SIGNIFICANCE OF PULMONARY VAGAL AFFERENTS FOR RESPIRATORY MUSCLE ACTIVITY IN THE CAT

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1 JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY 2008, 59, Suppl 6, W. MAREK 1, K. MUCKENHOFF 1, N.R. PRABHAKAR 2 SIGNIFICANCE OF PULMONARY VAGAL AFFERENTS FOR RESPIRATORY MUSCLE ACTIVITY IN THE CAT 1 Department of Physiology, Ruhr-University Bochum, Germany, 2 Case Western Reserve University, Department of Physiology/Biophysics, Cleveland Ohio, USA The influence of vagal stretch receptor afferents on respiratory motor-output and respiratory changes in esophageal pressure ( P es ) was studied in anaesthetized cats. Tracheal occlusions and lung inflations were performed during hyperoxic normocapnia, during electrical stimulation of one carotid sinus nerve (CSN) or the intracranial medullary chemosensitivity (MCS), during hypercapnia or the combination of CSN and hypercapnia. Tracheal occlusions during inspiration led to increased and prolonged inspiratory muscle (IM) activity. Moderate hyperinflation in inspiration decreased and shortened inspiratory motor output. Changes in esophageal pressure and in amplitude and discharge duration of IM are largely proportional (0.84>r<0.98) to lung volume above normal endexpiratory volume (FRC). The effects are described as the Hering-Breuer inspiration inhibitory reflex (HB-IIR). Tracheal occlusion or hyperinflation in end-inspiratory position not only prolonged expiration but also activated expiratory muscles (EM). The effects linearly (0.86>r<0.98) increased with elevation of lung volume. We refer to these effects as the Hering-Breuer expiration facilitatory reflex (HB-EFR). Severe hyperinflation or rapid inflation of the lungs during inspiration, however, led to an inspiratory facilitation with increased IM activity. During concomitant chemoreflex activation, CSN or MCS stimulation, respiratory hypercapnia, or the combination of both, the extent of the above described responses of IM and EM activity were significantly (>p<0.0002) enlarged. The changes in the discharge period of IM and EM following lung inflation were smaller in the presence of the increased chemical respiratory drive (0.01>p<). The relative changes in EM responses to lung inflations during increased respiratory drive were greater than those of IM. Bilateral vagotomy abolished the respiratory responses to tracheal occlusion and hyperinflation of the lungs. The results of the present investigation show that aside from the well-known inhibition of inspiration, vagal slowly adapting lung stretch receptors facilitate expiration. The sensitivity of the lung reflexes is enhanced with increasing respiratory drive. The HB-inspiration inhibitory reflex limits the depth of lung inflation, whereas the HB-expiration facilitatory reflex promotes an effective lung deflation. Both reflex mechanisms, the inspiratory and expiratory one, are present in eupnoeic breathing, but play an

