Neuromechanical control of the isolated upper airway of mice

We characterized the passive structural and active neuromuscular control of pharyngeal collapsibility in mice and hypothesized that pharyngeal collapsibility, which is elevated by anatomic loads, is reduced by active neuromuscular responses to airflow obstruction. To address this hypothesis, we examined the dynamic control of upper airway function in the isolated upper airway of anesthetized C57BL/6J mice. Pressures were lowered downstream and upstream to the upper airway to induce inspiratory airflow limitation and critical closure of the upper airway, respectively. After hyperventilating the mice to central apnea, we demonstrated a critical closing pressure (Pcrit) of -6.2 +/- 1.1 cmH(2)O under passive conditions that was unaltered by the state of lung inflation. After a period of central apnea, lower airway occlusion led to progressive increases in phasic genioglossal electromyographic activity (EMG(GG)), and in maximal inspiratory airflow (Vi(max)) through the isolated upper airway, particularly as the nasal pressure was lowered toward the passive Pcrit level. Moreover, the active Pcrit fell during inspiration by 8.2 +/- 1.4 cmH(2)O relative to the passive condition (P < 0.0005). We conclude that upper airway collapsibility (passive Pcrit) in the C57BL/6J mouse is similar to that in the anesthetized canine, feline, and sleeping human upper airway, and that collapsibility falls markedly under active conditions. Active EMG(GG) and Vi(max) responses dissociated at higher upstream pressure levels, suggesting a decrease in the mechanical efficiency of upper airway dilators. Our findings in mice imply that anatomic and neuromuscular factors interact dynamically to modulate upper airway function, and provide a novel approach to modeling the impact of genetic and environmental factors in inbred murine strains.     

Effect of age and weight on upper airway function in a mouse model

Defects in pharyngeal mechanical and neuromuscular control are required for the development of obstructive sleep apnea. Obesity and age are known sleep apnea risk factors, leading us to hypothesize that specific defects in upper airway neuromechanical control are associated with weight and age in a mouse model. In anesthetized, spontaneously breathing young and old wild-type C57BL/6J mice, genioglossus electromyographic activity (EMG(GG)) was monitored and upper airway pressure-flow dynamics were characterized during ramp decreases in nasal pressure (Pn, cmH?O). Specific body weights were targeted by controlling caloric intake. The passive critical pressure (Pcrit) was derived from pressure-flow relationships during expiration. The Pn threshold at which inspiratory flow limitation (IFL) developed and tonic and phasic EMG(GG) activity during IFL were quantified to assess the phasic modulation of pharyngeal patency. The passive Pcrit increased progressively with increasing body weight and increased more in the old than young mice. Tonic EMG(GG) decreased and phasic EMG(GG) increased significantly with obesity. During ramp decreases in Pn, IFL developed at a higher (less negative) Pn threshold in the obese than lean mice, although the frequency of IFL decreased with age and weight. The findings suggest that weight imposes mechanical loads on the upper airway that are greater in the old than young mice. The susceptibility to upper airway obstruction increases with age and weight as tonic neuromuscular activity falls. IFL can elicit phasic responses in normal mice that mitigate or eliminate the obstruction altogether.     

Upper airway neuromuscular compensation during sleep is defective in obstructive sleep apnea

Obstructive sleep apnea is the result of repeated episodes of upper airway obstruction during sleep. Recent evidence indicates that alterations in upper airway anatomy and disturbances in neuromuscular control both play a role in the pathogenesis of obstructive sleep apnea. We hypothesized that subjects without sleep apnea are more capable of mounting vigorous neuromuscular responses to upper airway obstruction than subjects with sleep apnea. To address this hypothesis we lowered nasal pressure to induce upper airway obstruction to the verge of periodic obstructive hypopneas (cycling threshold). Ten patients with obstructive sleep apnea and nine weight-, age-, and sex-matched controls were studied during sleep. Responses in genioglossal electromyography (EMG(GG)) activity (tonic, peak phasic, and phasic EMG(GG)), maximal inspiratory airflow (V(I)max), and pharyngeal transmural pressure (P(TM)) were assessed during similar degrees of sustained conditions of upper airway obstruction and compared with those obtained at a similar nasal pressure under transient conditions. Control compared with sleep apnea subjects demonstrated greater EMG(GG), V(I)max, and P(TM) responses at comparable levels of mechanical and ventilatory stimuli at the cycling threshold, during sustained compared with transient periods of upper airway obstruction. Furthermore, the increases in EMG(GG) activity in control compared with sleep apnea subjects were observed in the tonic but not the phasic component of the EMG response. We conclude that sustained periods of upper airway obstruction induce greater increases in tonic EMG(GG), V(I)max, and P(TM) in control subjects. Our findings suggest that neuromuscular responses protect individuals without sleep apnea from developing upper airway obstruction during sleep.     

