Shlgejl MATSUMOTO. First Department of Oral and Maxillofacial Surgery, Niigata University School of Dentistry, Niigata, 951 Japan

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1 Japanese Journal of Physiology, 37, , 1987 Effects of Temporal Trachea-Occlusion at the End of Expiration on Internal Intercostal Muscle Activity in the Rabbit Shlgejl MATSUMOTO First Department of Oral and Maxillofacial Surgery, Niigata University School of Dentistry, Niigata, 951 Japan Abstract The effects of temporal trachea-occlusion at the end of expiration on internal intercostal muscle activity (IIMA) and diaphragmatic activity (DMA) were studied in the vagi-intact rabbit. This tracheal occlusion caused a marked prolongation of inspiration time due to a diminution of the vagally mediated inspiratory inhibition but the significant change in the next IIMA was not observed after releasing tracheal occlusion. In addition, the effects of temporal trachea-occlusion on pulmonary stretch receptor activity (PSRA) and DMA were also studied in the unilaterally vagotomized rabbit. The procedures remarkably inhibited the respiratory modulation of PSRA from inspiration to expiration. These results indicate that the change of PSRA in response to temporal trachea-occlusion does not significantly affect the next IIMA. Key words : internal intercostal muscle activity, pulmonary stretch receptor activity, tracheal occlusion. A number of studies have shown that temporal trachea-occlusion at the end of expiration is a useful technique for testing the reaction of the central respiratory center to a sudden withdrawal of phasic vagal influences (GRUNSTEIN et al., 1973; YOUNES et al., 1975, 1978; EVANICH et al., 1976; SIAFAKAS et al., 1981). This idea can be supported by the finding that the respiratory modulation of pulmonary stretch receptor activity (PSRA) from inspiration to expiration is greatly diminished or is abolished in the first occluded breath following tracheal occlusion (RICHARDSON et al., 1973). The activity of the internal intercostal muscles (IIMA) during normal breathing is eliminated or is remarkably suppressed after sectioning the vagus nerves (ARITA and BISHOP, 1983). Similar results are obtained in other studies recorded Japan Received for publication February 12, 1987 Present Address: First Department of Physiology, Fukushima Medical College, Fukushima,

2 360 S. MATSUMOTO with the abdominal muscles (BisxoP,1964; KELSEN et al., 1977). These observations lead to the suggestion that the vagal afferent receptors play an important role in controlling the expiratory muscle activities during quiet breathing. Furthermore, recent studies have shown that high discharge rates in the pulmonary stretch receptors would determine the expiratory activities in the abdominal muscles (DAMES et al., 1980; FARBER, 1982). If the afferent activity from pulmonary stretch receptors is one of the major facilitatory inputs to the activation of expiratory muscle activity, it can be expected that the change of expiratory muscle activity in response to temporal trachea-occlusion at the end-expiratory phase would strongly be affected by the input from the pulmonary stretch receptors. The purpose of the present study was to investigate a possible interaction between expiratory muscle activity and pulmonary stretch receptor activity. Therefore, the effects of temporal trachea-occlusion at the end expiration on respiratory muscle activities (internal intercostal muscles and diaphragm) were studied in the rabbits with intact vagus nerve. In addition, the effects of such tracheal occlusion on PSRA and diaphragmatic activity (DMA) were also studied in the unilaterally vagotomized rabbits. MATERIALS AND METHODS Experiments were performed on 15 rabbits weighing kg. The animals were anesthetized with sodium pentobarbitone (25-30 mg/kg, i.v.).' The animals were placed supine on a table with a rigid head mount. The trachea was cannulated and a catheter inserted into the femoral artery for measurement of systemic blood pressure and for blood sampling. The anesthesia was maintaind by additional doses of sodium pentobarbitone (2-4 mg/(kg h)) throughout the experiments. Prior to the cannulation, heparin (500 unit/kg) was given intravenously. The rectal temperature was maintained at around 37 C by using a heating lamp. In order to avoid reflexes mediated by the aortic body, the aortic nerves were sectioned in advance. The muscle activity was recorded with small electrodes of two pairs of silver steel hooks. The two wires leaving the muscle were secured to prevent any movement of the electrodes. The electrodes were inserted into the sternal portion of the diaphragm through a small incision. The pectoralis and serratus anterior muscles were removed on one side to allow access to the internal intercostal muscles (T6-T9). This procedure was done carefully in order to avoid pneumothorax and damaging the inercostal nerves. After the electrodes were set, the superficial muscles were sutured together. The muscle activity was amplified, integrated by means of an integrator with a time constant of 0.1 s and recorded on a polygraph. In six rabbits, the left vagus nerve was exposed, sectioned and desheathed. Then, the peripheral end of the vagus nerve bundle was placed on bipolar silver electrodes and submerged under warm liquid paraffin. The electrical nerve activity was amplified, recorded and integrated, as described previously. The measurement of DMA was made by the same technique, as described previously. The identifi- Japanese Journal of Physiology