2 408 important role during increased chemoreflex drive and obstruction of expiration, e.g., with increased external airway resistance. Key words: cats, control of breathing, Hering-Breuer reflex, lung inflation, lung stretch receptors, respiratory motor-output, tracheal occlusion, vagus nerve INTRODUCTION Sensory afferents from the lung and airways play an important role in respiratory rhythm generation and in the control of respiratory nerves and muscle activity in man and in experimental animals. Respiratory motor output and the position of breathing within the range of vital capacity are largely modulated by vagal afferent sensory information. Stimulated in inspiration, vagal receptors may initiate inspiratory offswitch mechanisms without effecting expiratory muscle activity. Stimulated in expiration they may prolong expiratory period, activate expiratory muscles, and thus support active expiration. The classical Hering-Breuer reflex (HBR) includes an inspiration-inhibitory and an expiration-facilitatory mechanism (1, 2) and both are important for the neurogenesis of breathing (3, 4). The reflex effects are mediated by the slowly adapting stretch receptors of the lungs and trachea (5, 6). While the inspiration-inhibitory part of the HBR has been intensively investigated, relatively little is known about the expiration-facilitatory mechanism, which has been described as a prolongation of expiration during lung inflation in expiration or during positive pressure breathing (7-13). The responses to varying ventilatory parameters are shown to depend on the lung volume at the end of inspiration and on the time course of lung deflation. It is currently largely unknown whether the observed prolongation of expiration is due to an increase of expiratory activity or to an inhibition of inspiratory activity, which could lead to a postponed onset of the next inspiration (14, 15). The aim of the present study was to examine the influence of lung volume information for the generation of activity in inspiratory and expiratory muscles and their motor nerves under the conditions of quiet breathing and increased chemical respiratory drive. The effects were studied during normocapnic hyperoxia and during the combination of arterial and intracranial chemoafferents stimulation. While expiration is nearly passive in normal breathing, depending on the elasticity of the lung and chest walls, expiration is supported by expiratory muscles activity in case of increased chemical respiratory drive. MATERIAL AND METHODS The experiments were performed with written consent of the institutional Ethics Committee for Animal Experiments.

3 409 Preparations The experiments were carried out in 16 spontaneously breathing cats anaesthetised with glucochloralose (0.04g/kg) and urethane (0.2 g/kg). The animals were fixed in a stereotaxic holder in the supine position. The rectal temperature was kept constant at 37.0 C. The trachea was cannulated and a balloon catheter was inserted into the thoracic esophagus. The left femoral artery and vein were cannulated for measuring arterial pressure and for infusion of drugs. The following nerves and muscles on the right side were dissected as described earlier (16, 17). The carotid sinus (CSN) and aortic nerves (AN) were exposed; both vagal nerves (VN) were dissected and could be cut without interrupting the AN and the sympathetic trunks; one root of the phrenic nerve (PhrN) between Th6 and Th8. The oblique abdominal muscle, in most of the cases the internal layer, was exposed about 2 cm below the ribs. The respiratory nerves and muscles were kept under mineral oil. Experimental set-up The animals breathed from a spirometer system, in which CO 2 was absorbed and O 2 continuously replaced (16, 17). This system allowed recording tidal volume and respiratory frequency. Hypercapnia was obtained by adding CO 2 to the system in such a way that P ET CO 2 was doubled. A three-way valve proximal to the tracheal tube allowed occlusion of the trachea in different phases of inspiration and expiration. Lung inflation was performed starting from FRC with a 200 ml syringe connected to the three-way valve; esophageal pressure was measured through the balloon-catheter using a piezoelectric crystal. The balloon allowed recording positive esophageal pressure without blocking the catheter tip. Placement of the catheter was performed while recording pressure. From the position in which positive pressure was measured during normal breathing (inside stomach) the catheter was withdrawn about 3 to 5 cm until a negative end-expiratory pressure of -1 to -4 cmh 2 O was recorded. Recordings Tracheal PCO 2 was recorded by an infrared analyser (sampling rate ml/min). Bipolar stainless steel electrodes (0.2 mm diameter and 2 mm distance) were used to record the electrical activity of the respiratory nerves and muscles. The signals were differentially amplified and recorded on a tape recorder. Electrical neural and muscular activities were rectified, R-C integrated (time constant 0.1 s) and recorded together with arterial blood pressure, the spirometric signal, P ECO2 and esophageal pressure on a polygraph. Experimental protocol In series I (control breathing) tracheal occlusion and lung inflation were performed during eupneic breathing, when the animal inhaled almost pure O 2 and CO 2 was eliminated by soda lime. Tracheal occlusions started from different, randomly selected lung volumes above FRC and lasted 4 to 6 breaths. Lung inflation, starting from FRC, was performed with varied volumes, up to 60 ml/kg body weight (about eight times tidal volume). Lung inflation was steady and slow, extending approximately over the period of PhrN activity. At least two minutes for recovery were allowed between to tests. In series II (isocapnic peripheral chemoreceptor drive) tracheal occlusion was repeated, as in series I, while carotid sinus nerve (CSN) was stimulated under isocapnic (continuous stimulation during 30 min, pulse duration 2.0 ms, pulse hight V, frequency i/s) conditions.

