Lack of effect of vagal afferent input on central neural respiratory afterdischarge FREDERIC L, ELDRIDGE AND PRITAM GILL-KUMAR Departments of Medicine and Physiology, University of North School of Medicine, Chapel Hill, North Carolina 27514
ELDRIDGE,FREDERIC L., AND PRITAM GILL-KUMAR. Lack of effect of vagal afferent input on central neural respiratory afterdischarge. 3. Appl. Physiol.: Respirat. Environ. Exercise Physiol. 45(3): 339-344, 1978. -The effect of respiratory inhibition caused by vagal stimulation or lung inflation on the central neural mechanism that maintains respiration after cessation of a facilitatory stimulus was studied in anesthetized cats. Phrenic activity was increased by carotid sinus nerve stimulation or by squeezing or stretching calf muscle. On cessation of stimulation there was an immediate decrease in respiratory output followed by a slow decrease (afterdischarge) over a period of 5 min. Vagal stimulation or lung inflation, which caused marked inhibition of inspiration, had no effect on the development of the afterdischarge or on the course of the subsequent recovery process. The mechanism causing afterdischarge is probably a buildup of activity in a neural network in the medulla and pons. Since its activity is unaffected by vagal inhibition of respiration, it can be concluded that the network is separate from inspiratory output neurons and those involved in phase switching and that it is not dependent on increased central inspiratory neuron activity. regulation of respiration; neural control; nonchemical respiratory stimuli; neural feedback; poststimulation respiration; vagus nerve; lung inflation; phrenic activity; cat
mechanism that has the property of maintaining an increased but slowly declining respiratory activity for some minutes after cessation of a primary stimulus (2, 5). A variety of stimuli, including electrical stimulation of the carotid sinus nerve and chemical stimulation of the carotid body (Z), squeezing of the calf muscles (Z), electrical stimulation of the ventral surface of the medulla (8), and voluntary hyperventilation (10, 11) have been shown to activate the process. The level of the C02-H+ stimulus, if constant, does not affect the declining pattern resulting from the process (Z), but changes do interact with it (1). Anesthesia, or lack of it, and a number of ablative procedures, including decerebration (4), decerebellation (5), spinal cord section at CT-T, (2)) and carotid sinus nerve or vagal section (2) have not had obvious effects on the process. Changes in circulation do not appear to be causal (1, 2). The various findings have led to a conclusion that the mechanism involved is neural and located in the pontomedullary region of the brain, and that it probably acts through the medium of neural positive-feedback circuits THERE
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which produce an afterdischarge, or reverberation, in some neuronal network. This activity in turn results in the continuing but slowly decaying stimulation of respiration. Although such activity could be in the respiratory feedback loops involved in inspiratory-expiratory cycling, several pieces of evidence suggest that it lies outside these areas. First, the reverberatory process may take some time to become fully activated, even though the tidal phrenic output has already reached its maximum (2). Second, a large augmented breath, or sigh, occurring during the slow recovery period in vagally intact animals does not affect the process (4). Although the earlier studies showed that the vagus nerves did not have much effect beyond a questionable shortening of the slow recovery process, the specific effect of inhibitory vagal stretch receptor input was not tested. If the mechanism which causes respiration to be sustained lies outside the networks of inspiratory and expiratory output neurons and those concerned with respiratory phase switching, one would expect that even severe inhibition of inspiration by vagal input would have little or no effect on the process. The purpose of the present study was to test this hypothesis. METHODS
Studies were performed on 10 healthy adult cats. They were anesthetized with ether and then given chloralose (40 mg/kg) and urethan (250 mg/kg) via a foreleg vein. Femoral arterial pressure was measured by means of a strain gauge. Temperature was monitored with a rectal thermistor and maintained at 3738°C by a heating lamp. The trachea was cannulated through a neck incision and continuous sampling of airway carbon dioxide partial pressure (Pco2) was accomplished by means of a catheter placed in the airway with analysis by an infrared CO, analyzer (Beckman LB 2). Following these preparations the animal was placed supine on a table with a rigid head mount. Both carotid sinus nerves were exposed and crushed near the carotid body; one was then placed on bipolar platinum electrodes for stimulation. One phrenic nerve root (C5) was also exposed in the neck, cut, desheathed, and placed on platinum recording electrodes. All nerves were submersed in pools of mineral oil. The animal was then attached to a volume cycled
