Obstructive sleep apnea is a disorder whose pathogenesis remains poorly understood. This proposal outlines a series of studies designed to examine influences on the neuromuscular control of pharyngeal patency, chemosensitivity, and the genesis of sleep- disordered-breathing. Many investigators agree that the fundamental feature of most apneas is complete occlusion of the pharynx. Pharyngeal occlusion is a """"""""state-dependent"""""""" event which occurs only during sleep and often requires arousal for termination. Therefore, sleep influences on the muscular forces controlling pharyngeal patency are likely to be crucial. Unfortunately, we understand little about the muscular control of the human pharynx and less about how sleep influences human upper airway muscle activation and pharyngeal airway stability. As a result, the first section of this proposal includes a series of protocols designed to examine the influence of sleep on upper airway muscular mechanics and respiration in human subjects. The following major hypothesis will be addressed: 1) pharyngeal muscle activity is significantly reduced or altered during normal human sleep in comparison with wakefulness, 2) sleep-related changes in pharyngeal muscle activation are closely correlated with the increase in upper airway resistance known to occur during normal sleep, and 3) subjects with epidemiologic risk factors for obstructive sleep apnea (male gender, age, and obesity) have a greater propensity for sleep- related upper airway collapse resulting from sleep influences on pharyngeal muscular forces. Three pharyngeal muscle groups known to exhibit phasic activation with inspiration will be investigated. These muscles (genioglossus, geniohyoid, and tensor palatini) are strategically positioned to influence the collapsible pharynx at three important levels. The long-term objective of these studies is to improve our understanding of the mechanisms responsible for the development of periodic upper airway collapse during sleep. The second major line of investigation planned concerns the role of chemosensitivity destabilizes ventilatory rhythm under certain conditions. We hypothesize that individuals with high ventilatory responses to hypercapnia and hypoxia are more likely to develop cycling apneas following airway obstruction during sleep. We fist plan to test this hypothesis in normal subjects. Hypoxic and hypercapnic ventilatory responses will be measured during sleep and correlated with the tendency to develop hyperpnea and unstable breathing following artificial airway occlusion during sleep. We will then pharmacologically manipulate ventilatory responsiveness to asphyxic stimuli (with domperidone and dopamine) to determine the effect on ventilation and breathing pattern following airflow obstruction. Similar manipulations are planned in a group of patients with mild sleep-disordered-breathing to determine whether the quantity of apneas during sleep is altered. Finally, we plan to determine if the post-hyperpnea hypocapnia induced by air way obstruction alters activation of muscles controlling pharyngeal patency. These studies may support a unifying hypothesis relating variations in chemosensitivity to upper airway obstruction during sleep. We believe that by concurrently investigating pharyngeal muscle function and ventilatory chemoresponsiveness, we are likely to improve our understanding of the pathogenesis of obstructive sleep apnea.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL042911-05
Application #
2220742
Study Section
Respiratory and Applied Physiology Study Section (RAP)
Project Start
1989-07-01
Project End
1995-06-30
Budget Start
1993-07-01
Budget End
1995-06-30
Support Year
5
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Pennsylvania State University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
Waradekar, N V; Sinoway, L I; Zwillich, C W et al. (1996) Influence of treatment on muscle sympathetic nerve activity in sleep apnea. Am J Respir Crit Care Med 153:1333-8
Leuenberger, U; Jacob, E; Sweer, L et al. (1995) Surges of muscle sympathetic nerve activity during obstructive apnea are linked to hypoxemia. J Appl Physiol 79:581-8
Gleeson, K (1993) Ventilatory pattern following hypoxic stimulation in nonrapid eye movement and rapid eye movement sleep. Sleep 16:S146-7
Gleeson, K; Sweer, L W (1993) Ventilatory pattern after hypoxic stimulation during wakefulness and NREM sleep. J Appl Physiol 75:397-404
Gleeson, K; Zwillich, C W (1992) Adenosine stimulation, ventilation, and arousal from sleep. Am Rev Respir Dis 145:453-7
Robbins, M K; Gleeson, K; Zwillich, C W (1992) Effect of oxygen breathing following submaximal and maximal exercise on recovery and performance. Med Sci Sports Exerc 24:720-5
Gleeson, K; Zwillich, C W (1992) Adenosine infusion and periodic breathing during sleep. J Appl Physiol 72:1004-9
Leuenberger, U; Gleeson, K; Wroblewski, K et al. (1991) Norepinephrine clearance is increased during acute hypoxemia in humans. Am J Physiol 261:H1659-64
Wiegand, L; Zwillich, C W; Wiegand, D et al. (1991) Changes in upper airway muscle activation and ventilation during phasic REM sleep in normal men. J Appl Physiol 71:488-97
Wiegand, D A; Latz, B; Zwillich, C W et al. (1990) Geniohyoid muscle activity in normal men during wakefulness and sleep. J Appl Physiol 69:1262-9

Showing the most recent 10 out of 11 publications