4 410 In series III (hypercapnic drive) tracheal occlusion was similarly repeated as in series I, but during hypercapnia. End-expired PCO 2, normally between kpa, was about doubled by adding CO 2 into the inhaled gas, and min were allowed for attainment of a steady state. In series IV (isocapnic intracranial chemoreflex drive) tracheal occlusions were performed in four cats during isocapnic electrical stimulation of the intracranial chemosensitivity (continuous stimulation during 30 min, pulse duration 2.0 ms, pulse hight V, frequency i/s). In series V (both peripheral and central chemical drive) tracheal occlusion was performed as in series I, but during both CSN stimulation (as in series II) and hypercapnia (as in series III or during electrical stimulation of one CSN (as in series II) and the MCS (as in series IV). At the end of the experiment, after returning to steady state hyperoxic normocapnia, both vagi were cut (aortic and cervical sympathetic nerves spared) and series I, II, and III measurements were repeated. Measurements and Calculations The first breath after occlusion or lung inflation was considered for further calculations. Amplitude and rate of rise (slope) of the R-C integrated electrical activity of the inspiratory and expiratory nerves and muscles (PhrN, IM, EM) were taken as a measure of inspiratory and expiratory motor activity. Their effects on respiration during airway blockade were estimated from the esophageal pressure. The duration of inspiration (t I ), measured from PhrN or IM activities, was defined as starting from the beginning of the discharge until peak activity was reached. This was done because the decaying part of inspiratory activity ('post-inspiratory activity' or 'post-ramp period') does not influence the depth and duration of inspiration. The duration of expiration (t E ) was measured in the same way from the integrated EM activity. Statistical differences in the slope of the responses of P IN, PhrN, t I, P EX, EM, and t E under the different chemical respiratory drive conditions were assessed by a t-test for paired samples and were considered significant if P< (18, 29). In the figures and in the text, the CO 2 partial pressure is given in kpa. 1 kpa is equivalent to 7.5 Torr. RESULTS Tracheal Occlusion And Lung Inflation during Eupneic Breathing Tracheal occlusions During normal breathing, characteristic volume/pressure loops show negative pressure values in inspiration and nearly zero during expiration. Tracheal occlusions, starting at various phases of inspiration cause additional increases in P es which exceed the maximum value of P es recorded in the normal loop, P nb. The amplitude of this occlusion pressure above normal ( P oc - P nb ) depends on the preocclusion lung volume; at end-expiratory position ( V oc =0 ml/kg), P oc is about 3 times the normal pressure. P oc diminishes when occlusion occurs later in inspiration, until at end-inspiration occlusion P oc is equal to P nb. Occlusion during expiration results in excursions in P es in the opposite direction, whereby P oc attains positive values. The changes are more pronounced in early expiration and disappear toward end-expiration. Sample records in Fig. 1 indicate that P oc during inspiration is caused by IM activity. Thus integrated PhrN activity in the