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ventilator (Phipps & Bird) and paralyzed with gallamine triethiodide, 3 mg/kg iv initially, with additional doses given as needed to prevent muscular activity. To prevent significant changes in end-tidal and arterial PCO~ secondary to changes of cardiac output and venous return to the lungs, the DC voltage on the ventilator’s motor could be controlled by the animal’s end-tidal Pco2 (PET& level through an electronic circuit (9). The pump rate of the ventilator was thereby servo controlled to maintain PET co2 within 2 0.5 Torr of the desired level, which was set to yield a phrenic activity value in the normal quiet breathing range for that cat. The purpose of the experiments was to examine the effect of vagally induced inhibition of respi ration on the neural mechanism responsible for the afterdischarge. Two ways of increasing respiratory output were used. of the The first was continuous electrical stimulation carotid sinus nerve; frequency was 25 Hz and duration 0.5 ms for each pulse but voltages were varied (0.1-0.6 V) as necessary to obtain a satisfactory neural output response. The second was manual squeezing of calf muscles (1) or stretching of them by maintained manual flexion of the ankles. Two methods of stimulating pulmonary stretch receptor afferents were used in separate groups of animals. Electrical stimulation of vagus rterve. The vagosympathetic trunks were cut in the neck. The central cut end of the vagus on the right side was carefully separated from the sympathetic trunk, desheathed, and placed on bipolar platinum electrodes for stimulation. Frequency of stimulation was 100 Hz and pulse duration 0.1 ms, The voltage used was the lowest that would produce maximal inhibition of inspiration and was usually not far above the threshold for inhibitory effects. Lung inflation. The vagi remained intact in this group of animals and natural stimulation of bpul monary stretch receptors was achieved by increasing the volume of air in the lungs while containing ventilation. This was accomplished by means of applying positive airway pressure throughout expiration by connecting the expiratory tube to an underwater port. The positive expiratory pressure could be varied; it ranged between 7.5 and 10 cmH,O. The value to be used for a given experiment was selected to cause maximal inhibition of inspiration without serious impairment of circulation, as reflected by the arterial pressure. Experimental protocol After attaining a fixed PETITE were and stable respiratory output , base conditions recorded. Respiration was then increased by stimulation of carotid sinus nerve (CSN) or calf muscle afferents for 1 min. After withdrawal of the stimulus, recovery was recorded for another 5 min. This represented the control experimental run, After again reaching the stable base state, the CSN or calf muscle stimulus was repeated under the same conditions, with the exception that a vagal stimulation or lung inflation causing high grade inhibition of inspiratory output was given during the last 15-20 s of the facilitatory stimulation. Recovery was again followed for 5 min. Subsequent runs were the same except that vagal stimulation or l
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lung inflation was applied during the first 15-20 s of recovery or at a later time in recovery. Data obtained included arterial pressure, airway PcoZ, phrenic nerve impulses, a marker for the CSN or for vagal muscle stimul ation, and a second marker stimula .tion or lung in *flation, all of w *hich were recorded on magnetic tape and photographically by means of a galvanometer recorder. The peak 0.1-s value of integrated phrenic activity was determined by means of an integrating digital voltmeter as previously described (3). It has been shown that this value is a satisfactory index of neural respiratory (tidal) output for each breath (3). Breath-by-breath neural minute output was calculated as the product of this tidal value and respiratory frequency. For purposes of comparing the time courses of the several recovery runs in the same cat and in different cats, respiratory minute output for each breath during a recovery was calculated and the differences between all recovery breaths and final recovery level determined. These differences were plotted against time on a logarithmic scale, with the first recovery breath assigned a value of 100% and the final recovery level a value of 0%. 1 The resulting plot is exponential in form (2) . RESULTS
Carotid sinus nerve stimulation and calf muscle squeezing both led to an increase in inspiratory neural output (Figs. lA, 3A, and 4A). The calf muscle stimulation led to a different respiratory response, characterized by a much higher respiratory frequency, than did the CSN. Nevertheless, the poststimulus recovery patterns were similar in form. The off-transients consisted of two components, immediate decreases in respiratory output with the first poststimulus inspiration, but not to control levels, and then slow decreases to control over a period of minutes (Figs. lA, 3A, and 4A). The decline of the second component took the form of an exponential function, with a time constant of 58 s in the cat shown in Figs. IA and 2A. These findings are similar to those reported earlier (2). Stimulation of the inhibitory, Vagal stimulation. presumably stretch receptor, fibers of the vagus nerve always led to prompt inhibition of inspiratory neural output. Used alone in an animal during quiet breathing, there were often no significant effects on respiraoutput beyond the immedi ate inhibitory effect (Fig. although occasionally the first poststimulus breath showed slight residual effects of the preceding inhibition. During the slow recovery process caused by a preceding facilitatory stimulus (CSN or calf muscle), vagal inhibition had no lasting effect on its course once the immediate inhibitory effects had ended. All six animals ’ Note that in the experimental runs shown in Figs. ZC and 6C, the first breaths of recovery were under the influence of vagal stimulation or lung inflation. For the purpose of plotting these graphs, therefore, the magnitudes of the first recovery breaths (the 100% values) were assumed to be the same as those in runs not affected by vagal afferent stimulation,
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When calf muscle stimulation was used to produce increased respiratory output, the poststimulus recovery pattern was similar in form to that after CSN stimulaB. VAGAL STIMULATION FOR IO0 ‘:::.. .+, 20 set PRECEDING RECOVERY k, - - ..>* . . ‘...‘.
