Activity Of Upper Airway Dilator Muscles Research Articles

A novel TASK channel antagonist nasal spray reduces sleep apnea severity in physiological responders: a randomized, blinded, trial.

Preclinical and human physiological studies indicate that topical, selective TASK 1/3 K+ channel antagonism increases upper airway dilator muscle activity and reduces pharyngeal collapsibility during anesthesia and nasal breathing during sleep. The primary aim of this study was to determine the effects of BAY2586116 nasal spray on obstructive sleep apnea (OSA) severity and whether individual responses vary according to differences in physiological responses and route of breathing. Ten people (5 females) with OSA [apnea-hypopnea index (AHI) = 47 ± 26 events/h (means ± SD)] who completed previous sleep physiology studies with BAY2586116 were invited to return for three polysomnography studies to quantify OSA severity. In random order, participants received either placebo nasal spray (saline), BAY2586116 nasal spray (160 µg), or BAY2586116 nasal spray (160 µg) restricted to nasal breathing (chinstrap or mouth tape). Physiological responders were defined a priori as those who had improved upper airway collapsibility (critical closing pressure ≥2 cmH2O) with BAY2586116 nasal spray (NCT04236440). There was no systematic change in apnea-hypopnea index (AHI3) from placebo versus BAY2586116 with either unrestricted or nasal-only breathing versus placebo (47 ± 26 vs. 43 ± 27 vs. 53 ± 33 events/h, P = 0.15). However, BAY2586116 (unrestricted breathing) reduced OSA severity in physiological responders compared with placebo (e.g., AHI3 = 28 ± 11 vs. 36 ± 12 events/h, P = 0.03 and ODI3 = 18 ± 10 vs. 28 ± 12 events/h, P = 0.02). Morning blood pressure was also lower in physiological responders after BAY2586116 versus placebo (e.g., systolic blood pressure = 137 ± 24 vs. 147 ± 21 mmHg, P < 0.01). In conclusion, BAY2586116 reduces OSA severity during sleep in people who demonstrate physiological improvement in upper airway collapsibility. These findings highlight the therapeutic potential of this novel pharmacotherapy target in selected individuals.NEW & NOTEWORTHY Preclinical findings in pigs and humans indicate that blocking potassium channels in the upper airway with topical nasal application increases pharyngeal dilator muscle activity and reduces upper airway collapsibility. In this study, BAY2586116 nasal spray (potassium channel blocker) reduced sleep apnea severity in those who had physiological improvement in upper airway collapsibility. BAY2586116 lowered the next morning's blood pressure. These findings highlight the potential for this novel therapeutic approach to improve sleep apnea in certain people.

Effects of the Combination of Atomoxetine and Oxybutynin on OSA Endotypic Traits

We recently showed that administration of the combination of the noradrenergic drug atomoxetine plus the antimuscarinic oxybutynin (ato-oxy) prior to sleep greatly reduced OSA severity, likely by increasing upper airway dilator muscle activity during sleep. In patients with OSA who performed the ato-oxy trial with an esophageal pressure catheter to estimate ventilatory drive, the effect of the drug combination (n= 17) and of the single drugs (n= 6) was measured on the endotypic traits over a 1-night administration and compared vsplacebo. This study also tested if specific traits were predictors of complete response to treatment (reduction in apnea-hypopnea index [AHI] > 50%and< 10 events/h). The study was a double-blind, randomized, placebo-controlled trial. The arousal threshold, collapsibility (ventilation at eupneic drive [Vpassive]), ventilation at arousal threshold, and loop gain (stability of ventilatory control, LG1), were calculated during spontaneous breathing during sleep. Muscle compensation (upper airway response) was calculated as a function of ventilation at arousal threshold adjusted for Vpassive. Ventilation was expressed as a percentage of the eupneic level of ventilation (%eupnea). Data are presented as mean [95%CI]. Compared with placebo, ato-oxy increased Vpassive by 73 [54 to 91]%eupnea (P< .001) and muscle compensation by 29 [8 to 51]%eupnea (P= .012), reduced the arousal threshold by -9 [-14 to -3]%(P= .022) and LG1 by -11 [-22 to 2]%(P= .022). Atomoxetine alone significantly reduced arousal threshold and LG1. Both agents alone improved collapsibility (Vpassive) but not muscle compensation. Patients with lower AHI, higher Vpassive, and higher fraction of hypopneas over total events had a complete response with ato-oxy. Ato-oxy markedly improved the measures of upper airway collapsibility, increased breathing stability, and slightly reduced the arousal threshold. Patients with relatively lower AHI and less severe upper airway collapsibility had the best chance for OSA resolution with ato-oxy.