3 VAGAL INFLUENCES ON IIMA 361 Fig. 1. Effects of vagal cooling on pulmonary stretch receptor activity. The diaphragmatic activity and systemic blood pressure are also displayed. In order to determine the zero level of pulmonary stretch receptor activity, the vagus nerve was cooled and then rewarmed. A: the height of integrated inspiratory pulmonary stretch receptor activity and B: the height of integrated expiratory pulmonary stretch receptor activity. PSRA, pulmonary stretch receptor activity; DMA, diaphragmatic activity; and SBP, systemic blood pressure. cation of PSRA was done as follows: (1) by characteristic form of the activity during inspiration and expiration, (2) by changes of form and height in the integrated PSR curve with varied degrees of lung inflation and deflation and (3) by desappearance of the activity during cold block. Cooled water (0 C) was pumped from a large reservoir through a copper radiator with a flow of ml/min. The radiator was isolated from body tissue. During vagal cooling, the vagus nerve was periodically immersed with mineral oil. As shown in Fig, 1, the zero level of PSRA was determined by the vagal cooling procedure. The vagus nerve used for recording was cooled to a temperature (4-9 C) lower than that used by FARBER (1982). The maximum heights of integrated inspiratory PSRA (A) and integrated expiratory PSRA (B)-measured between the peak amplitude of the integrated PSR curves during inspiration and expiration and the zero level of the integrated PSR curve during vagal cooling, and the respiratory modulation of PSRA was also calculated by the difference between A and B. These parameters were obtained before tracheal occlusion and used for control values. The changes of these parameters in response Vol. 37, No. 3, 1987

4 362 S. MATSUMOTO to temporal trachea-occlusion were calculated and were expressed as a percent of the control levels. Before starting the experiments, blood was withdrawn from the femoral artery to measure arterial Poz, Pcoz, and ph in 9 vagi-intact and 6 unilaterally vagotomized animals and these values were , , and (mean + S.E.), respectively. The experiments were started after obtaining a stable condition in both respiratory muscle activities and arterial blood gas tensions. Temporal trachea-occlusion was performed at the end-expiratory phase by clamping the tubing (dead space, 3 ml) connected to the tracheal cannula and was immediately released after the onset of the first inspiratory effort. The procedure in each animal was performed three or four times at intervals of about 5 min. Statistical analysis was performed between control values and experimental values by using a paired t-test. RESULTS Effects of temporal trachea-occlusion at the end of expiration on respiratory muscle activities Figure 2 shows typical changes of IIMA and DMA in response to temporal trachea-occlusion in a vagi-intact animal. During the occluded breathing the duration of inspiration and the magnitude of integrated DMA were increased, but the rate of rise of integrated DMA was diminished. The appearance of these characteristic effects on inspiratory muscle activity occurred as a result of the Fig. 2. Effects of temporal trachea-occlusion at the end of expiration on respiratory muscle activities. --- period of tracheal occlusion. IIMA, internal intercostal muscle activity; and DMA, diaphragmatic activity. Japanese Journal of Physiology