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, “::$&.&::., ‘. This lack of effect of vagal inhibition applied before (Fig. 2B), at the onset (Fig. 2C), or during recovery (Fig. W) on the exponential form of the recovery is shown more conclusively when changes of breath-by-breath minute neural output are plotted semilogarithmically. The time constant of the control run (Fig. 2A) is 58 s. If the breaths occurring during vagal stimulation are not included, the time constants of the three vagal stimulation runs are 56 s (Fig. 2B), 64 s (F ig. ZC), and 55 s (Fig. W). The 95% confidence intervals for the regression lines for all four overlap, so it can be concluded that they are not significantly different from each other. Even when the inspiratory response to carotid sinus nerve stimulation and inspiratory-expiratory cycling was totally inhibited by simultaneous stimulation of the vagus nerve (Fig. 3B), a slowly waning afterdischarge similar to that of the control (Fig. 3A) occurred.
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FIG. 1. Respiratory outputs (integrated phrenic activity) in 5 experimental runs in 1 cat, showing base-line levels at left of each recording, facilitatory effect of 60 s of carotid sinus nerve (CSN) stimulation and slow recovery process (afterdischarge) following cessation of stimulation. A: control experiment. B: vagal stimulation during final 20 s of CSN stimulation. C: vagal stimulation during first 23 s of recovery. D: vagal stimulation during 22-42 s of recovery. E: vagal stimulation alone. Note that although vagal stimulation causes marked inhibition of inspiration, its effect does not long outlast its exhibition and it does not affect slow recovery process.
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FIG. 2. Plots of breath-by-breath neural minute respiratory outputs for runs A, B, C, and D of the cat shown in Fig. 1, during recovery from carotid sinus nerve stimulation. Oblique lines in A indicate range of breath-by-breath variation; this range is smaller than the 95% confidence limits calculated from the regressions. Dotted areas in B, C, and D denote control range. Note inhibition of inspiration by vagal stimulation has no significant subsequent effect on recovery slopes. PHRENIC
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3. Phrenic nerve recording and respiratory output in 2 runs in 1 vagotomized cat. A: control run, showing base-line activity at left, effect of CSN stimulation of 30 s duration, and recovery. B: showing base-line activity, effect of combined CSN and vagal stimulation, and recovery. Although inspiration is almost completely inhibited during combined stimulation, poststimulation respiratory activity is augmented in almost the same way as in control run and decays with approximately the same course. Note that base-line phrenic activity is less in B than in A. This accounts for differences in frequency and neural output between 2 recordings but should not affect conclusions to be drawn from figure. FIG.
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FIG. 4. Respiratory outputs in 3 runs in 1 cat showing base lines, facilitatory effect of squeezing calf muscle for approximately 1 min, and recovery. A : control run showing poststimulation augmentation of respiratory output. B: vagal stimulation during last 15 s of calf squeezing. C: vagal stimulation during first 15 s of recovery. Vagal inhibition of inspiration has no significant effect on recovery pattern.
