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Journal of Physiology (2001), 537.1, pp. 251-265
© Copyright 2001 The Physiological Society
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ABSTRACT |
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INTRODUCTION |
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Obstruction of the upper airway (UA) due to collapse of the pharynx is a common event during sleep. When the pharynx narrows, inspiratory efforts generate less airflow, but produce large negative pressures across the wall of the extra-thoracic airway below the site of obstruction. Upper airway negative pressure (UANP) distorts mechanoreceptors in the airway wall, inducing reflex responses including an increase in UA muscle activity and an inhibition of motor drive to the diaphragm (Mathew et al. 1982a,b; Amis et al. 1999). Activation of UA muscles serves to dilate and stabilize the UA while a reduction in diaphragm activity limits the collapsing inspiratory negative transmural pressure to which the UA is subjected. These reflex changes protect and maintain UA patency (Sant'Ambrogio et al. 1995).
While the rat is widely used as an experimental animal particularly for neurophysiological and neuropharmacological studies, the reflex responses to upper airway negative pressure have only been briefly explored in this species. Zhang & Bruce (1998) reported that genioglossus muscle activity is excited by UANP but this study did not confirm that the response was reflex in nature by determining the afferent pathway(s). A number of studies performed in other species have found that the superior laryngeal nerve (SLN) is the major afferent pathway mediating the reflex response to UANP (Mathew et al. 1982c; Mathew, 1984; Hwang et al. 1984a). However, other UA afferents, including the glossopharyngeal and trigeminal nerves, have been shown in different studies to contribute to, modify, or even play a dominant role in mediating the response to negative pressure (Mathew et al. 1982c; Hwang et al. 1984a; Horner et al. 1991; Curran et al. 1997). We conducted this study to examine in detail the respiratory responses to UANP in the anaesthetized rat and the role of the SLN as an afferent pathway for these responses.
UANP increases activity in muscles that dilate the UA (Mathew et al. 1982b; Mathew, 1984; van Lunteren et al. 1984; Amis et al. 1999). However, skeletal muscles surrounding the UA also include those that function to constrict the airway lumen, notably the tongue retractors (hyoglossus and styloglossus) and the pharyngeal constrictors. The function of these muscles is currently being re-evaluated as recent evidence suggests that under certain conditions airway constrictor muscle activity may stiffen (Fuller et al. 1998, 1999) or even dilate (Kuna & Vanoye, 1999) the UA resulting in an improvement of pharyngeal airflow mechanics and reduced airway collapsibility.
We hypothesized that UANP would activate tongue retractor and pharyngeal constrictor muscles, reflecting a role for these muscles in the maintenance of UA patency. We tested this hypothesis by examining the effect of UANP on efferent discharge in the lateral branch of the hypoglossal nerve (which innervates tongue retractors) and the pharyngeal branch of the vagus nerve (which innervates the pharyngeal constrictor muscles). We compared the responses obtained with those evoked in the medial branch of the hypoglossal nerve (which innervates the tongue protruder, the genioglossus) and the pharyngeal branch of the glossopharyngeal nerve (which innervates the pharyngeal dilator stylopharyngeus).
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METHODS |
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General procedures
Experiments were performed in 49 adult male Sprague-Dawley rats. Surgical anaesthesia was induced with sodium pentobarbitone (60 mg kg-1 I.P; Sagatal, Rhone Merieux, Ireland). The work was performed under license from the Department of Health and Children, Ireland, and conformed to national and university guidelines regarding animal experimentation. 
-Chloralose (10 mg kg-1 I.V., Sigma Aldrich, UK) was administered as required to maintain a stable systemic arterial pressure and respiratory rate as well as to suppress reflex withdrawal, arterial pressure and respiratory responses to paw pinch. The rats were placed in a supine position. Rectal temperature was monitored using a rectal thermistor probe and maintained at 37 °C with a thermostatically controlled heating blanket (Harvard homeothermic blanket system, Harvard Instruments, Kent, UK). The right femoral artery and vein were cannulated to record systemic arterial pressure (Statham P23Dd, Heto Rey, PR, USA) and for injection of drugs, respectively.
A midline ventral neck incision exposed the trachea, which was divided between the fifth and sixth cartilage rings, and a cannula was inserted into the caudal cut end. Care was taken to preserve the recurrent laryngeal nerves. The method of ventilation differed between experiments. Fourteen animals were allowed to breathe spontaneously through the tracheal cannula. Oxygen-enriched air was delivered past the tracheal cannula by means of a T-tube. The phrenic nerves were left intact. A bilateral thoracotomy was performed in the remaining 35 animals and these were artificially ventilated (CWE SAR-830/P, Charles Ward Electronics, Ardmore, PA, USA). The ventilator was modified so that lung inflation occurred in response to phrenic nerve activity. A rectified, moving-time-averaged phrenic electroneurogram signal was processed by a custom-designed interface that detected the onset of phrenic activity and also its sharp decline at the beginning of the post-inspiratory period. The interface generated electronic pulses marking these events, and these pulses were used to control the ventilator. The system was set so that when the onset of inspiratory phrenic activity was detected, the ventilator began delivery of a constant inspiratory airflow (6-9 ml s-1; inspired O2 fraction, FI,O2 = 0.33) to the lungs, which was terminated upon detection of the onset of post-inspiration (typical tidal volume, VT = 2-3 ml). This mode of ventilation is referred to as phrenic-controlled ventilation (PCV). This allowed us to withhold lung inflation and examine the effect of lung volume feedback on the response to UANP. A pressure transducer within the ventilator monitored tracheal pressure.