Contribution of male sex, age, and obesity to mechanical instability of the upper airway during sleep.

Male sex, obesity, and age are risk factors for obstructive sleep apnea, although the mechanisms by which these factors increase sleep apnea susceptibility are not entirely understood. This study examined the interrelationships between sleep apnea risk factors, upper airway mechanics, and sleep apnea susceptibility. In 164 (86 men, 78 women) participants with and without sleep apnea, upper airway pressure-flow relationships were characterized to determine their mechanical properties [pharyngeal critical pressure under hypotonic conditions (passive Pcrit)] during non-rapid eye movement sleep. In multiple linear regression analyses, the effects of body mass index and age on passive Pcrit were determined in each sex. A subset of men and women matched by body mass index, age, and disease severity was used to determine the sex effect on passive Pcrit. The passive Pcrit was 1.9 cmH(2)O [95% confidence interval (CI): 0.1-3.6 cmH(2)O] lower in women than men after matching for body mass index, age, and disease severity. The relationship between passive Pcrit and sleep apnea status and severity was examined. Sleep apnea was largely absent in those individuals with a passive Pcrit less than -5 cmH(2)O and increased markedly in severity when passive Pcrit rose above -5 cmH(2)O. Passive Pcrit had a predictive power of 0.73 (95% CI: 0.65-0.82) in predicting sleep apnea status. Upper airway mechanics are differentially controlled by sex, obesity, and age, and partly mediate the relationship between these sleep apnea risk factors and obstructive sleep apnea.     

Assessment of pharyngeal airway stability in normal and micrognathic infants

A current hypothesis for obstructive sleep apnea states that 1) negative airway pressure during inspiration can collapse the pharyngeal airway, and 2) neural control of pharyngeal airway-dilating muscles is important in preventing this collapse. To test this hypothesis we performed nasal mask occlusions to increase negative pharyngeal airway pressures during inspiration in eight normal and five micrognathic infants. Both groups developed midinspiratory pharyngeal obstruction, but obstruction was more frequent in micrognathic infants and varied in some infants with sleep state. The airway usually reopened with the subsequent expiration. The occasional failure to reopen was presumably due to pharyngeal wall adhesion. If airway obstruction occurred in sequential breaths during multiple-breath nasal mask occlusions in normal infants, there was a breath-by-breath change in the airway pressure associated with airway closure (airway closing pressure); the airway closing pressure became progressively more negative. Micrognathic infants showed less ability to improve the airway closing pressure, but this ability increased with age. These findings suggest that nasal mask occlusion can test the competence of the neuromuscular mechanisms that maintain pharyngeal airway patency in infants. Micrognathic infants had spontaneous midinspiratory pharyngeal airway obstructions during snoring. Their episodes of obstructive apnea began with midinspiratory pharyngeal obstruction similar to that seen during snoring and nasal mask occlusions. These findings imply a similar pathophysiology for snoring, spontaneous airway obstruction, and obstruction during snoring.     

Induction of airway collapse with subatmospheric pressure in awake patients with sleep apnea

To determine whether the pharyngeal airway is abnormal in awake patients with obstructive sleep apnea (OSA), we measured the ability of the pharyngeal airway to resist collapse from subatmospheric pressure applied to the nose in awake subjects, 12 with OSA and 12 controls. Subatmospheric pressure was applied to subjects placed in the supine position through a tightly fitting face mask. We measured airflow at the mask as well as mask, pharyngeal, and esophageal pressures. Ten patients developed airway obstruction when subatmospheric pressures between 17 and 40 cmH2O were applied. Obstruction did not occur in two patients with the least OSA. Obstruction did not occur in 10 controls; one obese control subject developed partial airway obstruction when -52 cmH2O was applied as did another with -41 cmH2O. We conclude that patients with significant OSA have an abnormal airway while they are awake and that application of subatmospheric pressure may be a useful screening test to detect OSA.     