5 411 Fig. 1. Changes in esophageal pressure ( P, ordinate) during tracheal occlusions at different lung volumes above FRC ( V oc, abscissa). Examples of integrated activities of PhrN and expiratory abdominal muscles (EM) are given; the occluded breaths are indicated by dots. The bigger the lung volume during tracheal occlusion V oc, the smaller the increase in the integrated PhrN activity and in P es in IN. The activity of EM and P es in EX increases with V oc. occluded breath is enhanced above that during normal breathing, the amplitude being directly related to the extent of P oc. Similarly, EM activity is responsible for P oc during expiration. After bilateral vagotomy, the responses in EM, IM, and PhrN disappear. However, some-what attenuated responses in P es can still be observed. Similar results, as reported here for the expiratory abdominal muscles, could be obtained from the external intercostal EM. Tracheal Occlusions During Increased Chemical Drives Carotid sinus nerve stimulation Fig. 2A shows experimental results of tracheal occlusions (arrows) during eupneic breathing. In Fig. 2B responses are shown during electrical stimulation of one CSN. Without lung inflation, V T and PhrN activity is increased compared to normocapnia and there is additional EM discharge. Accordingly, P es is more negative in inspiration and becomes slightly positive in expiration when compared with normocapnia. Tracheal occlusion at end-expiration enhances PhrN activity and causes cessation in EM activity. The result is a greater increase

6 412 Fig. 2. Responses of esophageal pressure P os, integrated activities of PhrN, and EM to tracheal occlusions at FRC ( V oc =0 ml/kg) and in peak inspiratory position. The occlusion volumes are given in the figure above the recordings of V T. A - occlusions were performed during O 2 breathing, B - during isocapnic electrical CSN stimulation (1.5V, 2 ms, 20 i/s), C - during hypercapnia (P ET CO 2 =7.0 kpa), and D - during the combination of CSN stimulation and hypercapnia. In E, the responses after bilateral vagotomy are displayed. in P es in inspiration, compared with normocapnia, but no positive pressure in expiration. Tracheal occlusion at peak inspiration does not alter PhrN, but amplifies EM activity and prolongs EM discharge period. The respiratory muscle responses are reflected in P es as well. Hypercapnia Results similar to those with CSN stimulation (Fig. 2B) are obtained with hypercapnia (Fig. 2C). Quantitatively, they are somewhat less pronounced. The reason may be that the chosen hypercapnic level increased respiratory motor output (PhrN and EM) and thus VT less than the CSN stimulation. The same responses as presented with hypercapnia were obtained with electrical stimulation of the caudal (L) field of intracranial chemosensitivity. Combination of hypercapnia or MCS stimulation and CSN stimulation When both stimuli, hypercapnia or MCS stimulation and CSN stimulation are applied simultaneously, the results are similar to those described above (Fig. 2D). The responses to tracheal occlusion are quantitatively the same, but the

7 413 Fig. 3. Quantitative changes in the esophageal pressure ( P es ) to tracheal occlusion and lung inflation ( V oc ) at different lung volumes during inspiration ( P in ) and expiration ( P ex ) under normo- ( ) and hypercapnic ( ) conditions during electrical CSN stimulations ( ), and during CSN stimulations after bilateral vagotomy ( ). Under normocapnic conditions, the lungs have been hyperinflated with volumes (x) up to 3 times the normal tidal volume to compare the same volume range under normo- and hypercapnic conditions, and CSN stimulation. The expiratory changes in P os have been included in calculating the regression line, whereas for the inspiratory changes in the oesophageal pressure, the regression line was only calculated for the normal range of V T. The control amplitudes of unoccluded breaths of P in are shown by the horizontal lines, connected to the regression lines. amplitudes of the responses in PhrN and inspiratory intercostal muscles and, to a greater extend of EM activity, are further increased, and so are the responses of esophageal pressure. Quantitative Responses Responses during inspiration During normocapnia, CSN stimulation, hypercapnia, and the combination of both, the responses of P IN and of the amplitude and discharge duration of PhrN to tracheal occlusions decrease linearly (0.8<r>0.96) in the volume range between FRC and FRC + V T with increasing V oc (Fig. 3 and Fig. 4) Hyperinflation of the lungs with volumes in the range between FRC+V T and up to about 3 times V T further diminishes P IN and PhrN activity (x), whereas further enlarged volumes