Upper airway preparation
The UA was isolated by inserting a second cannula in the trachea, pointing cranially with its tip lying approximately 5 mm below the vocal cords. A tight-fitting plastic mask was applied to the snout and an airtight seal ensured by sealing with Vaseline (see Fig. 1). Atropine sulphate (0.01 mg kg-1, Antigen Pharmaceuticals, Ireland) was administered to suppress mucus secretions in the UA. The isolated UA was connected to a pressure reservoir via a solenoid valve so that pulses of positive or negative pressure could be applied. Pressure stimuli began at end-expiration and were of 5 s duration. Pressures in the range 0 to -30 cmH2O were used. The 0 cmH2O intervention was performed by activating the solenoid valve but with the reservoir at atmospheric pressure, and served as the control for all studies. In some experiments we also examined the response to positive transmural pressures of +5 and +10 cmH2O. In all experiments, pressure was applied simultaneously to both the nasal mask and upper tracheal cannula so that the entire UA was subjected to the transmural pressure change. The pressure applied to the UA was recorded in all experiments using a transducer (Validyne DP45, ± 35 cmH2O, Northridge, CA, USA) connected to the upper tracheal cannula. The pressure within the lumen of the UA was directly measured in six animals using a fine saline-filled catheter and pressure transducer (Statham P23Dd) inserted through the upper tracheal cannula and advanced until its tip exited through one nostril. Pressure was then measured at different points along the entire UA by withdrawing the catheter in 5 mm increments, until its tip reappeared below the glottis.
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Figure 1. Schematic diagram of rat upper airway preparation | ||
In experiments using PCV, the responses to pressure stimuli applied during ongoing ventilation were compared to those obtained when lung inflation was withheld, eliminating phasic lung volume feedback, for the duration of the pressure stimulus. Airflow through the UA signified a leak in the system and was detected using a pneumotachograph and differential pressure transducer (Fleisch 00 and Validyne DP45 ± 2 cmH2O, see Fig. 1). Trials where airflow through the UA occurred were discarded and the leak eliminated by adjustment of the snout mask.
Nerve recording
All neural recordings were obtained using glass suction electrodes. Electrodes were pulled using a Narshige electrode puller (PC-10), broken back until the bore diameter matched that of the cut end of the nerve and fire polished (Intracel Microforge). Activity was amplified (Neurolog NL100AK pre-amplifier and NL104 amplifier, gain 20 000, Digitimer, Welwyn Garden City, UK), filtered (0.3-2 kHz, NL125), processed by a leaky integrator (time constant 100 ms, NL703) and fed to an audiomonitor and an oscilloscope.
The right phrenic nerve was identified at C5 and cut distally in all animals except those that were allowed breathe spontaneously. To access the hypoglossal (XII) and pharyngeal motor nerves the posterior belly of the digastric muscle on the right side was detached from the hyoid arch. The right XII nerve was identified as it looped over the external carotid. Efferent motor activity in the XII nerve was recorded either by sectioning the main trunk and recording from the cut central end (n = 8) or by separately sectioning the medial and lateral branches and simultaneously recording from their cut central ends (n = 8). Neural recordings were also obtained in a separate series of experiments from the central cut end of the pharyngeal branch of the vagus (PH-X, n = 8) or the pharyngeal branch of the glossopharyngeal nerve (PH-IX, n = 8). PH-IX recordings were obtained distal to the point where the carotid sinus nerve joins the glossopharyngeal nerve, and the carotid sinus nerve remained intact. The main trunk of the right SLN was identified and sectioned distal to its communication with the aortic nerve in six experiments, and neural recordings of whole nerve SLN afferent activity were made from the cut distal stump.
Experimental protocols
A stable plane of light anaesthesia was obtained following surgical procedures. During each experimental protocol, all neural signals together with blood pressure, tracheal pressure, upper airway pressure and upper airway airflow were recorded and stored onto computer using a CED micro1401 interface and Spike 2 software (CED, Cambridge, UK). Six series of experiments were conducted. The first series examined the effect of UANP in the range 0 to -30 cmH2O on the motor discharge of the XII main trunk in eight spontaneously breathing animals. A second series (n = 6 spontaneously breathing animals) recorded the pressure detected at points along the UA when -20 cmH2O was applied. The third series investigated the response to UANP in the range 0 to -30 cmH2O on PH-IX motor nerve activity in eight animals ventilated using PCV. The fourth series determined the effects of UA transmural pressures in the range +10 to -30 cmH2O on motor activity in the PH-X (n = 8) and in the medial and lateral branches of the XII nerve (n = 8) using PCV. We also examined the influence of UA pressure changes on the amplitude and timing of phrenic nerve activity in these animals (n = 16). Pressure stimuli applied with normal ongoing phrenic-driven lung inflation were compared to those where lung inflation was temporarily withheld. In each of the above series of experiments, the responses to UA pressure were recorded before and after bilateral section of the superior laryngeal nerves. The fifth series examined the effect of UA transmural pressures ranging from +10 to -30 cmH2O on the activity of the whole right SLN in six PCV animals. A final series of five experiments examined the effect of electrical stimulation (Grass S44 and SIU5 stimulus isolation unit, 0.5 ms pulse duration, intensity 0.1-3 V, frequency 5-30 Hz, train duration 5 s) of the cut central end of the right SLN using a bipolar silver electrode on ipsilateral XII and phrenic motor nerve activity.
Arterial blood gas samples were drawn intermittently to monitor arterial partial pressures of O2 and CO2 (Pa,O2, Pa,CO2), and arterial pH (pHa) level (Ciba Corning 278 blood gas system). Sodium bicarbonate (1 M) was administered intravenously as required to correct metabolic acidosis. At the end of each experiment animals were killed by an overdose of sodium pentobarbitone (200 mg kg-1 I.V.).