5 VAGAL INFLUENCES ON IIMA 363 Table 1. The changes of integrated IIMA, integrated DMA, TE, and to temporal trachea-occlusion at the end of expiration in the vagi-intact animals. TI in response Fig. 3. Effects of temporal trachea-occlusion at the end of expiration on pulmonary stretch receptor and diaphragmatic activities in a unilaterally vagotomized animal. - period of tracheal occlusion. PSRA, pulmonary stretch receptor activity; DMA, diaphragmatic activity; and SBP, systemic blood pressure. Vol. 37, No. 3, 1987

6 364 S. MATSUMOTO Table 2. The changes of integrated inspiratory PSRA and integrated expiratory PSRA in response to temporal trachea-occlusion at the end of expiration in the unilaterally vagotomized animals. Table 3. The changes of integrated DMA, TE, and TI in response to temporal trachea-occlusion at the end of expiration in the unilaterally vagotomized animals. removal of the vagally mediated inspiratory inhibition. Under such conditions, IIMA and expiration time (TE) were not significantly changed after releasing tracheal occlusion. The changes of integrated IIMA, intergrated DMA, TE, and inspiration time (T,) in response to tracheal occlusion at the end of expiration in 9 vagi-intact rabbits are summarized in Table 1. Note that the expiratory activity in the internal intercostal muscles was not significantly affected after releasing tracheal occlusion. Effects of temporal trachea-occlusion at the end of expiration on pulmonary stretch receptor activity and diaphragmatic activity Figure 3 shows characteristic responses of PSRA and DMA to tracheal occlusion at the end of expiration in a unilaterally vagotomized animal. In the occluded breath during tracheal occlusion done at the end-expiratory phase, the Japanese Journal of Physiology

7 VAGAL INFLUENCES ON IIMA 365 activity of inspiratory pulmonary stretch receptors was greatly diminished and this response was associated with an increase in TI and no significant effect on integrated DMA. After release of the occluded breath, the expiratory PSRA was only slighly increased. The changes of integrated inspiratory PSRA and integrated expiratory PSRA in response to temporal trachea-occlusion at the end of expiration in 6 unilaterally vagotomized rabbits are summarized in Table 2. These changes were calculated, as sown in Fig. 1. It is noteworthy that the respiratory modulation of PSRA from inspiration to expiration was greatly suppressed by tracheal occlusion. The changes in integrated DMA, TE, and TI are also summarized in Table 3. Note that the duration of inspiration was increased during the occluded breath but there were no significant changes in integrated DMA and TE after releasing tracheal occlusion. DISCUSSION The present study demonstrated that the changes of pulmonary stretch receptors in response to temporal trachea-occlusion at the end-expiratory phase did not cause any significant effects in the next IIMA but resulted in the charateristic effects of DMA due to the removal of vagal inhibitory influences. This suggests that the pulmonary stretch receptors responding to such tracheal occlusion would not be an important factor in determining the activity of internal intercostal muscles. The blockade of slowly adapting pulmonary stretch receptors by inhalation of sulphur dioxide eliminates the excitatory responses of abdominal muscle activity to head-up tilting and positive-pressure breathing (DAVIES et al., 1980). The continuous positive airway pressure (CPAP)-induced activation in abdominal muscle activity is completely abolished by cooling the vagal nerves to between 7 and 12 C; the effects of such a vagal cooling also inhibit the high rates of inspiratory and expiratoryphased discharge in the pulmonary stretch receptors (FARBER,1982). Furthermore, lung deflation inhibits abdominal muscle activation during chemical stimulation of breathing (FARBER, 1983). These observations seem to suggest that the pulmonary stretch receptors may be one of the major inputs in controlling the response of expiratory muscle activity during normal breathing at rest. On the other hand, it is well known that the afferent input from pulmonary stretch receptors is an important mediator of inspiratory inhibition (CLA1 and VON EULER, 1972; BRADLEY et al., 1975; MATSUMOTO, 1982). In the measurement with PSRA, temporal tracheaocclusion inhibited the respiratory modulation of PSRA from inspiration to expiration whereas the activity of expiratory pulmonary stretch receptors was not significantly changed after release of such tracheal occlusion. Similar findings are also obtaind in the discharge rate of the pulmonary stretch receptor afferent (RICHARDSON et a1.,1973). Thus, it is most likely that temporal trachea-occlusion at the end of expiration is a useful method for determining the effects of a sudden withdrawal of phasic vagal activities on the central respiratory center. If an inhibition of PSRA due to tracheal occlusion produces the characteristic effects of Vol. 37, No. 3, 1987