8 414 Fig. 4. Quantitative changes in the amplitude of integrated PhrN and EM activities to tracheal occlusion and lung inflation with different volumes ( V oc ) under normo- ( ) and hypercapnic ( ) conditions, during CSN stimulation ( ) and for CSN stimulation after bilateral vagotomy ( ), for the experimental animal, shown in Figs. 3. The largest amplitudes were set to 100. All data were calculated in relation to this value. either maximally decrease inspiratory motor output and transpulmonary pressure or result in a strong activation of phrenic nerve activity which is reflected in P IN, seen at V oc =24.1 ml/kg. Although after bilateral vagotomy no changes in PhrN and intercostal IM activity can be observed during tracheal occlusions, changes in transpulmonary pressure, with reduced amplitude, are still present. With increasing respiratory drive, the slope of the responses in esophageal pressure ( P IN / V oc ) and inspiratory motor activity ( units/ V co ) significantly increases, whereas the slope in the responses of the discharge duration ( t I / V oc ) significantly decreases with increasing lung volume (Table 1). Responses during expiration During normocapnia, CSN stimulation, hypercapnia, and the combination of both, the responses of transpulmonary pressure during expiration ( P EX ) and of the amplitude of expiratory muscles ( EM) activity linearly increase (0.85>r<0.97) with increasing occlusion volume in the range between FRC and FRC+V T. Hyperinflation of the lungs with volumes bigger than V T, performed under normocapnic conditions, further increases EM activity with the same slope. As observed for PhrN activity, no responses in EM activity were recorded

9 415 Table 1. Slopes of the responses in phrenic nerve (PhrN) and expiratory abdominal muscles (EM) during tracheal occlusions and lung inflations (n = 6). Eupneic Breathing CSN Stimulation Hypercapnia Hypercapnia + CSN Stimulation P IN / V oc (cmh 2 O/ml) ± 0.64 x s x ± 0.64 P< x s x P< x s x P< ± ± 0.70 PhrN/ V oc (units/ml) ± ± ± ± 0.47 t I / V oc (s/ml) ± ± ± ± 0.02 P EX / V oc (cmh 2 O/ml) ± ± ± ± 0.39 EM/ V oc (units/ml) 1.50 ± ± ± ± t E / V oc (s/ml) 0.26 ± ± ± ± 0.04 P IN / V oc - changes in inspiratory esophageal pressure per ml lung volume above FRC P EX / V oc - changes in expiratory esophageal pressure per ml lung volume above FRC PhrN/ V oc - changes in integrated PhrN activity per ml lung volume above FRC t I / V oc - changes in PhrN discharge period per ml lung volume above FRC EM/ V oc - changes in integrated EM activity per ml lung volume above FRC t E / V oc - changes in EM discharge period per ml lung volume above FRC V T (ml/kg) 7.08 ± ± ± ± 4.01 during tracheal occlusions after bilateral vagotomy, but small changes in P es were still present. During increased respiratory drive, spontaneous EM activity occurred, which disappeared after tracheal occlusions at FRC or small lung volumes. The volume threshold above FRC for EM activity decreased when respiratory drive was increased. With increasing respiratory drive, the slope of the responses in P EX ( P EX / V oc ) and in EM activity ( units/ V co ) significantly increases, whereas the slope of the responses of EM discharge duration ( t E / V oc ) significantly decreases (Table 1). The relative changes in activity of expiratory muscles and P EX are greater than those in IM and P IN. Critique of the methods DISCUSSION The inspiration-inhibitory and expiration-facilitatory parts of the Hering- Breuer reflex (HBR) were stimulated separately on the basis of changes in either mechanical ventilatory parameters or the respiratory motor output. Tracheal occlusions were performed to study the reflex responses to lung volumes ( V oc ) between the functional residual volume (FRC) and FRC plus V T. This method allows changing the lung volume information to the respiratory neurones in inspiration without influencing the activity of the lung stretch receptors in the preocclusion period. By inflating the lungs with a syringe, a bigger volume range was investigated (up to eight times V T ). During moderate hyperinflations with volumes