Postural preinspiratory cortical activity, genioglossus activity and fluid shift in awake obstructive sleep apnoea patients

What is the central question of this study? Transition to supine posture induces an inspiratory load associated with cortical activation in awake healthy subjects. Some obstructive sleep apnoea patients exhibit this cortical activity in the sitting position contributing to the arousal-dependent compensation of their upper airway abnormalities. Does a transition to the supine posture in awake obstructive sleep apnoea patients increase this cortical activity? What is the main finding and its importance? The transition to supine posture induces a reduction in the cortical activity despite evidence of an increase in genioglossus activity, suggesting that genioglossus activation is not driven by cortical activity. The anatomy and mechanical properties of the upper airway (UA) depend on posture. Lying in a supine position causes cephalad fluid shift to the neck, thus narrowing the UA and predisposing the individual to obstructive sleep apnoea (OSA). Increased UA dilator muscle activity during wakefulness prevents the UA collapse but the underlying mechanism has not yet been elucidated. In the sitting position during wakefulness, some OSA patients exhibit preinspiratory cortical activity (preinspiratory potential, PIP) probably related to UA abnormalities. The aim of this study was to investigate changes in the preinspiratory cortical activity and UA dilator muscle in OSA patients during postural challenge. An electroencephalogram was used to detect PIP, and the genioglossus electromyographic activity and ventilation were analysed in 17 awake, male OSA patients while they were sitting, just after lying down, and then in response to leg positive pressure to enhance cephalad fluid shift. The prevalence of PIP decreased from 53% (sitting) to 12% (supine) (P=0.002) in association with increased genioglossus activity (tonic from median (25th, 75th centiles) 2.3 (1.8, 2.8)% to 3.6 (1.7, 5.0)% of voluntary deglutition, P=0.019; phasic from 2.3 (1.9, 2.8)% to 3.7 (2.0, 6.1)%, P=0.024), and with increased transcutaneous carbon dioxide pressure (from 43.0 (42.4, 44.2) to 44.6 (43.5, 45.2) mmHg). No change was observed during leg-positive-pressure application. Moving from the sitting position to the supine position reduces respiratory-related premotor cortical activity in awake OSA patients. The concomitant increase in genioglossus activity, therefore, is not driven by cortical respiratory activity.

Muscarinic Inhibition of Hypoglossal Motoneurons: Possible Implications for Upper Airway Muscle Hypotonia during REM Sleep.

Proper function of pharyngeal dilator muscles, including the genioglossus muscle of the tongue, is required to maintain upper airway patency. During sleep, the activity of these muscles is suppressed, and as a result individuals with obstructive sleep apnea experience repeated episodes of upper airway closure when they are asleep, in particular during rapid-eye-movement (REM) sleep. Blocking cholinergic transmission in the hypoglossal motor nucleus (MoXII) restores REM sleep genioglossus activity, highlighting the importance of cholinergic transmission in the inhibition of hypoglossal motor neurons (HMNs) during REM sleep. Glutamatergic afferent input from neurons in the parahypoglossal (PH) region to the HMNs is critical for MoXII respiratory motor output. We hypothesized that state-dependent cholinergic regulation may be mediated by this pathway. Here we studied the effects of cholinergic transmission in HMNs in adult male and female mice using patch-clamp recordings in brain slices. Using channelrhodopsin-2-assisted circuit mapping, we first demonstrated that PH glutamatergic neurons directly and robustly activate HMNs (PHGlut → HMNs). We then show that carbachol consistently depresses this input and that this effect is presynaptic. Additionally, carbachol directly affects HMNs by a variable combination of muscarinic-mediated excitatory and inhibitory responses. Altogether, our results suggest that cholinergic signaling impairs upper airway dilator muscle activity by suppressing glutamatergic input from PH premotoneurons to HMNs and by directly inhibiting HMNs. Our findings highlight the complexity of cholinergic control of HMNs at both the presynaptic and postsynaptic levels and provide a possible mechanism for REM sleep suppression of upper airway muscle activity.SIGNIFICANCE STATEMENT Individuals with obstructive sleep apnea can breathe adequately when awake but experience repeated episodes of upper airway closure when asleep, in particular during REM sleep. Similar to skeletal postural muscles, pharyngeal dilator muscles responsible for maintaining an open upper airway become hypotonic during REM sleep. Unlike spinal motoneurons controlling postural muscles that are inhibited by glycinergic transmission during REM sleep, hypoglossal motoneurons that control the upper airway muscles are inhibited in REM sleep by the combination of monoaminergic disfacilitation and cholinergic inhibition. In this study, we demonstrated how cholinergic signaling inhibits hypoglossal motoneurons through presynaptic and postsynaptic muscarinic receptors. Our results provide a potential mechanism for upper airway hypotonia during REM sleep.

