Journal of Applied Physiology AJP: Heart and Circulatory Physiology
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J Appl Physiol 103: 600-607, 2007. First published May 24, 2007; doi:10.1152/japplphysiol.01286.2006
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Airway mechanoreceptor deactivation

J. Guardiola,1 M. Proctor,1 H. Li,1 R. Punnakkattu,1 S. Lin,1 and J. Yu1,2

Departments of 1Medicine, and 2Physiology and Biophysics, University of Louisville, Louisville, Kentucky

Submitted 14 November 2006 ; accepted in final form 28 April 2007


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Airway sensors play an important role in control of breathing. Recently, it was found that pulmonary slowly adapting stretch receptors (SARs) cease after a brief excitation following sodium pump blockade by ouabain. This deactivation can be explained by overexcitation. If this is true, mechanical stimulation of the SARs should also lead to a deactivation. In this study, we recorded unit activity of the SARs in anesthetized, open-chest, and mechanically ventilated rabbits and examined their responses to lung inflation at different constant pressures. Forty-seven of 137 units had a clear deactivation during the lung inflation. The deactivation threshold varied from unit to unit. For a given unit, the higher the inflation pressure, the sooner the deactivation occurs. For example, the SARs deactivated at 3.0 ± 0.3 and 4.8 ± 0.4 s when the lungs were inflated to constant pressures of 30 and 20 cmH2O, respectively (n = 25, P < 0.0001). The units usually ceased after a brief intense discharge. In some units, their activity shifted to a lower level, indicating a pacemaker switching. Our results support the notion that SARs deactivate due to overexcitation.

slowly adapting stretch receptors; lung inflation

THE BEHAVIOR OF THE PULMONARY slowly adapting receptor (SAR) has been investigated intensively since its identification decades ago (11) and has been reviewed extensively by various authors (3, 5, 18, 19, 23–25, 28). In a sensory unit, multiple receptors (or encoders) can coexist (29). An encoder is a part of the sensory neuron that can generate action potentials if it receives sufficient stimulation. Activities in a SAR unit are the result of multiple encoder interactions (integration), sending a chain of action potentials to the central nervous system, resulting in an unit action (28). Ouabain alters properties of the hippocampal neurons (22) and has been extensively used to investigate the sensory property of stretch receptors, such as renal pressure mechanoreceptors (12), atrial stretch receptors (30), and baroreceptors (10). Ouabain lowers activation thresholds of these sensors. Similarly, it affects the airway sensors, such as SARs (14, 26). SAR discharges paradoxically (cessation during lung inflation but very active during lung deflation) after ouabain was administered to block Na+-K+-ATPase (15). Ouabain's effects are believed to be on SARs directly but not mediated through alteration of airway smooth muscle, because no changes in lung mechanics are detected after ouabain treatment (13–15). By comparing SARs responses to lung mechanical changes before and after microinjection of ouabain locally to inactivate the sodium pump, the paradoxical discharge of SARs was found to result from overexcitation (26). The discharge pattern returned to normal (discharging more during lung inflation and less during deflation) after reducing the overall cyclic mechanical stimulation. Similar to mechanical activation of other mechanoreceptors, SARs convert mechanical energy, or stretch, into an electrical signal (7, 28). The greater the stretch, the greater the generator potential (GP) created within a SAR encoder. If the GP reaches the threshold, voltage-dependent sodium channels open and create action potentials. The discharge continues as long as the GP is above the threshold. The discharge frequency is directly proportional to the magnitude of the GP, which is proportional to the stretch intensity. Distribution of Na+ and K+ ions at the SAR sensory terminal membrane is restored by the sodium pump. Inhibition of Na+-K+-ATPase prevents ion restoration and prevents the GP from falling below the firing threshold for the SAR. As a result, the SAR discharges continuously. The GP increases as the lung is stretched during inspiration. If the potential is too great and is beyond the sodium conductance range, SAR activity ceases (26). Thus cessation of SAR activity results from overexcitation, not from inhibition. Conversely, increasing mechanical stimulation increases GP and should cause the same receptor behavior. In the current experiments, we attempted to reproduce and reinforce the ouabain phenomenon by using high-sustained mechanical stimulation of the SAR.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Experiments were performed on 45 New Zealand rabbits (body weight 2.0–2.4 kg) anesthetized intravenously with a 20% solution of urethane (1 g/kg). The rabbits were placed in a supine position on an operating table, and a tracheostomy was performed by a cervical midline dissection and cannulated. Airway pressure was monitored through the tracheal tube with a pressure transducer (Statham P23). Mechanical ventilation was provided at 10 ml/kg tidal volume and 3 cmH2O positive end-expiratory pressure. The chest was opened by a midline sternotomy. A polyethylene catheter was inserted into the femoral vein for administration of additional anesthesia or other agents as needed. A similar catheter was placed in the femoral artery to monitor arterial blood pressure.