8 366 S. MATSUMOTO inspiratory and expiratory motor activities, one can expect that the duration of inspiration and the peak amplitude of integrated DMA would be increased whereas the expiratory activity in the internal intercostal muscles would be decreased. Indeed, in the vagi-intact state the changes in DMA during the occluded inspiration reflected the result of removal of the vagally mediated inspiratory inhibition. The finding that in the unilaterally vagotomized animals the prolongation of T, showing no significant change in integrated DMA is observed during the occluded inspiration, leads to the suggestion that the rate of leak of the inspiratory integration process would be altered by the reduction of vagal feedback due to unilateral vagotomy. In contrast, expiratory activity of the internal intercostal muscles in such conditions was not significantly changed after releasing tracheal occlusion. The latter effect argues strongly against an important role of the pulmonary stretch receptor mechanism on the expiratory muscle activity. However, it cannot completely rule out the possibility that the difference may be due to the different experimental conditions, most probably those involving different mechanical actions between IIMA and abdominal muscle activity in the respiratory muscle system. What are the mechanisms underlying these unaltered IIMA's after tracheal occlusion is released? According to SIAFAKAS et al. (1981), the lower rib cage expands in such a way that diaphragmatic length does not change much. The fact that the magnitude of integrated IIMA is not significantly influenced by tracheal occlusion suggests that internal intercostal muscle length would be held at the level of control breathing. Under such conditions, the segmental inputs from proprioceptive receptors of the intercostal muscles serve to determine the response of IIMA to tracheal occlusion (EKLUND et al., 1964; SEARS, 1964), because there is evidence that lung inflation after bilateral vagotomy still activates IIMA (ARITA and BISHOP, 1983). In this study, it was impossible to differentiate these two influences on the IIMA respone. There are observations that the expiratory activity of the abdominal or internal intercostal muscles is greatly diminished or is eliminated by bilateral vagotomy (KELSEN et al., 1977; ARITA and BISHOP, 1983; MATSUMOTO, 1987). However, it is still unclear whether one of the major facilitatory factors during expiration to the expiratory motoneurons is due to the afferent input from slowly adapting pulmonary stretch receptors or rapidly adapting pulmonary stretch receptors or some tonically active pulmonary vagal receptors being different from the pulmonary stretch receptors (FISHMAN et al., 1973; DAVIES et al., 1980; FARBER, 1982; ARITA and BISHOP, 1983). ARITA and BISHOP (1983) proposed that the irritant receptors or some tonically active pulmonary vagal receptors would cause facilitation during expiration to the spinal expiratory motoneurons, probably mediating through the bulbospinal expiratory neurons and some central interneurons. The irritant receptors increase their activity after release of tracheal occlusion (RICHARDSON et al., 1973). In the experiments using the technique of vagal cooling (9-16 C) in the awake dog, FISHMAN et al. (1973) also found that an acceleration of expiratory flow Japanese Journal of Physiology