Exposure to mild intermittent hypoxia increases loop gain and the arousal threshold in participants with obstructive sleep apnoea

Exposure to mild intermittent hypoxia increases loop gain and the arousal threshold in participants with obstructive sleep apnoea

Progesterone receptor isoform B expression in pulmonary neuroendocrine cells decreases cell proliferation

The progesterone receptor (PR) has been reported to play important roles in lung development and function, such as alveolarization, alveolar fluid clearance (AFC) and upper airway dilator muscle activity. In the lung, pulmonary neuroendocrine cells (PNECs) are important in the etiology and progression of lung neuroendocrine tumors (NETs). Women with lung NETs had significantly better survival rates than men, suggesting that sex steroids and their receptors, such as the PR, could be involved in the progression of lung NETs. The PR exists as two major isoforms, PRA and PRB. How the expression of different PR isoforms affects proliferation and the development of lung NETs is not well understood. To determine the role of the PR isoforms in PNECs, we constructed H727 lung NET cell models expressing PRB, PRA, Green Fluorescence Protein (GFP) (control). The expression of PRB significantly inhibited H727 cell proliferation better than that of PRA in the absence of progestin. The expression of the unrelated protein, GFP, had little to no effect on H727 cell proliferation. To better understand the role of the PR isoform in PNECs, we examined PR isoform expression in PNECs in lung tissues. A monoclonal antibody specific to the N-terminus of PRB (250H11 mAb) was developed to specifically recognize PRB, while a monoclonal antibody specific to a common N-terminus epitope present in both PRA and PRB (1294 mAb) was used to detect both PRA and PRB. Using these PR and PRB-specific antibodies, we demonstrated that PR (PRA&PRB) and PRB were expressed in the PNECs of the normal fetal and adult lung, with significantly higher PR expression in the fetal lung. Interestingly, PRB expression in the normal lung was associated with lower cell proliferation than PR expression, suggesting a distinct role of PRB in the PNECs. A better understanding of the molecular mechanism of PR and PR isoform signaling in lung NET cells may help in developing novel therapeutic strategies that will benefit lung NET patients in the future.

The effects of noradrenergic and antimuscarinic agents on upper airway dilator muscle activity, breathing and sleep in healthy individuals

The effects of noradrenergic and antimuscarinic agents on upper airway dilator muscle activity, breathing and sleep in healthy individuals

Desipramine improves upper airway collapsibility and reduces OSA severity in patients with minimal muscle compensation.

We recently demonstrated that desipramine reduces the sleep-related loss of upper airway dilator muscle activity and reduces pharyngeal collapsibility in healthy humans without obstructive sleep apnoea (OSA). The aim of the present physiological study was to determine the effects of desipramine on upper airway collapsibility and apnoea-hypopnea index (AHI) in OSA patients.A placebo-controlled, double-blind, randomised crossover trial in 14 OSA patients was performed. Participants received treatment or placebo in randomised order before sleep. Pharyngeal collapsibility (critical collapsing pressure of the upper airway (Pcrit)) and ventilation under both passive (V'0,passive) and active (V'0,active) upper airway muscle conditions were evaluated with continuous positive airway pressure (CPAP) manipulation. AHI was quantified off CPAP.Desipramine reduced active Pcrit (median (interquartile range) -5.2 (4.3) cmH2O on desipramine versus -1.9 (2.7) cmH2O on placebo; p=0.049) but not passive Pcrit (-2.2 (3.4) versus -0.7 (2.1) cmH2O; p=0.135). A greater reduction in AHI occurred in those with minimal muscle compensation (defined as V'0,active-V'0,passive) on placebo (r=0.71, p=0.009). The reduction in AHI was driven by the improvement in muscle compensation (r=0.72, p=0.009).In OSA patients, noradrenergic stimulation with desipramine improves pharyngeal collapsibility and may be an effective treatment in patients with minimal upper airway muscle compensation.