Lung volume and collapsibility of the passive pharynx in patients with sleep-disordered breathing.

Lung volume dependence of pharyngeal airway patency suggests involvement of lung volume in pathogenesis of obstructive sleep apnea. We examined the structural interaction between passive pharyngeal airway and lung volume independent of neuromuscular factors. Static mechanical properties of the passive pharynx were compared before and during lung inflation in eight anesthetized and paralyzed patients with sleep-disordered breathing. The respiratory system volume was increased by applying negative extrathoracic pressure, thereby leaving the transpharyngeal pressure unchanged. Application of -50-cmH(2)O negative extrathoracic pressure produced an increase in lung volume of 0.72 (0.63-0.91) liter [median (25-75 percentile)], resulting in a significant reduction of velopharyngeal closing pressure of 1.22 (0.14-2.03) cmH(2)O without significantly changing collapsibility of the oropharyngeal airway. Improvement of the velopharyngeal closing pressure was directly associated with body mass index. We conclude that increase in lung volume structurally improves velopharyngeal collapsibility particularly in obese patients with sleep-disordered breathing.     

Compensatory responses to upper airway obstruction in obese apneic men and women

Defective structural and neural upper airway properties both play a pivotal role in the pathogenesis of obstructive sleep apnea. A more favorable structural upper airway property [pharyngeal critical pressure under hypotonic conditions (passive Pcrit)] has been documented for women. However, the role of sex-related modulation in compensatory responses to upper airway obstruction (UAO), independent of the passive Pcrit, remains unclear. Obese apneic men and women underwent a standard polysomnography and physiological sleep studies to determine sleep apnea severity, passive Pcrit, and compensatory airflow and respiratory timing responses to prolonged periods of UAO. Sixty-two apneic men and women, pairwise matched by passive Pcrit, exhibited similar sleep apnea disease severity during rapid eye movement (REM) sleep, but women had markedly less severe disease during non-REM (NREM) sleep. By further matching men and women by body mass index and age (n = 24), we found that the lower NREM disease susceptibility in women was associated with an approximately twofold increase in peak inspiratory airflow (P = 0.003) and inspiratory duty cycle (P = 0.017) in response to prolonged periods of UAO and an ～20% lower minute ventilation during baseline unobstructed breathing (ventilatory demand) (P = 0.027). Thus, during UAO, women compared with men had greater upper airway and respiratory timing responses and a lower ventilatory demand that may account for sex differences in sleep-disordered breathing severity during NREM sleep, independent of upper airway structural properties and sleep apnea severity during REM sleep.     

Modulation of upper airway collapsibility during sleep: influence of respiratory phase and flow regimen.

We hypothesized that upper airway collapsibility is modulated dynamically throughout the respiratory cycle in sleeping humans by alterations in respiratory phase and/or airflow regimen. To test this hypothesis, critical pressures were derived from upper airway pressure-flow relationships in six tracheostomized patients with obstructive sleep apnea. Pressure-flow relationships were generated by varying the pressure at the trachea and nose during tracheostomy (inspiration and expiration) (comparison A) and nasal (inspiration only) breathing (comparison B), respectively. When a constant airflow regimen was maintained throughout the respiratory cycle (tracheostomy breathing), a small yet significant decrease in critical pressure was found at the inspiratory vs. end- and peak-expiratory time point [7.1 +/- 1.6 (SE) to 6.6 +/- 1.9 to 6.1 +/- 1.9 cmH(2)O, respectively; P < 0.05], indicating that phasic factors exerted only a modest influence on upper airway collapsibility. In contrast, we found that the inspiratory critical pressure fell markedly during nasal vs. tracheostomy breathing [1.1 +/- 1.5 (SE) vs. 6.1 +/- 1.9 cmH(2)O; P < 0.01], indicating that upper airway collapsibility is markedly influenced by differences in airflow regimen. Tracheostomy breathing was also associated with a reduction in both phasic and tonic genioglossal muscle activity during sleep. Our findings indicate that both phasic factors and airflow regimen modulate upper airway collapsibility dynamically and suggest that neuromuscular responses to alterations in airflow regimen can markedly lower upper airway collapsibility during inspiration.     