The cervical vagus nerve of the recorded side was dissected from its carotid sheath and sectioned high in the neck. The peripheral end of the nerve was freed for 3–4 cm from the surrounding tissues and placed on a dissecting plate covered with paraffin oil. Nerve filaments were separated from the main trunk of the nerve with a pair of watchmaker forceps under a dissecting microscope. Each filament was then placed between a pair of platinum recording electrodes and connected to a high impedance probe, and the outputs were fed to a Grass amplifier. Dissection of each filament was continued until a single unit activity was recorded. Unit activity of SARs was identified by their regular discharge, which increased with each inspiration, and slow adaptation to a constant airway pressure inflation generated by an outside pressure source (27). Action potentials were monitored by a loud speaker and counted by a rate meter at a binwidth of 0.1 s. The raw signals of action potentials were also fed into a PowerLab (8sp, AD Instruments, Castle Hill, Australia) computer system for amplitude and duration analysis to ensure measurement of single unit activity. The receptive fields were identified by locating the most sensitive points in the lung with a cotton applicator.

During lung inflation, airway pressure was adjusted by connecting the opening of the tracheal tube to a reservoir, which was pressurized to the targeted airway pressure. Airway and arterial pressures were monitored by pressure transducers. These signals, along with action potentials, were recorded by an Astro-Med thermal recorder. All protocols conformed to the ethical requirements as stipulated by the Internal Animal Use and Care Committee of the University of Louisville.

We encountered 137 SAR units. Once a SAR unit was identified, the lungs were hyperinflated to a constant pressure of 30 cmH2O for 6–8 s. If the unit did not deactivate, it was considered a nonresponder. In some cases, the lungs were inflated to 20 and 10 cmH2O. It lasted ~6 s longer than the latency to deactivation at the previous higher inflation level. The discharge frequencies and latencies to deactivation were recorded and compared.

Encoder deactivation may be related to stretching force or its activity.

To differentiate between these two factors, we used a two-step test in another series of experiments with 19 SAR units. The lungs were first inflated to a control pressure (30–40 cmH2O), and the latency to deactivation was recorded. The SARs were then subjected to a priming pressure (half of the control, i.e., 15–20 cmH2O) for a short period of time (~4 s) before doubling it to the test pressure (30–40 cmH2O). The latency to deactivation at the test pressure was compared with the first latency observed.

In open-chest rabbits, application of high airway pressure decreased cardiac output, which reduced perfusion to the sensors. This reduction in perfusion may lead to SAR deactivation. To assess such a possibility, we examined SAR activity before and during reduction of perfusion (unilateral or bilateral pulmonary artery occlusion) for 2 min.