Data analysis
The activity of all nerves was quantified in arbitrary units (a.u.) where 1 a.u. was defined as a change of 1 mV in the amplitude of the integrated electroneurogram. Amplifier gain was the same, at 20 000, for all recordings from upper airway motor nerves. The phasic inspiratory activity of UA motor nerves was measured as the difference between the tonic end-expiratory activity for the preceding breath and the peak activity reached during inspiration. Phasic inspiratory activity was measured for the first breath of each stimulus to avoid effects attributable to changes in arterial blood gas composition. We also measured the change in end-expiratory UA motor nerve activity on the first breath of each pressure stimulus compared with the control breath immediately preceding the stimulus. Afferent discharge in the whole SLN was quantified by recording the level of activity above electrical zero at end-inspiration and end-expiration. The latter value was taken to be tonic activity and the difference between these values as the degree of inspiratory modulation of this activity.
Phrenic nerve activity was quantified in experiments using PCV and data were obtained only from the first breath of each pressure stimulus. Inspiratory time (TI) was recorded as the interval between the onset of phrenic nerve activity and the beginning of its sharp decline at the end of inspiration. Total respiratory cycle time (TTOT) was recorded as the interval between the onset of phrenic inspiratory activity and the onset of the inspiratory burst of the next respiratory cycle. We calculated expiratory time (TE) by subtracting TI from TTOT. The amplitude of phrenic nerve activity was measured at its peak (PHRmax) and the rate of rise of phrenic nerve activity (phrenic slope, PHRslope) calculated by dividing PHRmax by TI.
Analysis of variance (ANOVA) for repeated measures was used to test statistical hypothesis. The Student-Newman-Keuls test was used for post hoc multiple comparisons. Data were log transformed when required to eliminate skewness or to homogenize variance across groups. P < 0.05 was accepted as indicating a statistically significant effect.
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RESULTS |
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The group mean (± S.E.M., n = 49) Pa,O2 at the time recordings were made was 191 ± 12 mmHg, Pa,CO2 was 43.1 ± 0.7 mmHg and pHa was 7.39 ± 0.02.
Effect of UANP on XII main trunk activity in spontaneously breathing rats
UANP increased XII nerve activity in the spontaneously breathing rat (Fig. 2A). A significant increase in XII activity occurred on the first breath of the -5 cmH2O stimulus (P < 0.001, Fig. 2C). The magnitude of the response increased as more negative pressures were applied (P < 0.001) until a maximal response was obtained upon exposure to -20 cmH2O. The magnitude of the response to -30 cmH2O was not significantly greater than that to -20 cmH2O. End-expiratory XII activity significantly increased on the first breath of -20 and -30 cmH2O UANP stimuli (P < 0.01, Fig. 2C). Bilateral SLN section significantly increased phasic inspiratory XII nerve activity (P < 0.001, Fig. 2D) and abolished the responses to UANP. While XII nerve activity at 0 cmH2O transmural pressure increased after cutting the SLNs it was significantly less than the maximum activity evoked by UANP (-30 cmH2O) with both SLNs intact (P < 0.001).
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Figure 2. The effect of upper airway negative pressure on motor activity in the main trunk of the hypoglossal (XII) nerve in spontaneously breathing rats The original record shows the response to -20 cmH2O upper airway pressure before (A) and after (B) bilateral section of the superior laryngeal nerves (SLNs). Graphs show group mean (± S.E.M., n = 8) phasic inspiratory XII discharge (circles) and end-expiratory activity (diamonds) on the first breath of exposure to upper airway negative pressure (UANP), before (filled symbols, C) and after (open symbols, D) bilateral SLN section. *Significant effect of the applied pressure compared to 0 cmH2O (P < 0.05, ANOVA and Student-Newman-Keuls test). §P < 0.05 comparing activity at 0 cmH2O before and after SLN section. | ||
PH-IX motor response to UANP
Negative pressure significantly increased phasic inspiratory PH-IX activity during the first recorded breath of each pressure intervention (P < 0.001, Fig. 3A) in eight PCV animals. This increase in PH-IX activity saturated at -20 cmH2O UANP. Pressures of -20 and -30 cmH2O also evoked a significant (P < 0.05, data not shown) increase in tonic end-expiratory activity. Failure to inflate the lungs significantly increased inspiratory PH-IX activity (P < 0.05, Fig. 3C). However, lung inflation did not alter the activity evoked by UANP (P > 0.4). Bilateral SLN section significantly increased PH-IX activity (P < 0.01, Fig. 3D) and also abolished the response evoked by UANP. PH-IX nerve activity at 0 cmH2O transmural pressure increased after cutting the SLNs; the level of activity observed was significantly less than the maximum activity evoked by UANP (-30 cmH2O) with both SLNs intact (P < 0.001).