Upper airway pressure-flow relationships in obstructive sleep apnea

We examined the pressure-flow relationships in patients with obstructive sleep apnea utilizing the concepts of a Starling resistor. In six patients with obstructive sleep apnea, we applied incremental levels of positive pressure through a nasal mask during non-rapid-eye-movement sleep. A positive critical opening pressure (Pcrit) of 3.3 +/- 3.3 (SD) cmH2O was demonstrated. As nasal pressure was raised above Pcrit, inspiratory airflow increased in proportion to the level of positive pressure applied until apneas were abolished (P less than 0.01). However, at pressures greater than Pcrit, esophageal pressures either did not correlate or correlated inversely with inspiratory airflow provided that esophageal pressure was less than Pcrit. When pressure was applied to a full face mask, inspiratory airflow did not occur and Pcrit could not be obtained at pressures well above Pcrit demonstrated with the nasal mask. These results are consistent with the view that the upper airway functions as a Starling resistor with a collapsible segment in the oropharynx. These findings offer a unifying construct for the association of sleep apnea, periodic hypopnea, and snoring.     

Pharyngeal resistance in normal humans: influence of gender, age, and obesity

Investigation into the etiology of obstructive sleep apnea is beginning to focus increasing attention on upper airway anatomy and physiology (patency and resistance). Before conclusions concerning upper airway resistance in these patients can be made, the normal range of supraglottic and, more specifically, pharyngeal resistance needs to be better defined. We measured supraglottic and pharyngeal resistances during nasal breathing in a normal population of 35 men and women. Our technique measured epiglottic pressure with a balloon-tipped catheter, choanal pressure using anterior rhinometry, and flow with a sealed face mask and pneumotachograph. Resistance was measured at a flow rate of 300 ml/s during inspiration. Men had a mean pharyngeal resistance (choanae to epiglottis) of 4.6 +/- 0.8 (SE) cmH2O X l-1 X s, whereas women demonstrated a significantly (P less than 0.01) lower value, 2.3 +/- 0.3 cmH2O X l-1 X s. Supraglottic resistance was also higher in men (P = 0.01). Age (r = 0.73, P less than 0.01) correlated closely with pharyngeal resistance in men, but no such correlations could be found in women. These results may have implications in the epidemiology of obstructive sleep apnea.     

Site and mechanics of spontaneous, sleep-associated obstructive apnea in infants.

To examine the mechanics of infantile obstructive sleep apnea (OSA), airway pressures were measured using a triple-lumen catheter in 19 infants (age 1-36 wk), with concurrent overnight polysomnography. Catheter placement was guided by correlations between measurements of magnetic resonance images and body weight of 70 infants. The level of spontaneous obstruction was palatal in 52% and retroglossal in 48% of all events. Palatal obstruction predominated in infants treated for OSA (80% of events), compared with 38.6% from infants with infrequent events (P = 0.02). During obstructive events, successive respiratory efforts increased in amplitude (mean intrathoracic pressures -11.4, -15.0, and -20.4 cmH(2)O; ANOVA, P < 0.05), with arousal after only 29% of the obstructive and mixed apneas. The soft palate is commonly involved in the upper airway obstruction of infants suffering OSA. Postterm, infant responses to upper airway obstruction are intermediate between those of preterm infants and older children, with infrequent termination by arousal but no persisting "upper airway resistance" and respiratory efforts exceeding baseline during the event.     

Effect of cleft palate repair and pharyngeal flap surgery on upper airway obstruction during sleep

The effect of von Langenbeck palatoplasty and pharyngeal flap surgery on upper airway obstruction during sleep was studied by obtaining polysomnographic sleep studies on 10 patients undergoing each procedure at 1 to 2 days prior to surgery, 2 to 3 days postoperatively, and approximately 3 months postoperatively. The effects of von Langenbeck palatoplasty on sleep-related upper airway obstruction were usually minimal and clinically insignificant, whereas severe obstructive sleep apnea was present in all but one of the patients undergoing pharyngeal flap surgery at 2 to 3 days postoperatively. In most patients the upper airway obstruction was resolved at the 3-month postoperative sleep study. These data suggest that palatoplasty carries with it a very slight risk of upper airway obstruction, whereas pharyngeal flap surgery has as a very frequent concomitant the occurrence of severe obstructive sleep apnea in the immediate postoperative period.     

