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Abstract
Obstructive sleep apnea (OSA) is characterized by repetitive partial/complete collapse of the pharynx during sleep, which results in apnea/hypopnea leading to arterial oxygen desaturations and arousals. Repetitive apnea/hypopnea-arousal episodes cause hypoxia/reoxygenation cycles, which increase free radical generation and oxidative stress that cause motor/sensory nerve impairments and muscle damage. We hypothesize that antioxidants may protect and/or reverse from oxidative stress-induced damage in OSA patients. To understand the acute protective effects of antioxidants on respiratory muscles, we studied the systemic effects of a membrane permeable superoxide dismutase mimetic, Tempol, on genioglossus (EMGGG) and diaphragmatic (EMGDIA) electro-myographic activities, hypoglossal motoneuron (HMN) nerve activity and cardiorespiratory parameters (mean arterial blood pressure, heart rate) in adult isoflurane-anesthetized obese Zucker rats (OZR) and age-matched lean Zucker rats (LZR). Tempol dose-dependently (1–100 mg/kg) increased EMGGG without changing EMGDIA in OZR and LZR. Tempol increased respiratory rate and tidal volume in OZR and LZR. Tempol (1–25 mg/kg) dose-dependently increased HMN nerve activity in healthy Sprague Dawley rats. Tempol (100 mg/kg) increased EMGGG output by 189% in OZR and 163% in LZR. With respect to mechanisms of effect, Tempol (100 mg/kg) did not augment EMGGG after bilateral HMN transection in Sprague Dawley rats. Although future studies are warranted, available data suggest that in addition to its antioxidant and antihypertensive properties, Tempol can selectively augment EMGGG through modulating HMN and this effect may prevent collapsibility and/or improve stability of the upper airway pharyngeal dilator muscles during episodes of partial and/or complete collapse of the upper airway in OSA human subjects.
Highlights
Obstructive sleep apnea (OSA) is a common sleep breathing disorder characterized by repetitive episodes of partial or complete obstructions of the upper airway during sleep, despite ongoing efforts to breathe, which leads to decreased blood oxygenation and fragmentation of sleep (Banno and Kryger, 2007; Dempsey et al, 2014; Javaheri et al, 2017)
In order to establish the effects of Tempol on respiratory muscles in obese and age-matched lean Zucker rats, the total amplitude of genioglossus (EMGGG) and diaphragm (EMGDIA) muscle activities were recorded before and after injection of Tempol in isoflurane-anesthetized spontaneously breathing animals
At least 10–15 min were allowed between each dose of Tempol to recover cardiorespiratory parameters and to have stable recording of respiratory muscle activities The finding that the Tempol-induced increases in genioglossus EMG (EMGGG) were comparable in obese and lean Zucker rats (Figure 1) suggests that the mechanisms involved in augmentation of EMGGG was independent of its antioxidant properties (Wilcox, 2010)
Summary
Obstructive sleep apnea (OSA) is a common sleep breathing disorder characterized by repetitive episodes of partial (hypopnea) or complete (apnea) obstructions of the upper airway during sleep, despite ongoing efforts to breathe, which leads to decreased blood oxygenation and fragmentation of sleep (Banno and Kryger, 2007; Dempsey et al, 2014; Javaheri et al, 2017). OSA disorder is determined to be present when greater than five abnormal breathing disturbances (apnea-hypopnea events per hour) occur in combination with daytime symptoms of excessive sleepiness, which affects 2–3% of children, 3–7% of middle-aged adults and 10–15% of the elderly population (Jordan et al, 2014). The hypoglossal motoneurons in turn receive direct and/or indirect excitatory and inhibitory synaptic inputs from brain structures that depend on the activity of the central nervous system, with drive during wakefulness being reduced during sleep and increased during exercise. During non-rapid eye movement sleep, excitatory neuromodulatory inputs provided by noradrenergic, serotonergic and cholinergic neurons decrease while during REM sleep there is direct synaptic inhibition of hypoglossal motoneuron activity by glycinergic inhibitory postsynaptic currents (see Fregosi and Ludlow, 2014). The discharge pattern of hypoglossal motoneurons and the activity of genioglossus muscles are strongly respiratorydependent (see Fregosi and Ludlow, 2014). Increase in respiratory drive with hypercapnia and hypoxia increases hypoglossal motoneuron discharge frequency (see Ludlow, 2011; Fregosi and Ludlow, 2014; Ludlow, 2015)
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