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Figure 3. Responses of the pharyngeal branch of the glossopharyngeal nerve (PH-IX) to UANP in rats with phrenic-controlled ventilation The original record shows the response to -20 cmH2O upper airway pressure before (A) and after (B) bilateral section of the SLNs. The graphs show group mean (± S.E.M., n = 8) PH-IX responses to UANP stimuli applied during ongoing lung inflation (circles) or together with temporary cessation of ventilation (squares) before (filled symbols, C) and after (open symbols, D) bilateral section of the SLN. *P < 0.05 compared with 0 cmH2O. §P < 0.05 comparing activity at 0 cmH2O before and after SLN section. | ||
Effect of UA pressure changes on motor activity of the medial and lateral branches of XII
The medial and lateral branches of XII both exhibited phasic inspiratory activity under baseline conditions and the activity of both branches was increased by UANP (Fig. 4 and Fig. 5). Baseline activity of lateral XII was significantly less than that of the medial XII (P < 0.01, Fig. 5). The phasic inspiratory activity of both XII branches increased in response to UANP (P < 0.001) and there was no significant difference between the branches in their responses to UANP (P = 0.51). Increases in end-expiratory medial XII branch activity were observed but were statistically significant only when pressures of -20 and -30 cmH2O were applied without lung inflation (P < 0.05, data not shown). While there were changes in tonic lateral XII discharge in response to UANP in some animals, there was no significant effect across the experimental group. Positive UA pressure caused a small but significant decrease in phasic inspiratory activity of both XII branches when the lungs inflated (P < 0.01, Fig. 5A and C). This effect was only demonstrable in the medial branch at +10 cmH2O when lung inflation was withheld.
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Figure 4. Responses to UANP of the medial and lateral branches of the hypoglossal nerve The effect of -20 cmH2O UANP in a rat with phrenic-controlled ventilation (PCV) before (A) and after (C) bilateral section of the superior laryngeal nerve. The middle panel (B) shows the effect of a no-inflation test on phrenic and hypoglossal branch discharge, where the thick lines are the discharge on a control breath with normal lung inflation and the thin lines superimposed on these are the discharge in the next breath where lung inflation was withheld. | ||
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Figure 5. Group mean (± S.E.M., n = 8) responses to changes in upper airway pressure of the medial and lateral branches of the hypoglossal nerve The response to changes in upper airway transmural pressure in the medial (A and B) and lateral (C and D) hypoglossal branches before (A and C) and after (B and D) bilateral section of the superior laryngeal nerves are shown. UA transmural pressure stimuli were applied during ongoing lung inflation (circles) or together with temporary cessation of ventilation (squares). *Significant response (P < 0.05) compared to 0 cmH2O. †Significant difference (P < 0.05) in nerve activity with lung inflation. §P < 0.05 comparing phasic inspiratory hypoglossal branch activity at 0 cmH2O before and after bilateral SLN section. | ||
Failure to inflate the lungs significantly increased activity in both the medial and lateral branch of the XII (P < 0.001). While in general lung inflation did not alter the activity evoked by UANP, lateral XII branch activity at -30 cmH2O was significantly greater when the lungs did not inflate (Fig. 5C). Bilateral SLN section significantly increased phasic inspiratory activity in both XII branches (P < 0.001, Fig. 4 and Fig. 5) and abolished the responses to both positive and negative UA pressures. The activity of both branches at 0 cmH2O transmural pressure after cutting the SLNs was significantly less than the maximum activity evoked by UANP (-30 cmH2O) with both SLNs intact (P < 0.01).
Effect of UA pressure changes on PH-X motor activity
Phasic inspiratory activity was consistently recorded from PH-X in all eight animals studied (Fig. 6). UANP significantly increased (P < 0.001) and positive UA pressure decreased (P < 0.001) this activity (Fig. 7A). The response to UANP was maximal at pressures of -20 cmH2O. End-expiratory PH-X activity significantly increased on the first breath of exposure to -20 cmH2O and -30 cmH2O (P < 0.01, data not shown). Bilateral SLN section increased PH-X discharge (P < 0.001) and abolished the response to both positive and negative UA pressures (Fig. 7B). The PH-X nerve activity at 0 cmH2O transmural pressure after cutting the SLNs was significantly less than the maximum activity evoked by UANP (-30 cmH2O) with both SLNs intact.
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Figure 6. The effect of UANP on the activity of the pharyngeal branch of the vagus (PH-X) The effect of -20 cmH2O UANP in a PCV rat before (A) and after (B) bilateral section of the SLN. | ||
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Figure 7. Group mean (± S.E.M., n = 8) response of the pharyngeal branch of the vagus (PH-X) to changes in upper airway pressure The PH-X response to pressure stimuli before (A, filled symbols) and after (B, open symbols) bilateral SLN section. The nerve activity recorded in the presence of normal lung inflation (circles) is compared to that recorded when lung inflation was withheld (squares). *P < 0.05 compared with 0 cmH2O. †P < 0.05 comparing lung inflation with failure to inflate the lungs. §P < 0.05 comparing 0 cmH2O before and after SLN section. | ||
Failure to inflate the lungs increased PH-X activity at 0 cmH2O UA transmural pressure (P = 0.0002, Fig. 7A). This effect of withdrawing lung inflation was more marked after SLN section. The level of PH-X activity recorded during UANP stimuli, delivered with ongoing PCV, was not significantly different from that seen when ventilation was withheld except for pressures of -10 cmH2O.
Effect of changes in UA pressure and lung volume feedback on the pattern of central respiratory activity
UANP prolonged TI (P < 0.001) but only when the lungs did not inflate (Fig. 8A). Withholding lung inflation alone also increased TI (P < 0.001). Prolongation of TI by negative pressure was abolished by SLN section. Positive UA pressures had no significant effect on TI.
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Figure 8. Group mean (± S.E.M., n = 16) effect of changes in upper airway pressure on respiratory timing and rate of rise of phrenic nerve activity in inspiration A, inspiratory time, and B, expiratory time, for the first breath of pressure stimuli with (circles) and without (squares) lung inflation before (filled symbols) and after (open symbols) SLN section. C and D, effect of changes in upper airway pressure on phrenic slope on the first breath of pressure stimuli with (circles) and without (squares) lung inflation, before (filled symbols, C) and after (open symbols, D) SLN section. *P < 0.05 compared with 0 cmH2O. † (A and B) significant effect (P < 0.05) of lung inflation at all pressures studied. N.S. (C and D), P > 0.05 for effect of lung inflation. | ||
UANP significantly reduced TE (P < 0.001, Fig. 8B). Failure to inflate the lungs also significantly reduced TE (P < 0.001). Positive UA pressures did not influence TE. Bilateral SLN section abolished the effect of UANP on TE but did not alter the effect of lung inflation.