Effects of leptin and obesity on the upper airway function

Obesity is associated with alterations in upper airway collapsibility during sleep. Obese, leptin-deficient mice demonstrate blunted ventilatory control, leading us to hypothesize that (1) obesity and leptin deficiency would predispose to worsening neuromechanical upper airway function and that (2) leptin replacement would acutely reverse neuromuscular defects in the absence of weight loss. In age-matched, anesthetized, spontaneously breathing C57BL/6J (BL6) and ob(-)/ob(-) mice, we characterized upper airway pressure-flow dynamics during ramp decreases in nasal pressure (P(N)) to determine the passive expiratory critical pressure (P(CRIT)) and active responses to reductions in P(N), including the percentage of ramps showing inspiratory flow limitation (IFL; frequency), the P(N) threshold at which IFL developed, maximum inspiratory airflow (Vi(max)), and genioglossus electromyographic (EMG(GG)) activity. Elevations in body weight were associated with progressive elevations in P(CRIT) (0.1 ± 0.02 cmH(2)O/g), independent of mouse strain. P(CRIT) was also elevated in ob(-)/ob(-) compared with BL6 mice (1.6 ± 0.1 cmH(2)O), independent of weight. Both obesity and leptin deficiency were associated with significantly higher IFL frequency and P(N) threshold and lower VI(max). Very obese ob(-)/ob(-) mice treated with leptin compared with nontreated mice showed a decrease in IFL frequency (from 63.5 ± 2.9 to 30.0 ± 8.6%) and P(N) threshold (from -0.8 ± 1.1 to -5.6 ± 0.8 cmH(2)O) and increase in VI(max) (from 354.1 ± 25.3 to 659.0 ± 71.8 μl/s). Nevertheless, passive P(CRIT) in leptin-treated mice did not differ significantly from that seen in nontreated ob(-)/ob(-) mice. The findings suggest that weight and leptin deficiency produced defects in upper airway neuromechanical control and that leptin reversed defects in active neuromuscular responses acutely without reducing mechanical loads.     

Variable site of airway narrowing among obstructive sleep apnea patients

The purpose of this was to determine whether the site of physiological narrowing within the upper airway was uniform or differed among patients with obstructive sleep apnea. Inspiratory pressures were measured with an esophageal balloon catheter and three catheters located at different sites along the upper airway: supralaryngeal airway, oropharynx, and nasopharynx. Peak inspiratory pressure differences between catheters allowed assessment of pressure gradients across three airway segments: lungs-larynx-retroepiglottal airway (esophageal-supralaryngeal pressure), hypopharynx (supralaryngeal-oropharynx pressure), and transpalatal airway (oropharynx-nasopharynx pressure). In five patients, hypopharyngeal obstruction was present, and in four patients no hypopharyngeal obstruction existed. In these four patients the site of obstruction was located at the level of the palate. In a given subject, the site of obstruction was the same during repeated measurements. The presence or absence of hypopharyngeal narrowing during sleep was not predictable from gradients measured across different segments of the upper airway during wakefulness. We conclude that the site of physiological upper airway obstruction varies among patients with obstructive sleep apnea and is not predictable from pressure measured during wakefulness. We speculate that uvulopalatopharyngoplasty may not relieve obstructive apneas in patients with hypopharyngeal obstruction.     

Influence of passive changes of lung volume on upper airways

The total upper airway resistances are modified during active changes in lung volume. We studied nine normal subjects to assess the influence of passive thoracopulmonary inflation and deflation on nasal and pharyngeal resistances. With the subjects lying in an iron lung, lung volumes were changed by application of an extrathoracic pressure (Pet) from 0 to 20 (+Pet) or -20 cmH2O (-Pet) in 5-cmH2O steps. Upper airway pressures were measured with two low-bias flow catheters, one at the tip of the epiglottis and the other in the posterior nasopharynx. Breath-by-breath resistance measurements were made at an inspiratory flow rate of 300 ml/s at each Pet step. Total upper airway, nasal, and pharyngeal resistances increased with +Pet [i.e., nasal resistance = 139.6 +/- 14.4% (SE) of base-line and pharyngeal resistances = 189.7 +/- 21.1% at 10 cmH2O of +Pet]. During -Pet there were no significant changes in nasal resistance, whereas pharyngeal resistance decreased significantly (pharyngeal resistance = 73.4 +/- 7.4% at -10 cmH2O). We conclude that upper airway resistance, particularly the pharyngeal resistance, is influenced by passive changes in lung volumes, especially pulmonary deflation.     