   RESULTS
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 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
One hundred thirty-seven SAR units were examined in 45 rabbits. Among them, 47 units deactivated during lung inflation to 30 cmH2O, evidenced by an abrupt decrease in activity. Figure 1 illustrates one such unit. Comparing discharge frequencies, activity during the predeactivation period was higher in responders (120 ± 4 imp/s; n = 47) than in nonresponders (97 ± 3 imp/s; n = 90). The difference was statistically significant (P < 0.001). Among the responders, there was a negative correlation between the latency and discharge frequencies, although not statistically significant. Thirty-four of the 47 SAR units dropped their activity to a low yet sustained level (Fig. 2). Some decreases were subtle (Fig. 3, C and D), whereas others were quite dramatic (Fig. 2, B–F). Thirteen SAR units ceased their activity completely (Fig. 3, D–G). The deactivation threshold varied widely from SAR to SAR. In a given unit, deactivation occurred more quickly at higher inflation pressures (Figs. 2 and 3). We examined the activity of 47 deactivated SAR units at two different levels of constant pressures (10 and 20 cmH2O). At 10 cmH2O, only one SAR deactivated during the inflation period, whereas at 20 cm H2O 25 SARs deactivated. Comparing paired data for these 25 SAR units, the deactivation latencies were shorter at 30 cmH2O (3.0 ± 0.3 s) than at 20 cmH2O (4.8 ± 0.4 s), and the discharge frequencies were higher at 30 cmH2O (124 ± 6 imp/s) than at 20 cmH2O (108 ± 4 imp/s). Both differences were statistically significant (n = 25; P < 0.0001). The inverse relationship between the latency and discharge frequency existed in all seven deactivated units tested at multiple levels of inflation pressure. Figure 4 illustrates five of the seven SARs tested.


Figure 1
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  		Fig. 1. Deactivation of a typical high-threshold slowly adapting receptor (SAR). The traces from top to bottom are impulses (imp)/s, where the SAR unit activity is counted by binwidth of 0.1 s; impulses, SAR activity; and airway pressure (Paw). A: a slow speed recording of the SAR in response to airway inflation pressure of 30 cmH2O. The unit gives an initial high discharge frequency, which gradually adapts and shows an abrupt, although small, decrease (indicated by the first arrow on top of the graph). The unit then continues to discharge at a lower level. On releasing the pressure, the unit activity rebounds (indicated by the second arrow). B and C: continuous recordings of this same unit with faster speed, showing the detailed behavior of the unit response. The unit discharges at high frequency initially and gradually adapts at the initial part of C. The unit shows a transition period (indicated by the black bar at the bottom of the figure), during which the unit discharge is relatively irregular, followed by a regular discharge at a lower level. On the release of inflation pressure, the unit decreases its discharge frequency and then rebounds after a brief period of inactivity (2.5 ms). The rebound activity is indicated by the second black bar. The paper speeds are indicated at the bottom of the figures.

 

Figure 2
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  		Fig. 2. Responses of a typical lower-threshold SAR unit to different levels of lung inflation. A–F are at 10, 15, 20, 25, 30, and 35 cmH2O, respectively. This SAR deactivates earlier at higher lung inflation pressures. The deactivations occurred at 7, 4.5, 3, 1.8, and 1.0 s after inflation to the pressures of 15, 20, 25, 30, 35 cmH2O, respectively. The deactivation is indicated by the arrow in each figure. Please note that, after each deactivation, the unit continued to discharge at a lower but constant level (activity is from low-frequency encode, i.e., encoder B), independent of airway pressure. G–I represent the responses to constant pressure inflation at 20, 30, and 35 cmH2O, respectively, after blocking encoder A (high discharging encoder) with 2% lidocaine (20 µl). Again, the receptor discharge is independent of Paw and is already saturated at the lowest inflation pressure. J–L are the unit's responses to the lung inflation at different pressures after recovery from the effect of the local anesthetic. Clearly, the source of the receptor discharge is from encoder A, since discharge occurs only in encoder B after deactivation of encoder A (B–F, K, and L).

 

Figure 3
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  		Fig. 3. Relationship between inflation pressure and latency to deactivation. A: positive end-expiratory pressure (PEEP) removal. B–G: recorded during lung inflation to 10, 20, 30, 35, 40, and 50 cmH2O, respectively. When the lung inflated to 30 cmH2O (D), the unit started to deactivate after a high-frequency discharge lasting 3.8 s (indicated by the second arrow). During the subsequent higher inflation pressures, the unit deactivated sooner at 2.4 s (35 cmH2O), 1.8 s (40 cmH2O), and 1 s (50 cmH2O) (indicated by arrows). The arrow in C and the first arrow in D indicate a subtle decrease in SAR activity, suggesting an encoder switch. Thus this unit demonstrates multiple encoder behavior.