UANP significantly reduced the rate of rise of phrenic nerve discharge during inspiration (P < 0.001, Fig. 8C). This effect saturated at -20 cmH2O. No significant change in phrenic slope in response to positive pressure was observed. The reduction in phrenic slope was sufficient to significantly reduce the peak level of phrenic activity (PHRmax) recorded at the end of inspiration (P < 0.001, data not shown). Withdrawal of lung volume feedback did not have any significant effect on phrenic slope (P = 0.65), nor its response to negative pressure (P = 0.69). After bilateral section of the SLN there was no significant effect of UANP on phrenic slope (Fig. 8D). Bilateral section of the SLN had no significant effect on the baseline TI, TE, PHRslope or PHRmax recorded at 0 cmH2O UA transmural pressure.
SLN afferent response to UA pressure changes
We recorded tonic afferent activity from the cut distal end of the whole right SLN nerve in all six animals studied. This tonic discharge was modulated by respiration in four animals with a decrease in whole nerve activity during neural inspiration (Fig. 9A). This modulation was not always stable over time (Fig. 9B). UANP inhibited tonic expiratory SLN activity (Fig. 9A and C). This effect was statistically significant at the smallest transmural pressure examined (-5 cmH2O) and pressures more negative than this did not have a significantly greater effect on SLN afferent activity. There was a large phasic increase in SLN afferent discharge in neural inspiration during negative pressure stimuli in all six animals (Fig. 9A), reversing the modulation seen at zero transmural pressure in some animals. UANP reduced SLN afferent activity whether we recorded only end-expiratory activity (Fig. 9C) or measured the mean activity over the whole respiratory cycle (Fig. 9D). Positive airway pressures of +5 and +10 cmH2O evoked an immediate significant increase in tonic SLN discharge that showed no respiratory modulation. The response to +10 cmH2O was significantly greater than that to +5 cmH2O. At the termination of positive pressure stimuli a rebound inhibition of SLN activity was observed which returned to baseline levels within a few breaths (Fig. 9B).
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Figure 9. Effect of changes in upper airway pressure on afferent activity in the SLN Original traces show the change in whole-nerve SLN afferent discharge in response to negative pressure (A) and positive pressure (B). Graphs show group mean (± S.E.M. n = 6) data for end-expiratory (or tonic) activity measured at the end of the first breath of the pressure stimuli (C) and also the mean activity averaged over the entire first respiratory cycle (D). *P < 0.05 compared to 0 cmH2O. | ||
Direct measurement of UA transmural pressure
Figure 10 shows the pressure measured at different points along the airway when -20 cmH2O UANP was applied simultaneously to both the face mask and upper tracheal cannula, as it was for all experiments reported above. The applied pressure was detected at all points along the length of the airway, though the stimulus was somewhat attenuated in a region 40-50 mm from the external nares. Bilateral SLN section did not alter the pressure recorded within the UA.
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Figure 10. Group mean (± S.E.M. n = 6) results of direct measurement of upper airway pressure in spontaneously breathing rats Graph shows mean pressure recorded at discrete points along the length of the upper airway from the external nares to below the glottis when a known pressure of -20 cmH2O was applied simultaneously to the face mask and upper tracheal cannula before ( | ||
Effect of electrical stimulation of the SLN on activity of the whole XII and phrenic nerve
Electrical stimulation of the SLN at 10 Hz and voltages greater than 0.5 V significantly reduced PHRmax (P < 0.001, Fig. 11A and B) and decreased PHRslope (P < 0.01, data not shown). There was no significant change in TI at any stimulus voltage (P > 0.39) but TE was significantly prolonged (P < 0.05). As a result there was a significant increase in total respiratory cycle time (P < 0.05). Phasic XII activity was significantly reduced (P < 0.001, Fig. 11A and C) even at the lowest voltage of 0.1 V (Fig. 11C). When SLN stimulation induced a swallow, a large post-inspiratory burst of XII activity was observed. Stimulation at 5 Hz gave qualitatively similar but less marked responses, while higher frequency trains (20 and 30 Hz) produced similar effects at low stimulus intensity and apnoea with or without swallowing at high stimulus intensity (data not shown).
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Figure 11. Influence of SLN stimulation on phrenic and whole XII nerve activity in PCV rats A, effect of electrical stimulation of the SLN at a frequency of 10 Hz, 0.5 ms pulse width and 1 V, for the period marked SLN stim. The burst of hypoglossal discharge on the last breath of the stimulus occurs during post-inspiration and represents an evoked swallow. The group mean (± S.E.M. n = 5) effect of SLN stimulation (10 Hz, 0.5 ms pulse width) over a range of voltages (0.1-3 V) on peak phrenic amplitude (B) and phasic hypoglossal activity (C) on the first breath of the stimulus ( | ||
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DISCUSSION |
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There are three major new findings arising from this study. First, UANP increases the activity of a wide variety of UA motor nerves in the rat, including motor nerves to tongue retractor and pharyngeal constrictor muscles. Second, the SLN is the major afferent pathway mediating the responses to UANP in this species. Third, ongoing activity in SLN afferent fibres at zero transmural pressure exerts a marked tonic inhibitory effect on UA motor outflow.