Effects of Depth of Propofol and Sevoflurane Anesthesia on Upper Airway Collapsibility, Respiratory Genioglossus Activation, and Breathing in Healthy Volunteers.

Volatile anesthetics and propofol impair upper airway stability and possibly respiratory upper airway dilator muscle activity. The magnitudes of these effects have not been compared at equivalent anesthetic doses. We hypothesized that upper airway closing pressure is less negative and genioglossus activity is lower during deep compared with shallow anesthesia. In a randomized controlled crossover study of 12 volunteers, anesthesia with propofol or sevoflurane was titrated using a pain stimulus to identify the threshold for suppression of motor response to electrical stimulation. Measurements included bispectral index, genioglossus electromyography, ventilation, hypopharyngeal pressure, upper airway closing pressure, and change in end-expiratory lung volume during mask pressure drops. A total of 393 attempted breaths during occlusion maneuvers were analyzed. Upper airway closing pressure was significantly less negative at deep versus shallow anesthesia (-10.8 ± 4.5 vs. -11.3 ± 4.4 cm H2O, respectively [mean ± SD]) and correlated with the bispectral index (P < 0.001), indicating a more collapsible airway at deep anesthesia. Respiratory genioglossus activity during airway occlusion was significantly lower at deep compared with light anesthesia (26 ± 21 vs. 35 ± 24% of maximal genioglossus activation, respectively; P < 0.001) and correlated with bispectral index (P < 0.001). Upper airway closing pressure and genioglossus activity during airway occlusion did not differ between sevoflurane and propofol anesthesia. Propofol and sevoflurane anesthesia increased upper airway collapsibility in a dose-dependent fashion with no difference at equivalent anesthetic concentrations. These effects can in part be explained by a dose-dependent inhibiting effect of anesthetics on respiratory genioglossus activity.

Phasic respiratory modulation of pharyngeal collapsibility via neuromuscular mechanisms in rats

Obstructive sleep apnea patients experience recurrent upper airway (UA) collapse due to decreases in the UA dilator muscle activity during sleep. In contrast, activation of UA dilators reduces pharyngeal critical pressure (Pcrit, an index of pharyngeal collapsibility), suggesting an inverse relationship between pharyngeal collapsibility and dilator activity. Since most UA muscles display phasic respiratory activity, we hypothesized that pharyngeal collapsibility is modulated by respiratory drive via neuromuscular mechanisms. Adult male Sprague-Dawley rats were anesthetized, vagotomized, and ventilated (normocapnia). In one group, integrated genioglossal activity, Pcrit, and maximal airflow (V(max)) were measured at three expiration and five inspiration time points within the breathing cycle. Pcrit was closely and inversely related to phasic genioglossal activity, with the value measured at peak inspiration being the lowest. In other groups, the variables were measured during expiration and peak inspiration, before and after each of five manipulations. Pcrit was 26% more negative (-15.0 ± 1.0 cmH(2)O, -18.9 ± 1.2 cmH(2)O; n = 23), V(max) was 7% larger (31.0 ± 1.0 ml/s, 33.2 ± 1.1 ml/s), nasal resistance was 12% bigger [0.49 ± 0.05 cmH(2)O/(ml/s), 0.59 ± 0.05 cmH(2)O/(ml/s)], and latency to induced UA closure was 14% longer (55 ± 4 ms, 63 ± 5 ms) during peak inspiration vs. expiration (all P < 0.005). The expiration-inspiration difference in Pcrit was abolished with neuromuscular blockade, hypocapnic apnea, or death but was not reduced by the superior laryngeal nerve transection or altered by tracheal displacement. Collectively, these results suggest that pharyngeal collapsibility is moment-by-moment modulated by respiratory drive and this phasic modulation requires neuromuscular mechanisms, but not the UA negative pressure reflex or tracheal displacement by phasic lung inflation.