 

Figure 4
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  		Fig. 4. Relationship between latency to deactivation and lung inflation pressure. This illustrates 5 of 7 sensory units, which have been tested and deactivated under multiple inflation pressures. Each symbol represents a specific unit. It appears that the relationship is not linear and that the units deactivated much faster under higher pressures.

 
In 19 SAR units, we used a two-step test (Figs. 5 and 6 ). Their discharge frequencies were 186 ± 7, 129 ± 7, and 191 ± 7 imp/s at the control pressure (30–40 cmH2O), priming pressure (15–20 cmH2O), and testing pressure (30–40 cmH2O), respectively. The latency to sensory deactivation was significantly shorter when the sensors were primed with a low level of inflation pressure (3.0 ± 0.4 s) vs. the control (6.0 ± 0.8 s; P < 0.0001). The action potentials discharged before deactivation, however, were similar in these two groups. It was 1,138 ± 176 imp in the control group and 1,187 ± 161 imp in the two-step testing group (P = 0.269). The pressure-time integral before deactivation was significantly higher in the control group (203 ± 36 cmH2O·s) than the testing group (176 ± 26 cmH2O·s; n = 19; P < 0.05).


Figure 5
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  		Fig. 5. Response of a typical high-threshold SAR to a two-step pressure regime (20 and 40 cmH2O). A: the SAR discharged vigorously (210 imp/s) as the lung was inflated to a pressure of 40 cmH2O and then deactivated after 12.5 s. On release of the airway pressure, the unit gave a burst discharge. B: the SAR unit was subjected to an inflation pressure of 20 cmH2O for 6 s, followed by 40 cmH2O for 7.5 s, and finally the pressure was returned to 20 cmH2O for ~4 s before normal ventilation was resumed. In this case, the unit discharged at 160 imp/s during the first period of 20-cmH2O lung inflation and at 210 imp/s when the pressure was increased to 40 cmH2O but deactivated after 6.5 s. On inflation pressure returning to 20 cmH2O, the unit discharged abruptly again at 140 imp/s. C: the SAR was first tested at an inflation pressure of 20 cmH2O for 10 s, followed by 40 cmH2O for 5.5 s, and then returned to 20 cmH2O for 2.5 s. With this longer priming period at a lower pressure, the unit deactivated even more quickly (4.5 s) at 40 cmH2O. D: the sensory unit did not deactivate at a constant pressure inflation of 20 cmH2O for 20 s.

 

Figure 6
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  		Fig. 6. A–C: responses of a typical low-threshold SAR to lung inflation pressures of 10, 20, and 30 cmH2O. At 30-cmH2O inflation, the unit deactivated 2 s after lung inflation. D and E: a typical response to a negative pressure deflation (–7 cmH2O; D) and PEEP removal (E). F: as the lung was inflated to 15 cmH2O, the unit discharged at 160 imp/s, then abruptly dropped to 130 imp/s after 5 s, indicating deactivation of a higher discharge encoder. The lower activity was maintained by encoder B. H: a two-step inflation regime (15 and 30 cmH2O). Again, the unit activity dropped from 170 to 140 imp/s after ~5 s at 15 cmH2O and increased sharply to 190 imp/s on further inflation to 30 cmH2O. Then, the unit deactivated completely, suggesting that both encoders A and B were deactivated at the higher pressure. When the inflation pressure was returned to 15 cmH2O, the unit remained silent. G: a two-step inflation regime (10 and 20 cmH2O). The unit discharged at 120 imp/s at the inflation pressure of 10 cmH2O, discharged at 190 imp/s at 20 cmH2O, and deactivated (encoder A) after only 1.5 s. The unit continued to discharge (encoder B) at 140 imp/s for 4 s before complete deactivation. After reduction of inflation pressure to 10 cmH2O, the unit abruptly resumed discharging, firing at 70 imp/s. This resumed activity could only be from encoder B, because encoder A discharged at 120 imp/s at an airway pressure of 10 cmH2O. By comparing G and H, and also C and F, it is obvious that encoder A has a higher discharge frequency, a lower deactivation threshold, and a higher reactivation threshold. Arrows (in C, F, G, and H) indicate deactivation of encoder A.

