In subjects with obstructive sleep apnea, integrity of pharyngeal dilator muscle contraction in the face of hypoxia is critical for the restoration and maintenance of upper airway patency and ventilation. Conductance through K+ channels influences muscle contractile force by regulating resting membrane potential and action potential duration. During repetitive contractions, efflux of K- depolarizes the cell membrane, which can contribute to muscle fatigue. In cardiac muscle activation of ATP-dependent K= current appears to underlie hypoxia-induced reductions in contractile force. K- channel blockers increase diaphragm muscle twitch force; however, their effects on twitch force of other muscles, and their influence on fatigueability and hypoxia-induced contractile dysfunction of skeletal muscle, are not known. The overall hypothesis to be tested is the K+ channel blockers improve pharyngeal muscle contractile function.
Specific Aim 1 will determine the degree to which K+ channel blockers with different pharmacologic profiles affect muscle contractile force, and the extent to which there is heterogeneity among muscles in the response to K+ channel blockers.
Specific Aims 2 and 3 will delineate the effects of K+ channel blockade on pharyngeal muscle fatigueability and hypoxia-induced contractile dysfunction, respectively, and determine whether modulation of muscle contractile function by K- channel blockade is influenced by the rate and intensity of muscle contraction and the degree of hypoxia. Effects of K+ channel blockers on pharyngeal muscle will be assessed in vitro, and compared with effects on diaphragm, soleus, and extensor digitorum longus muscle, using tissue derived from normal and hypertensive rats. Studies will utilize relatively broad K+ channel blockers (eg. tetraethylammonium, 4-aminopyridine) as well as more specific blockers of subtypes of K+ channels (eg. glybenclamide for ATP- dependent K+ channels; charybdotoxin and apamin for Ca++ -dependent K+ channels) to characterize the role of K+ channel subtypes in muscle contractile function. Delineation of the roles of K+ channel blockers in regulating contractility and endurance of normal and hypoxic muscle, and an identification of the K+ channel blockers in regulating contractility and endurance of normal and hypoxic muscle, and an identification of the K+ channel subtypes which influence muscle contractile function, will result in a greater understanding of the pathophysiology of obstructive sleep apnea, and may lead to new therapeutic options in the management of this disease.
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