Changes in lung volume and diaphragm muscle activity at sleep onset in obese obstructive sleep apnea patients vs. healthy-weight controls

Obese obstructive sleep apnea (OSA) patients potentially defend end-expiratory lung volume (EELV) during wakefulness via increased expiratory diaphragmatic activity (eEMG(dia)). A reduction in eEMG(dia) and EELV at sleep onset could, therefore, increase upper airway collapsibility via reduced tracheal traction. The aim of this study was to establish if eEMG(dia) is greater in obese OSA patients vs. healthy-weight controls during wakefulness, and to compare eEMG(dia) and EELV changes at sleep onset between groups as a function of stable breathing, hypopnea vs. apnea events developing within the first few breaths after sleep onset. Eight obese men with OSA and eight healthy-weight men without OSA were studied in the supine position while instrumented with an intraesophageal catheter to measure eEMG(dia) and magnetometer coils to assess changes in EELV. While eEMG(dia) expressed as %maximal activity was not significantly different between groups during wakefulness, OSA patients experienced a greater fall in eEMG(dia) following sleep onset (group × breath, P < 0.001) and a greater decrease when respiratory events accompanied sleep onsets (category × breath, P < 0.001). The decrease in EELV by the third postsleep onset breath was small (OSA, 61.4 ± 8.0 ml, P < 0.001; controls, 34.0 ± 4.2 ml, P < 0.001), with the decrease significantly greater in OSA patients over time (group × breath, P = 0.007). There was a greater decrease with more severe events (category × breath, P < 0.001), with EELV decreasing by 89.6 ± 14.2 ml (P < 0.001) at the onset of apneas in the OSA group. These data support that diaphragm tone and EELV frequently decrease following sleep onset, with greater falls at transitions accompanied by respiratory events. In addition to decrements in upper airway dilator muscle activity, decreasing lung volume potentially contributes to an increased propensity for upper airway collapse in OSA patients at sleep onset.

Down‐regulation of hypoxia inducible factor‐1α: a possible explanation for the protective effects of estrogen on genioglossus fatigue resistance

Patients with obstructive sleep apnea/hypopnea syndrome (OSAHS) often exhibit fatigued or inefficient upper airway dilator muscle activity. It has been shown that estrogen may have some impact on upper airway contractility under normoxic conditions. Chronic intermittent hypoxia (CIH) is a frequent feature of OSAHS, and it may alter muscle susceptibility to oxidative stress, a characteristic of a fatigable nature. Hypoxia inducible factor-1 (HIF-1) is a transcription factor that is responsible for the regulation of oxygen homeostasis under hypoxic conditions. We examined the effects of estrogen on the contractility of the genioglossus by exposing rats to alternating cycles of 6-8% O(2) every 15 s for a total duration of 35 d. The results showed that muscle fatigue resistance was significantly decreased after CIH but was partially reversed after estrogen treatment. Compared with the control group, real-time reverse transcription-polymerase chain reaction and western blotting showed higher levels of HIF-1alpha messenger RNA and protein in the CIH group, but estrogen treatment reduced, in a dose-independent manner, the levels of HIF-1alpha messenger RNA and protein in rats exposed to CIH. We conclude that CIH induced the expression of HIF-1alpha in the genioglossus and altered the physical properties towards a more fatigable phenotype, whereas estrogen inhibited the over-expression of HIF-1alpha, and this may account for the improvement of upper airway muscle endurance in CIH rats.

Auto-PEEP to Treat Obstructive Sleep Apnea

In this issue of the Journal of Clinical Sleep Medicine, Rosenthal et al.1 describe the results of a study assessing the ability of nasal expiratory resistors (PROVENT™) to reduce sleep disordered breathing in a group of OSA patients with a relatively wide range of apnea severity. A study such as this raises a number of fundamental questions:

Pentobarbital Dose-dependently Increases Respiratory Genioglossus Muscle Activity while Impairing Diaphragmatic Function in Anesthetized Rats