Effect of UA pressure changes on UA motor nerve activity
A major objective of the present study was to describe in detail the reflex responses to UANP in the anaesthetized rat, given the potential utility of this species for studies of the central neurophysiology and neuropharmacology of these responses. Our initial experiments in anaesthetized spontaneously breathing animals clearly showed that subatmospheric pressures within the isolated UA cause a reflex increase in the motor discharge of the hypoglossal nerve. Our results support the recent study by Zhang & Bruce (1998) who found an increase in genioglossus activity in response to UANP in the urethane-anaesthetized rat, though the reported increase in genioglossus muscle activity was very much less than the increase in XII nerve activity seen in our experiments.
UANP reflexly activates a variety of UA muscles in the species studied to date (Mathew et al. 1982b; Mathew, 1984; van Lunteren et al. 1984; Amis et al. 1999). We set out to confirm that, in the rat, responses to UANP could be observed in pharyngeal motor nerves other than the XII. We compared the responses of the pharyngeal branch of the glossopharyngeal nerve with those of the hypoglossal nerve because (i) it is a different cranial nerve, (ii) it supplies a muscle of the pharyngeal wall rather than that of the tongue, and (iii) its response to UANP has not been studied. The PH-IX innervates the stylopharyngeus muscle (Bieger & Hopkins, 1987), which acts to pull the lateral walls of the pharynx upwards and outwards and is thus considered to be an airway dilator (Guilleminault et al. 1978). PH-IX exhibited phasic inspiratory activity at rest and was recruited in response to UANP. This accords with the finding in decerebrate cats that single fibres of the PH-IX discharge during inspiration and are reflexly activated by electrical stimulation of the superior laryngeal nerve (Grelot et al. 1989).
Studies of the reflex UA motor responses to UANP have focused on those muscles that, on anatomical grounds, would be expected to dilate the airway. There are no studies on the muscles that are traditionally thought to narrow the airway, such as the tongue retractors (hyoglossus and styloglossus) and the pharyngeal constrictors. This is an important gap in our knowledge, because the function of these muscles is currently under review. Recent work suggests an important role for the tongue retractor muscles in stabilizing the pharyngeal airway (Schwartz et al. 1993; Eisele et al. 1995; Fuller et al. 1998). When the tongue retractor muscles are electrically stimulated together with the genioglossus, the combined action of these antagonist muscles leads to a significantly greater reduction in airway collapsibility than activation of the genioglossus muscle alone (Fuller et al. 1999). Similarly, while the pharyngeal constrictor muscles have long been known to actively close the pharynx during swallowing, new evidence indicates that activation of the pharyngeal constrictors stiffens the pharyngeal wall and under certain conditions may even dilate the airway (Kuna & Vanoye, 1999).
These observations suggest that tongue retractor and pharyngeal constrictor muscles will be recruited to defend airway patency, and indeed these muscles are activated by hypoxia and hypercapnia (Kuna & Vanoye, 1997; Kuna et al. 1997; Fuller et al. 1998; O'Halloran et al. 1999). However, distortion of UA mechanoreceptors by negative transmural pressure is a specific signal that the UA is narrow or obstructed. If muscles are activated by this stimulus, it strongly suggests they act to prevent pharyngeal collapse. The present study demonstrates that UANP causes a reflex increase in motor activity in both the medial and lateral XII and in the PH-X, so that tongue retractor and pharyngeal constrictor muscles would be recruited by this stimulus. These data suggest that when the pharynx narrows and the transmural pressures across the wall of the extra-thoracic airway become more negative, the ensuing reflex motor response is not confined to airway 'dilators' but involves a variety of muscles with differing individual actions. It is a limitation of the present study that we recorded activity from motor nerves rather than electromyographic signals from individual muscles of interest, and therefore cannot know which individual tongue retractor or pharyngeal constrictor muscles are activated by UANP.
PH-X exhibited only phasic inspiratory activity under our experimental conditions, but pharyngeal constrictor muscles are usually reported to increase their activity in expiration (Sherrey & Megirian, 1974; Kuna & Vanoye, 1997; O'Halloran et al. 1999). However, single fibres of PH-X with inspiratory discharge have been detected (Grelot et al. 1989), and may be especially prominent in the rat (Frugiere & Barillot, 1994). Furthermore, recordings from the inferior pharyngeal constrictor in chronically instrumented sleeping rats showed only phasic inspiratory activity, and that this activity depended upon body position (Sherrey et al. 1986). The mounting evidence that pharyngeal constrictor muscles may be involved in the maintenance of UA patency should prompt a re-evaluation of the significance of inspiratory activities in these muscles and the various factors that promote or suppress this activity.
We also examined the effect of UA positive pressures on the discharge of the medial and lateral branches of XII and PH-X. Positive pressure significantly reduced, or tended to reduce, the activity of these motor outflows, though the effect was relatively small compared with the response to negative transmural pressure. This is in agreement with prior reports showing a reduction in genioglossus electromyographic activity in response to UA positive pressures in anaesthetized rats and rabbits (Mathew et al. 1982b; Zhang & Bruce, 1998).