Mechanical properties of the passive pharynx in Vietnamese pot-bellied pigs. I. Statics.

The static mechanical properties of the passive pharynx were investigated in Vietnamese pot-bellied pigs by using an isolated upper airway preparation. During general anesthesia and neuromuscular blockade, cross-sectional area (A) of the pharynx was measured while airway pressure (Paw) was held at various pressures in the absence of airflow. The static A-Paw relationship was measured during application of 0, 1, and 2 cm of caudal tracheal displacement. Relative to humans, closing pressures (Pclose) of the pig pharynx were very low (-15 to -35 cmH(2)O). Tracheal displacement significantly decreased compliance of the hypopharynx (from 0.074 +/- 0.02 cm(2)/cmH(2)O with no displacement to 0.052 +/- 0.01 cm(2)/cmH(2)O with 2 cm of displacement) and decreased Pclose of the oropharynx (from -18.2 +/- 9.9 cmH(2)O to -24.1 +/- 10.5 and -28.7 +/- 12.3 cmH(2)O with 1 and 2 cm of displacement, respectively). Tracheal displacement did not affect A of the pharyngeal segments. In conclusion, tracheal displacement decreased collapsibility of the passive pharynx. The pharynx of the pot-bellied pig is structurally more resistant to collapse than the human pharynx.     

Effect of inspiratory nasal loading on pharyngeal resistance

Nasal obstruction has been shown to increase the number of apneas during sleep in normal subjects and in some may actually cause the sleep apnea syndrome. We postulated that the pharynx may act as a Starling resistor, where increases in negative inspiratory pressure result in elevated resistance across a collapsible pharyngeal segment. To test this theory in normal subjects we studied 10 men and 10 women during wakefulness. Pharyngeal resistance (the resistance across the airway segment between the choanae and the epiglottis) was determined in the normal state and with three inspiratory loads added externally. Flow was measured using a pneumotachometer and a sealed face mask; epiglottic pressure by a latex balloon placed just above the epiglottis and choanal pressure by anterior rhinometry. Pharyngeal resistance (measured at 300 ml/s) could thus be determined. Base-line inspiratory pharnygeal resistance was 1.6 +/- 0.2 cmH2O . l-1 . s. This increased to 2.3 +/- 0.3, 2.8 +/- 0.4, and 2.9 +/- 0.4 cmH2O . l-1 . s, respectively, with the addition of 1.3, 2.7, and 6.7 cmH2O . l-1 . s inspiratory load. The resistance at each level of load was significantly different from the base-line resistance determination (P less than 0.05) but not different from each other. We conclude that added nasal resistive loads during inspiration cause an increase in pharyngeal resistance during wakefulness but that this resistance does not increase further with additional increments of load.     

Pressure-volume behavior of the upper airway

The study was performed to investigate the relationship between force generation and upper airway expansion during respiratory efforts by upper airway muscles. In 11 anesthetized dogs we isolated the upper airway (nasal, oral, pharyngeal, and laryngeal regions) by transecting the cervical trachea and sealing the nasal and oral openings. During spontaneous respiratory efforts the pressure within the sealed upper airway, used as an index of dilating force, decreased during inspiration. On alternate breaths the upper airway was opened to a pneumotachograph, and an increase in volume occurred, also during inspiration. Progressive hyperoxic hypercapnia produced by rebreathing increased the magnitude of change in pressure and volume. At any level of drive, peak pressure or volume occurred at the same point during inspiration. At any level of drive, volume and pressure changes increased with end-expiratory occlusion of the trachea. The force-volume relationship determined from measurements during rebreathing was compared with pressure-volume curves performed by passive inflation of the airway while the animal was apneic. The relationship during apnea was 1.06 +/- 0.55 (SD) ml/cmH2O, while the force-volume relationship from rebreathing trials was -1.09 +/- 0.45 ml/cmH2O. We conclude that there is a correspondence between force production and volume expansion in the upper airway during active respiratory efforts.     

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.