Anesthetics depress both ventilatory and upper airway dilator muscle activity and thus put the upper airway at risk for collapse. However, these effects are agent-dependent and may involve upper airway and diaphragm muscles to varying degrees. The authors assessed the effects of pentobarbital on upper airway dilator and respiratory pump muscle function in rats and compared these results with the effects of normal sleep. Tracheostomized rats were given increasing doses of pentobarbital to produce deep sedation then light and deep anesthesia, and negative pressure airway stimuli were applied (n = 11). To compare the effects of pentobarbital with those of natural sleep, the authors chronically instrumented rats (n = 10) with genioglossus and neck electromyogram and electroencephalogram electrodes and compared genioglossus activity during wakefulness, sleep (rapid eye movement and non-rapid eye movement), and pentobarbital anesthesia. Pentobarbital caused a dose-dependent decrease in ventilation and in phasic diaphragmatic electromyogram by 11 +/- 0.1%, but it increased phasic genioglossus electromyogram by 23 +/- 0.2%. Natural non-rapid eye movement sleep and pentobarbital anesthesia (10 mg/kg intraperitoneally) decreased respiratory genioglossus electromyogram by 61 +/- 29% and 45 +/- 35%, respectively, and natural rapid eye movement sleep caused the greatest decrease in phasic genioglossus electromyogram (95 +/- 0.3%). Pentobarbital in rats impairs respiratory genioglossus activity compared to the awake state, but the decrease is no greater than seen during natural sleep. During anesthesia, in the absence of pharyngeal airflow, phasic genioglossus activity is increased in a dose-dependent fashion.

Management of neuromuscular block: time for a change?

Management of neuromuscular block: time for a change?

Neostigmine but not sugammadex impairs upper airway dilator muscle activity and breathing

BackgroundCholinesterase inhibitor-based reversal agents, given in the absence of neuromuscular block, evoke a partial upper airway obstruction by decreasing skeletal upper airway muscle function. Sugammadex reverses neuromuscular block by encapsulating rocuronium. However, its effects on upper airway integrity and breathing are unknown. MethodsFifty-one adult male rats were anaesthetized with isoflurane, tracheostomized, and a femoral artery and vein were cannulated. First, we compared the efficacy of sugammadex 15 mg kg−1 and neostigmine 0.06 mg kg−1 to reverse respiratory effects of rocuronium-induced partial paralysis [train-of-four ratio (T4/T1)=0.5]. Subsequently, we compared the safety of sugammadex and neostigmine given after recovery of the T4/T1 to 1, by measuring phasic genioglossus activity and breathing. ResultsDuring partial paralysis (T4/T1=0.5), time to recovery of minute volume to baseline values was 10.9 (2), 75.8 (18), and 153 (54) s with sugammadex, neostigmine, and placebo, respectively (sugammadex was significantly faster than neostigmine and placebo, P<0.05). Recovery of T4/T1 was also faster for sugammadex than neostigmine and placebo. Neostigmine administration after complete recovery of T4/T1 decreased upper airway dilator muscle activity to 64 (30)% of baseline and decreased tidal volume (P<0.05 for both variables), whereas sugammadex had no effect on either variable. ConclusionsIn contrast to neostigmine, which significantly impairs upper airway dilator muscle activity when given after recovery from neuromuscular block, a reversal dose of sugammadex given under the same conditions does not affect genioglossus muscle activity and normal breathing. Human studies will be required to evaluate the clinical relevance of our findings.

Differential Effects of Isoflurane and Propofol on Upper Airway Dilator Muscle Activity and Breathing

Anesthesia impairs upper airway integrity, but recent data suggest that low doses of some anesthetics increase upper airway dilator muscle activity, an apparent paradox. The authors sought to understand which anesthetics increase or decrease upper airway dilator muscle activity and to study the mechanisms mediating the effect. The authors recorded genioglossus electromyogram, breathing, arterial blood pressure, and expiratory carbon dioxide in 58 spontaneously breathing rats at an estimated ED50 (median effective dose) of isoflurane or propofol. The authors further evaluated the dose-response relations of isoflurane under different study conditions: (1) normalization of mean arterial pressure, or end-expiratory carbon dioxide; (2) bilateral lesion of the Kölliker-Fuse nucleus; and (3) vagotomy. To evaluate whether the markedly lower inspiratory genioglossus activity during propofol could be recovered by increasing flow rate, a measure of respiratory drive, the authors performed an additional set of experiments during hypoxia or hypercapnia. In vagally intact rats, tonic and phasic genioglossus activity were markedly higher with isoflurane compared with propofol. Both anesthetics abolished the genioglossus negative pressure reflex. Inspiratory flow rate and anesthetic agent predicted independently phasic genioglossus activity. Isoflurane dose-dependently decreased tonic and increased phasic genioglossus activity, and increased flow rate, and its increasing effects were abolished after vagotomy. Impairment of phasic genioglossus activity during propofol anesthesia was reversed during evoked increase in respiratory drive. Isoflurane compared with propofol anesthesia yields higher tonic and phasic genioglossus muscle activity. The level of respiratory depression rather than the level of effective anesthesia correlates closely with the airway dilator muscle function during anesthesia.