10 416 up to three times the control V T, the inflation always started at the beginning of inspiratory motor activity in order to simulate a normal inflation, so that the desired inflation volume was reached at the termination of neural inspiratory discharge. Therefore, lung volume during the following expiration remained constant and expiration could not be influenced by further volume changes. This means that the expiration-facilitatory responses under these conditions in fact depend on different inflation volumes and not on additional dynamic effects of volume changes. Since our method did not allow to measure or control FRC directly in the first approach, FRC was assumed to be more or less unchanged. Changes in the blood gas tensions during the first occlusion and the inflations were performed with gas mixtures taken from the respiratory system itself. Role of tracheo-pulmonary receptors Tracheo-pulmonary afferents are classified into three main groups (1, 6, 16, 19). Slowly adapting pulmonary stretch receptors (SAR) activity was related to lung volumes changes during respiration and these afferents are responsible for the HBR. Bartlett et al (20) described that the SAR activity reflected the transpulmonary pressure, which is the link from neural respiratory activity to alveolar ventilation. The HBR responses are abolished after bilateral vagotomy or by inhibition of the thick myelinated receptor afferents by cooling the vagi to 11-5 C (1, 21). The receptor afferents project into cell complexes of the brainstem, known to be responsible for the generation of the respiratory rhythm (3). The result of eliminating vagal volume information is an increased tidal volume and also a decreased respiratory frequency due to prolonged phases of inspiration and expiration, but without concomitant changes in ventilation (22). Stimulation of the second group, the rapidly adapting lung stretch receptors (RAR) or 'irritant' receptors, by rapid and severe hyperinflation of the lungs, as described in the literature (23-26), increases the slope and amplitude of the inspiratory nerve and muscle activity. Stimulated by lung deflation in expiration, they cut off expiratory motor output and initiate new phrenic burst. These receptors should be responsible for the inspiration-facilitatory responses during hyperinflation of the lungs. These inspiration-facilitatory and expirationinhibitory responses, described as 'paradoxical responses' by Sellik and Widdicombe (27), can be differentiated from the HBR. The third important group of pulmonary vagal afferents contains the juxtacapillary or J-receptors (1), causing rapid shallow breathing, and C-fiber afferents reviewed by the Coleridges (28) and by Barnes et al (29). An involvement of these fibers in both parts of the HBR cannot be expected. The intercostal propioceptors, although being able to influence the central respiratory mechanisms in the same way as the slowly adapting tracheo-pulmonary stretch receptors (30), only play a minor role during tracheal occlusion and lung inflation

11 in the investigated volume range, shown by the complete loss of the reflex responses after bilateral vagotomy. Reflex mechanisms 417 Following von Euler (4), the HBR is responsible for the termination of inspiration ('off-switch') and not for the inspiratory ramp-generation, i.e., the slope of the integrated inspiratory motor activity. This was confirmed in the present investigation. The slope of the integrated inspiratory activity was almost unchanged without vagal feedback. However, a slight positive feedback facilitation of phrenic nerve activity in dogs to lung inflation from a constant flow ventilator was described in the literature (31). The effects were possibly due to high flow rates stimulation predominantly RAR (25, 27). DiMarco et al (32) have found a low threshold facilitation in phrenic nerves and more effectively in inspiratory intercostal muscles of pentobarbitone anesthetized cats. The described inspiratory facilitation from SAR quantitatively does not considerably modify the prevailing inspiration-inhibitory effect being responsible for the inspiratory off-switch. The termination of inspiration is suggested to be mediated via a special pool of interneurons ('off-switch' neurones) receiving excitatory input from SAR (4, 33), a moderate excitatory input of inspiratory neurones would not much influence the specialized 'off-switch' neurones. The threshold for the termination of inspiration was shown to decrease hyperbolically during the course of inspiration (22). The expiratory facilitation is described as a mechanism prolonging expiration, depending on the change of lung volume during expiration (7, 10-12, 34-37), being important during positive pressure breathing (13) or expiratory resistive loading. In the present study, by recording from the inspiratory and expiratory muscles and by simultaneously monitoring esophageal pressure, we showed that the vagal volume information not only postpones the onset of the following inspiration, but also causes an active expiration when lung deflation is hindered. This could not be seen in former experiments, when the experimental animals were paralyzed and when only phrenic nerve activity was taken as respiratory output, or where expiration was defined as the duration of the phrenic pause. The prolongation of expiration depends on the actual lung volume and the time course of lung deflation during expiration (11). A prolongation of expiration, measured as the silent period between two phrenic bursts, can be due to an inhibition of medullary inspiratory neurones, postponing the onset of the next inspiratory motor activity, or to an activation of expiratory neurones, inhibiting the inspiratory ones, or both mechanisms work synergistically. In this investigation we could show that expiratory nerves and muscles can also be activated directly and expiration is facilitated without changing the vagal afferent activity in the previous inspiration. The increase in the inspiratory intercostal muscle or phrenic nerve activity and the prolongation of discharge period during tracheal occlusion at FRC is due to the reduction of pulmonary stretch receptor activity, as shown by Richardson et