 
In addition, to rule out deactivation resulting from a reduction in sensory unit perfusion, we compared SAR activities before and 2 min after reduction of perfusion. There was no sensory receptor deactivation during this observation period, and control SAR activity (55 ± 10 imp/cycle) was not substantially different from that (70 ± 17 imp/cycle; n = 5; P > 0.05) at 2 min after occlusion of pulmonary artery.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Our results from mechanical stimulation of SARs support the theory that overexcitation deactivates SAR units, possibly due to exceeding the operating capacity of Na+-K+-ATPase. In 1933, Adrian (1) reported that, during extreme inflation of the lung, SARs discharge fell suddenly and became irregular and then ceased altogether. The discharge reappeared when lung inflation was reduced. He named this phenomenon the Wedensky effect and believed that it resulted from damage to the sensory apparatus. Farber et al. (8) reported that ~10% of SARs in the North American opossum (unilaterally vagotomized) displayed a breakup, followed by complete failure (i.e., deactivation) of discharge in response to static lung inflation of 20 cmH2O. Deactivation occurred most often when the discharge rate was very high. The authors did not comment on an underlying mechanism, however. Pack and his associates observed that two SAR units abruptly changed their behavior in response to ramp inflation of the lung (17). By measuring the variability in action potential intervals, they found differences before and after the abrupt changes. They reasoned that changes were due to a pacemaker switch or an encoder switch and suggested that a SAR unit may possess multiple encoders. Coexistence of multiple encoders in a single sensory unit has been reported in somatic sensory neurons (20) and SARs (29). Figure 1 shows abrupt changes in unit activity that demonstrate the encoder-switch theory. In our current study, a significant number of SARs (~25%; 34/137 units) exhibited encoder switch during lung hyperinflation, evidenced by their discharge frequency dropping sharply to a low level.

Figure 2 best illustrates an encoder switch, because the two encoders show dramatic differences in their discharge frequency. This unit possesses two encoders with higher (encoder A) and lower (encoder B) discharge frequencies. Encoder A deactivates before encoder B at the inflation pressures tested. SARs can be classified as type I or type II (16). Type I SARs plateau at inflation pressures above 10 cmH2O, whereas type II SARs show a linear response up to 30-cmH2O pressure. Encoder A discharge positively correlated with airway pressure (type II SAR), whereas encoder B discharge frequency plateaued at 15 cmH2O (type I SAR), demonstrating the coexistence of type I and type II SARs in a single unit. To prove that the unit activity is coming from two seperate encoders, we identified the sensory receptive fields and blocked encoder A by direct microinjection of 2% lidocaine (20 µl) into the receptive field. Figure 2, G–I, demonstrates the sole operation of encoder B. Thus this encoder switch was due to deactivation of the encoder with the high discharge frequency.

Figure 5 illustrates two points. First, after deactivation, the unit resumes activity after pressure release or reduction. The onset of the resumed activity is marked. Thus the sensory unit ceases activity and then reactivates abruptly, oscillating between zero and high frequencies (Figs. 5, A–C, and 6, C and G). This indicates that the sensory unit resumes activity at a higher level of excitation. Second, sensory deactivation correlates more closely with unit activity than with airway pressure. Under constant pressure inflation, deactivation depends on both inflation pressure and length of time. In a given unit, the higher the inflation pressure, the earlier the unit deactivates (Fig. 4). The two most likely factors for deactivation are 1) stretch intensity and 2) receptor activity. It is clear that unit activity is a better determinant than airway pressure. The sensor deactivates earlier if primed with a lower level pressure and deactivates even more quickly if the priming duration is extended. That less airway pressure was required during the two-step test was probably due to the nonlinear relationship between airway pressure and sensory activity. The discharge frequencies are the same under both control and test pressures. At priming pressure (half of the control pressure), the discharge frequency was far greater than 50% of the control, reaching 70%. Thus less pressure is needed to fire the same number of action potentials. This deactivation can be explained by increased consumption of ATP. ATP is continuously produced. At a low activation level, ATP production is adequate, and there is no deactivation. This explains why, at low levels of lung inflation, SARs may not deactivate, as observed by Davenport and Sant'Ambrogio (6). At a very high activation level, the demand on the sodium pump is greater, and when pump operation exceeds its capacity, ATP production cannot match its consumption, and sensory activity ceases. Functionally, the sensor acts as if exhaustion or suppression of ATP occurs, even though ATP production is at its maximum. This phenomenon has been demonstrated by deactivation of sensory units after ouabain treatment to block Na+-K+-ATPase (26). In a given unit, the inverse relationship (Fig. 4) between latency and discharge frequency supports that sensory discharge frequency influences the deactivation time course. The negative correlation between latency and discharge frequency among different units, however, was not statistically significant. This suggests that discharge frequency is not the only factor that determines deactivation, but instead multiple factors influence encoder deactivation.