Pharyngeal motor control and the pathogenesis of obstructive sleep apnea

The upper airway in patients with obstructive sleep apnea (OSA) is thought to collapse during sleep at least in part, because of a sleep related reduction in upper airway dilator muscle activity. Therefore, a comprehensive understanding of the neural regulation of these muscles is warranted. The dilator muscles can be classified in two broad categories; those that have respiratory related activity and those that fire constantly throughout the respiratory cycle. The motor control of these two groups likely differs with the former receiving input from respiratory neurons and negative pressure reflex circuits. The activity of both muscle groups is reduced shortly after sleep onset, indicating that both receive input from brainstem neurons involved in sleep regulation. In the apnea patient, this may lead to pharyngeal airway collapse. This review briefly describes the currently proposed sleep and respiratory neural pathways and how these circuits interact with the upper airway dilator muscle motorneurones, including recent evidence from animal studies.

Functional contribution of mandibular advancement to awake upper airway patency in obstructive sleep apnea

In the narrowed upper airway of patients with obstructive sleep apnea (OSA), a neuromuscular compensatory mechanism augments the activity of the upper airway dilator muscles in defense of upper airway patency, particularly during inspiration. We hypothesized that mechanical enlargement of the upper airway by a mandibular advancement oral appliance would permit a reduction in this neuromuscular compensation during wakefulness. To test this hypothesis, we focused on changes in the cross-sectional (CS) area of the upper airway before and after emplacement of a ventrally titrated oral appliance in 12 awake OSA patients. The CS areas at the end of tidal expiration (CS area-EET) and at the nadir of intraluminal pressure during inspiration (CS area-IN) were obtained using videoendoscopy. The median apnea-hypopnea index decreased with mandibular advancement. Before mandibular advancement, there was no difference between CS area-EET and CS area-IN in the velopharynx, oropharynx, and hypopharynx. This indicates that upper airway dilator muscle activity increased during inspiration to counteract the intraluminal negative pressure of the upper airway. After mandibular advancement, CS area-EET increased in the velopharynx, oropharynx, and hypopharynx, but CS area-IN was unchanged at any level and was less than CS area-EET in the velopharynx and oropharynx. These findings suggest that mandibular advancement enlarges the upper airway and may reduce upper airway dilator muscle activity during inspiration. We conclude that oral appliances act to return the upper airway towards a normal configuration and pattern of muscle function in OSA patients.

Genioglossus reflex inhibition to upper-airway negative-pressure stimuli during wakefulness and sleep in healthy males.

During wakefulness, obstructive sleep apnoea patients appear to compensate for an anatomically narrow upper airway by increasing upper airway dilator muscle activity, e.g. genioglossus, at least partly via a negative-pressure reflex that may be diminished in sleep. Previous studies have assessed the negative-pressure reflex using multi-unit, rectified, moving-time-average EMG recordings during brief pulses of negative upper-airway pressure. However, moving-time averaging probably obscures the true time-related reflex morphology, potentially masking transient excitatory and inhibitory components. This study aimed to re-examine the genioglossus negative-pressure reflex in detail, without moving-time averaging. Bipolar fine-wire electrodes were inserted per orally into the genioglossus muscle in 17 healthy subjects. Two upper airway pressure catheters were inserted per nasally. Genioglossus EMG reflex responses were generated via negative-pressure stimuli (approximately -10 cmH2O at the choanae, 250 ms duration) delivered during wakefulness and sleep. Ensemble-averaged, rectified, genioglossus EMG recordings demonstrated reflex activation (onset latency 26+/-1 ms; peak amplitude 231+/-29% of baseline) followed by a previously unreported suppression (peak latency 71+/-4 ms; 67+/-8% of baseline). Single-motor-unit activity, clearly identifiable in approximately 10% of trials in six subjects, showed a concomitant increase in the interspike interval from baseline (26+/-9 ms, P=0.01). Genioglossus negative-pressure reflex morphology and amplitude of the initial peak were maintained in non-rapid eye movement (NREM) sleep but suppression amplitude was more pronounced during NREM and declined further during REM sleep compared to wakefulness. These data indicate there are both excitatory and inhibitory components to the genioglossus negative-pressure reflex which are differentially affected by state.