9 VAGAL INFLUENCES ON IIMA 367 occurred under particular conditions abolishing the Hering-Breuer inflation reflex. Although the effects of temporal trachea-occlusion on irritant receptor activity was not examined in this study, it is probable that stimulation of the irritant receptors by tracheal occlusion may, in part, participated in the occurrence of the unaltered IIMA. At present there are no data concerning the interaction between some tonically active pulmonary vagal receptors and bulbospinal expiratory neurons. REFERENCES ARITA, H. and BISHOP, B. (1983) Responses of cat's internal intercostal motor units to hypercapnia and lung inflation. J. Appl. Physiol., 54: BISHOP, B. (1964) Reflex control of abdominal muscles during positive-pressure breathing. J. Appl. Physiol., 19: BRADLEY, G. W., VON EULER, C., MARTTILA, I., and Roos, B. (1975) A model of the central and reflex inhibition of inspiration in the cat. Biol. Cyber.,19: CLARK, F. J. and VON EULER, C. (1972) On the regulation of depth and rate of breathing. J. Physiol. (Lond.), 222: DAVIES, A., SANT'AMBROGIO, F. B., and SANT'AMBROGIO, G. (1980) Control of postural changes of end expiratory volume (FRC) by airways slowly adapting mechanoreceptors. Respir. Physiol., 41: EKLUND, G., VON EULER, C., and RUTKOWSKI, S. (1964) Spontaneous and reflex activity of intercostal gamma motoneurons. J. Physiol. (Lond.), 171: EVANICH, M. J., LOPATA, M., and LoRENCO, R. (1976) Phrenic nerve activity and occlusion pressure changes during C02 breathing in cat. J. App!. Physiol., 41: FARBER, J. P. (1982) Pulmonary receptor discharge and expiratory muscle activity. Respir. Physiol., 47: FARBER, J. P. (1983) Expiratory motor response in the suckling opossum. J. App!. Physiol., 54: FISHMAN, N. H., PHILLIPSON, E. A., and NADEL, J. A. (1973) Effecrs of differential vagal cold blockade on breathing pattern in conscious dogs. J. App!. Physiol., 34: GRUNSTEIN, M. M., YOUNES, M., and MILIC-EMILI, J. (1973) Control of tidal volume and respiratory frequency in anesthetized cats. J. App!. Physiol., 35: KELSEN, S. G., ALTOSE, M. D., and CHERNIACK, N. S. (1977) Interaction of lung volume and chemical drive on respiratory EMG and respiratory timing. J. App!. Physiol., 42: MATSUMOTO, S. (1982) Effects of vagal stimulation and carotid body chemoreceptor stimulating agents on phrenic nerve activity in vagotomized rabbits. Arch. Int. Pharmacodyn., 256: MATSUMOTO, S. (1987) Effects of transient hypoxia on internal intercostal muscle activity in vagotomized rabbits. Jpn. J. Physiol., 37: RICHARDSON, P. S., SANT'AMBROGIO, G., MARTOLA, J., and BIANCONI, R. (1973) The activity of lung afferent nerves during tracheal occlusion. Respir. Physiol., 18: SEARS, T. A. (1964) Efferent discharges in alpha and fusiomotor fibers of intercostal nerves of the cat. J. Physiol. (Lond.), 74: SIAFAKAS, N. H., CHANG, H. K., BONORA, M., GAUTIER, H., MILIC-EMILI, J., and DURON, B. (1981) Time course of phrenic activity and respiratory pressure during airway Vol. 37, No. 3, 1987

10 368 S. MATSUMOTO occlusion in cats. J. App!. Physiol., 51: YoUNES, M., IscoE, S., and MILK-EMILI, J. (1975) A method for assessment of phasic vagal influence on tidal volume. J. App!. Physiol., 38: YOUNES, M., REMMERS, J. E., and BARKER, J. P. (1978) Characteristics of inspiratory inhibition of phasic volume feedback in cats. J. App!. Physiol., 45: Japanese Journal of Physiology