12 418 al (38). Tracheal occlusion in peak inspiratory position does not effect that inspiration any more, but facilitates following expiration. Moderate hyperinflation during inspiration increases activities of SAR and RAR. But the effects of SAR, having the lower volume threshold, dominates and inspiration is cut off earlier. The consequence is that the amplitude of inspiratory motor activity decreases and so does transpulmonary pressure. During severe hyperinflation in inspiration, excitation of RAR dominates and facilitates inspiration. However, their activity decrease within a short period (13) and during the following expiration SAR activity remains, stimulating expiratory motor output and prolonging the discharge period of EM. SAR in normal breathing and in hypercapnia limit the depth of inspiration by mediating the inspiratory 'off-switch' mechanisms, which is the inspiratory-inhibitory part of the HBR. When expiration is hindered and end-expiratory gas volume increases above FRC, the activity of SAR declines slower and facilitates expiration by activating EM and causing an active expiration. The importance of SAR under pathophysiological conditions is indicated by the fact that an airway resistance of only 10 cmh 2 O after bilateral vagotomy leads to severe alveolar hypoventilation, and the animal dies within five minutes because of asphyxia (7), whereas with intact vagi, ventilation only decreases by 48%. After vagotomy, without the support of EM, the elastic recoil forces of the lungs are not sufficient enough to deflate the lungs. During increased respiratory drive, expiration, passive in quiet breathing, is supported by the expiratory intercostal and abdominal muscles. Under these conditions, the slope of IM and EM responses to variations in lung volume is increased, i.e., the same volume above FRC ( V oc ) causes a bigger inhibition in the depth of IN and a stronger facilitation of expiratory effort. This means that the lung volume information becomes more effective for the generation of respiratory motor activity. On the other hand, with the same occlusion volume, the discharge duration of inspiratory and expiratory motor activity is less increased during hyperpnea. The effects in both IM and EM motor activity work synergistically in maintaining ventilation. The change in IM and EM activity per time increases during hyperpnea and the reflex mechanisms become more effective. The active support of expiration prevents a prolongation of respiratory period, which would diminish ventilation (17). In hyperpnea, fr is either unaltered or increased (22). In summary, the inspiration-inhibitory part of the HBR limits the depth of lung inflation by terminating the ramp-like rising inspiratory motor output. The expiration-facilitatory part not simply prolongs expiration, but activates expiratory muscles in order to keep FRC unaltered, when deflation is hindered. Both reflex mechanisms become more effective during increased respiratory drive. Both parts of the HBR preserve the position of breathing near FRC and prevent too large alterations of intrathoracic gas volume, which increases respiratory muscle work and leads to the sensation of dyspnea or to the development of pulmonary emphysema.

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