce a non-state dependent augmentation of upper airway muscle activity thereby reducing airway collapsibility awake and asleep. We propose to determine the influence of estrogen, progesterone and testosterone on pharyngeal muscle activity and airway collapsibility awake and asleep. 4. Neuromodulators: In an attempt to better understand the influence of several state-related neuromodulators on pharyngeal muscle activity, currently available agents influencing the serotonergic and cholinergic systems will be systematically studied. These studies should substantially improve our understanding of the mechanisms controlling upper airway muscle activity awake and asleep and should hopefully lead to improved strategies for the treatment of obstructive sleep apnea.
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