In many cases, on the release of airway pressure, unit activity rebounds (an "off" response). Such a rebound (Fig. 2, B–E) is due to reactivation of the high discharge frequency encoder because it occurs only after deactivation. If a unit is in a temporary inhibitory state, for example after lung hyperinflation (13), it does not discharge on the release of pressure. Furthermore, such a rebound disappeared by blocking the high frequency encoder with local anesthesia (Fig. 2, G–I) and was regained after recovery from the anesthesia (Fig. 2, K and L). This supports the theory of overexcitation.

Increasing airway CO2 can suppress SAR activity (4), and deactivation may be caused by CO2 accumulation during lung inflation. This explanation is unlikely, however, because deactivation occurs earlier at higher lung inflation pressures. If CO2 accumulation is responsible, deactivation would occur earlier at lower inflation pressures. Since CO2 production is the same, its concentration should increase more quickly at lower lung volumes. In addition, CO2 builds up continuously, so SAR activity should decrease gradually instead of abruptly. Although high concentrations of CO2 can suppress SAR activity, the effects are relatively small. The influence is greater at low concentrations, far below the normal range, whereas the influence is minimal at our experimental condition, i.e., at CO2 concentrations from the normal to a higher value (35–65 Torr). The SARs were inhibited by 30% or less when the airway CO2 was increased from 19 to 65 Torr (9). SAR activity increased by 46% as CO2 decreased from 19 to 3 Torr, and the activity changed <3% as CO2 changed between 50 and 20 Torr (4).

It can still be argued that applying high pressure to the airway may increase pulmonary vascular resistance and decrease cardiac output. As a result, especially when inflation is prolonged, tissues surrounding the SARs may become ischemic, and intravascular CO2 may increase and deactivate SARs. This scenario is also unlikely. Arterial CO2 has less influence on SAR activity than alveolar CO2. Inhalation of CO2 depressed SAR activity despite arterial CO2 being kept constant. Conversely, changing arterial CO2 with a constant airway CO2 had minimal effects on SAR activity (2). Furthermore, reducing the inflation pressure during deactivation reactivated the SAR immediately (Figs. 5, B and C, and 6G) as CO2 continued to increase. In the current studies, SAR activity did not decrease when perfusion of SARs was decreased by occluding the pulmonary artery. If anything, it increased. This is consistent with reports that occlusion of the pulmonary artery had no significant effect on the resting discharge of both high- and low-threshold SARs (21) or increased SAR activity (4). CO2 fell far below normal levels because limiting the perfusion significantly decreased the amount of CO2 delivered to the receptors. For this reason, pulmonary artery occlusion may actually increase SAR activity (4). These observations refute the theory that alteration in CO2 disrupts SAR activity.

It is possible that alteration of airway smooth muscle tone during severe stretch may produce SAR deactivation. Our bias is that any changes in SAR activity caused by alterations in smooth muscle tone during lung inflation will be gradual and not abrupt. At this point, we cannot measure the mechanical status surrounding the individual receptors. Thus, for the present, this issue will remain unsolved.

In summary, blocking Na+-K+-ATPase with ouabain has been reported to prevent restoration of the membrane potential and abruptly ceases SAR unit discharge. We have duplicated these results by mechanical stimulation with sustained inflation pressures. Our current methodology also allows us to explore interactions between different encoders, and our data support that overexcitation may deactivate the mechanosensor.


   FOOTNOTES
 

Address for reprint requests and other correspondence: J. Yu, Dept. of Medicine (Pulmonary), Univ. of Louisville, Louisville, KY 40292 (e-mail: j0yu0001{at}louisville.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


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