Role of the SLN in mediating the UA motor response to UA pressure changes
A major objective of this study was to confirm that the UA motor responses to changes in UA pressure were reflex in nature by defining the afferent pathway for these responses. Bilateral section of the SLN abolished the effect of UA pressures on all the motor outflows studied. The majority of studies in other species suggest that the SLN plays a major role in the responses to airway pressure changes (Mathew et al. 1982c; Mathew, 1984; Hwang et al. 1984a), although most studies have shown that sensory receptors in the nasal cavity or the nasopharynx also make an important contribution (Mathew et al. 1982c; Hwang et al. 1984a; Horner et al. 1991; Curran et al. 1997). Nonetheless, Amis and co-workers (1999) failed to detect significant responses to UANP from the nasal airway in the anaesthetized dog. However, Curran and colleagues (1997) have shown that SLN section may alter the extent to which pressure changes applied via a nasal mask or tracheostomy are transmitted to the UA. They found that bilateral SLN section caused extensive collapse of the nasopharyngeal airway in sleeping dogs, so that this region was no longer exposed to applied negative pressures. However, we have demonstrated that under our experimental conditions, where pressure is applied simultaneously to the nasal mask and upper tracheal cannula, the entire UA is exposed to negative transmural pressure before and after cutting both SLNs. Given that we did not record a significant reflex response to UANP in any UA motor outflow after bilateral SLN section, and we have confirmed that the stimulus was applied to the entire UA, we conclude that receptors outside the larynx do not contribute to the response to UANP in the anaesthetized rat.
Bilateral section of the SLN significantly increased the phasic inspiratory activity of all UA motor nerves. This implies that afferent activity in the SLN exerts a tonic inhibitory influence on motor drive to UA muscles. While a small tonic influence of the SLN on the control of breathing has been demonstrated (Citterio et al. 1985), the present work is the first to describe a tonic effect on UA motor activity. However, it is an effect consistent with our knowledge of the discharge properties of SLN afferents. In the rat and rabbit, most superior laryngeal afferents are tonically active and are inhibited by negative transmural pressure (Tsubone et al. 1987; Sekizawa & Tsubone, 1991), so that whole-nerve recordings of afferent activity show a tonic discharge, which is reduced by negative transmural pressure. If UANP increases the motor drive to UA muscles in the rat by decreasing the activity of afferent fibres in the SLN, then one might expect that removal of SLN afferent input to the central nervous system by cutting these nerves might also increase UA motor outflow. We have shown this to be the case, so that reducing SLN afferent input to the brain stem by means of these two quite different interventions causes an increase in the activity of UA motor nerves, though the responses to UANP and SLN section were quantitatively different for each of the motor outflows studied. This strongly suggests that at least some of the UA motor response to UANP in the rat is due to disinhibition of UA motor neurons as a result of reduced tonic inhibition from SLN afferents.
We performed a set of experiments to ensure that UANP reduced SLN afferent discharge under our experimental conditions. The results obtained were similar to those of Sekizawa & Tsubone (1991) in that UANP brings about a clear reduction in whole-nerve SLN sensory activity. While there were differences between these two studies in how ongoing respiratory movement modulated SLN discharge, we found a significant reduction in activity whether expressed as tonic end-expiratory activity or mean activity across the whole respiratory cycle.
The relationship between alterations in SLN afferent activity and the evoked reflex changes in UA motor nerve activity is complex. UANP reduces SLN sensory discharge and reflexly increases pharyngeal motor activity. However, the response of whole SLN afferent activity to negative transmural pressure saturates at -5 to -10 cmH2O, while the reflex motor response does not saturate until more negative transmural pressures (approximately -20 cmH2O). Furthermore, positive pressure, despite producing a large increase in SLN afferent discharge, has a relatively small effect on UA motor activity. This suggests that the central processing of SLN afferent information is complex and non-linear.
The above considerations may only apply to the rat, as there are important species differences in the properties of laryngeal sensory receptors. While most superior laryngeal afferents are inhibited by negative pressure in the rat and rabbit (Tsubone et al. 1987; Sekizawa & Tsubone, 1991), the majority of SLN afferents are stimulated by negative transmural pressure in the dog and cat (Sant'Ambrogio et al. 1983; Hwang et al. 1984b). Despite this, UANP causes a reflex increase in upper airway muscle activity in all species studied (van Lunteren et al. 1984; Sant'Ambrogio et al. 1995; Zhang & Bruce, 1998). This suggests that the central mechanisms involved in elaborating the reflex response to UANP, which seem complex in the rat, may also vary across species.
Effect of lung inflation on the UA motor responses to UA pressure changes
The use of a ventilator driven by phrenic nerve activity allowed us to examine the effect of normal lung inflation on XII and PH-X motor activities and their responses to UANP. Failure to inflate the lungs significantly increased the activity of these UA motor nerves. Conversely, when the pharyngeal motor output was increased in response to UANP, withdrawal of lung inflation had no additional effect on UA motor nerve discharge. This is in contrast with findings in other species where reductions in lung volume feedback augment the genioglossus response to UANP (McNamara et al. 1986; Zhang & Mathew, 1992; Gauda et al. 1994). It appears that, in the rat, a reduction in SLN afferent activity in response to negative transmural pressure disinhibits UA motor neurons, as does the withdrawal of lung volume feedback. However, a simultaneous decrease in both these afferent inputs has no greater effect than an isolated reduction in feedback from one source alone. The interaction between pulmonary and superior laryngeal inputs in the control of pharyngeal motor outflows seems to be less significant in the rat than in other species.
The effect of UA pressure changes on phrenic nerve activity and respiratory timing
An important aspect of the reflex response to UANP is adjustment of the timing and magnitude of thoracic pump muscle activity. We were able to examine the interaction between UA pressure changes and lung volume feedback in controlling the timing and amplitude of phrenic nerve activity.
We, like others (Mathew & Farber, 1983; van Lunteren et al. 1984), observed a clear reduction in inspiratory drive to the diaphragm in response to UANP. This was expressed as a reduction in the rate of rise of phrenic activity during inspiration and, because this effect was more marked than the accompanying increase in TI, we also saw a reduction in peak inspiratory phrenic nerve activity (Mathew & Farber, 1983). These changes will reduce inspiratory pressure generation by the thoracic pump, and should limit the collapsing transmural pressure to which the airway is subjected. It has been reported that the reduction in peak inspiratory flow in response to UANP is more marked when lung volume feedback is reduced (Zhang & Mathew, 1992). We did not observe this effect; the reduction in phrenic slope in response to UANP was the same whether or not the lungs inflated.
While the inhibitory effect of UANP on the motor drive to the diaphragm is in agreement with previous reports (Mathew & Farber, 1983; van Lunteren et al. 1984) it does raise an interesting question. UANP reduces the activity of SLN afferents in the rat, and this evokes a reflex decrease in phrenic discharge. However, it is well known that electrical stimulation of SLN afferents also inhibits phrenic activity (Donnelly et al. 1989; Bellingham et al. 1989). Hayashi & McCrimmon (1996) report that sustained electrical stimulation of the SLN in the anaesthetized rat causes graded inhibition of the inspiratory motor activity of the phrenic, XII, PH-X and PH-IX nerves. We have confirmed that over a wide range of stimulus parameters, electrical stimulation of the ipsilateral SLN inhibits inspiratory activity in both the phrenic and XII nerves. We can only speculate on how electrical stimulation of the SLN and UANP-induced reductions in SLN afferent activity can both inhibit phrenic nerve discharge. We note that changes in transmural pressure alter the activity of a defined subgroup of laryngeal afferent fibres, but electrical stimulation of the SLN will recruit all fibres for which the stimulus is above threshold, irrespective of their sensory function. One possible explanation of our findings is that electrical stimulation of the SLN not only stimulates afferent fibres that respond to transmural pressure changes, but also excites other afferent fibres that exert a powerful and over-riding inhibitory effect on the central respiratory pattern generator.
UANP significantly prolonged TI, but only when the lungs did not inflate. Previous investigations in other species have also shown that UANP prolongs TI (Mathew & Farber, 1983; van Lunteren et al. 1984), but this effect is usually demonstrable in the presence of normal ongoing lung inflation, and is exaggerated when lung inflation is prevented (McNamara et al. 1986; Gauda et al. 1994). The only other study in the rat reports an extremely small effect of UANP on TI in spontaneously breathing animals (Zhang & Bruce, 1998). We conclude that the effectiveness of UANP in prolonging TI is reduced when the lungs expand in all species but this effect of lung inflation may be more marked in the rat, so that the TI response to UANP is small or absent in the presence of lung volume feedback in this species.
Expiratory time was significantly shortened by UANP in our study, an effect unaltered by inflation of the lungs. The most commonly reported positive finding is this regard is that UANP prolongs TE (Mathew & Farber, 1983; Citterio et al. 1985; Harms et al. 1996). A number of other studies (van Lunteren et al. 1984; Hwang et al. 1984b; McNamara et al. 1986; Gauda et al. 1994), including the previous work on the rat (Zhang & Bruce, 1998), show no significant effect on TE. The significance of our observation that UANP shortens TE is not clear.
We found that TI increased when the lungs did not inflate, a well-described phenomenon related to the role of lung volume feedback in the termination of inspiration (Clark & von Euler, 1972). However, failure to inflate the lungs is most commonly associated with either an increase (Sica et al. 1984; Bartlett & St John, 1988) or no change in TE (Bartoli et al. 1975), but we found that TE was reduced when lung inflation was withheld. The most likely explanation for this discrepancy is that it is artefactual. Inspection of our original records showed that withdrawal of lung inflation was associated with a slow decline in tracheal pressure relative to the end-expiratory pressure reached during normal ventilation. If lung volume were lower during the expiratory period of the no-inflation test, this relative deflation would tend to shorten TE (Knox, 1973).
Positive pressures applied to the UA had no effect on phrenic amplitude or respiratory timing. Studies that report responses to positive pressure for these variables find them to be smaller and less consistent than the responses to negative pressure (Mathew & Farber, 1983). It is of interest that bilateral SLN section did not affect baseline TI, TE or phrenic nerve activity. This implies that the tonic discharge of SLN afferents at zero UA transmural pressure has no effect on the control of phrenic nerve activity or respiratory pattern in the rat, which contrasts sharply with their marked tonic influence on UA motor outflow.
Conclusion
This study clearly demonstrates that in the rat, as in other species, subatmospheric pressures within the UA evoke significant reflex changes in the activity of UA and thoracic respiratory motor outflows, which seem to be a concerted attempt to stabilize the pharyngeal airway and minimize the collapsing stress to which it is subjected during inspiration. This reflex response is abolished by bilateral SLN section, and SLN afferents exert a tonic inhibitory influence on UA motor nerve activity. We also show that tongue retractor and pharyngeal constrictor muscles respond to UA transmural pressure changes which lends significant support to the idea that these muscles play a role in keeping the airway patent. Studies of the central neurophysiology and neuropharmacology of the reflex responses to UANP could usefully and practicably be conducted in rat, which has a clear response to this stimulus.
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Acknowledgements
This study was supported by the Health Research Board (Ireland).
Corresponding author
P. Nolan: Department of Human Anatomy and Physiology, Conway Institute for Biomolecular and Biomedical Research, University College Dublin, Earlsfort Terrace, Dublin 2, Ireland.
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) and after (
) bilateral section of the SLN. The glottis lay 55-60 mm from the external nares.
) is compared with the activity of a control breath (
) immediately preceding the stimulus. Note that the stimulus voltage scale is non-linear above 1.5 V.