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tion (Fig. 4A). Again, vagal stimulation causing inhibition of inspiration had no effect on the poststimulation recovery pattern or time course whether it was applied during the last part of muscle squeezing (Fig. 4B) or during the early portion of recovery (Fig. 4C). In this group of cats, the end-tidal CO, was servo controlled so changes of less than 1 Torr occurred, regardless of the experimental intervention. Arterial pressure changes were generally small and, as noted before (2, 4), showed no consistent relationship to the afterdischarge pattern whether or not vagal stimulation was used. Lung inflation. Because the vagi were intact in these animals and the ventilator’s cycle was usually out of phase with the animal’s own neural respiration, vagal stretch reflexes caused greater breath-to-breath variability of phrenic discharge than in the vagotomized animals. Nevertheless, the findings in the four animals were essentially the same as with electrical stimulation of the vagus. The volume of sustained lung inflation was not measured but positive expiratory pressures of 7.5-10 cmH,O were sufficient to produce marked inspiratory inhibition, In the example shown in Fig. 5, the control run (Fig. 5A) shows the typical poststimulation slow recovery after a minute of CSN stimulation. Lung inflations causing inspiratory inhibition during the last part of the CSN stimulation (Fig. 5B), during the first part of recovery (Fig. 5C), or later recovery (Fig. So), again
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5. Respiratory outputs in 5 runs in 1 cat, showing base lines at left, facilitatory effect of 60 s of CSN stimulation, and slow recovery following cessation of stimulation. A : control experiment. B: lung inflation during final 17 s of CSN stimulation. C: lung inflation during 1st 17 s of recovery. D: lung inflation during 16-31 s of recovery. E: lung inflation alone. FIG.
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FIG. 6. Plots of breath-by-breath neural minute respiratory outputs for runs A, B, C, and D of cat (Fig+ 51, during recovery from CSN stimulation, Oblique lines in A indicate range of breath-bybreath variation; approx the same as 95% confidence limits calculated from regression. Dotted areas in 23, C, and D denote control range. Inhibition of inspiration by lung inflation has no significant subsequent effect on slow recovery slopes.
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had no significant effect on the subsequent recovery patterns which were sim .ilar to the control. This is also is plotted semilogashown in Fig. 6 where recovery rithmically. The time constant of the control run (Fig. 6A) is 43 s in this cat. Those of three lung inflation runs are 49 s (Fig. 6B), 43 s (Fig, 6C), and 46 s (Fig. 6D), again not significantly different from the control or each other. Lung inflation alone (Fig. 5E) did not cause aftereffects like those of CSN or calf muscle stimulation, although again there were slight residual inhibitory effects for several breaths after the lungs were allowed to deflate. Some inspiratory activity often did occur during simultaneous CSN stimulation and lung inflation, This can be seen in Fig. 7B where the poststimulation augmentation of respiratory output is similar to that of the control run (Fig. 7A). Figure 7C shows that several brief CSN stimulations, causing the same number of large inspirations as in the vagally inhibited run (Fig. 7B), produced a much smaller afterdischarge. Thus, the continuous CSN stimulation of the vagally inhibited run activated the mechanism caus #ing the afterdischarge despite the few actual inspirations. Again, arterial pressure changes were generally small despite the lung inflation and showed no consistent relationship to the afterdischarge pattern. DISCUSSION
This study reaffirms the existence of a mechanism which is located in the central nervous system and which maintains respiration for a significant time after cessation of an external stimulus. It also shows that
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C
I I 1
CSNSTIMFIG. 7. Respiratory outputs in 3 runs in 1 cat. A: control, showing base line at left, facilitators effect of continuous CSN stimulation and recovery. k effect oflcombined CSN stimulation and lung inflation, foilowed by slow recovery. C: effect of 3 brief CSN stimulations alone. Note continuous CSN stimulation activates slow recovery process despite vagal inhibition (B), whereas 3 similar inspirations due to CSN stimulation alone (0 cause onlv minimal activation of slow recovery mechanism.
this process is unaffected by inhibition caused by stimstretch recepulation of vagal afferents or pulmonary tors. Although it might be argued that electrical stimulation of the vagus nerve does not necessarily produce pure stretch receptor fiber activation, it has been shown that it can satisfactorily mimic the effects of natural stimulation of stretch receptors (12). In any case the finding that lung inflation yielded the same results as vagal stimulation makes any difference unimportant from the point of view of the conclusions of this study. It was suggested earlier that the mechanism causing the afterdischarge involves a buildup of activity in some neuronal network in the medulla and pons (2, 4). We originally suggested that the networks of inspiratory and expiratory output neurons might be the locus of the feedback activity. However, since augmented inspirations (4), as well as inhibition of inspiratory neurons (this study) leave the process unaffected, we can conelude that neither the inspiratory-expiratory networks nor any of those involved in the switching mechanisms are the seat of the poststimulus activity. Our findings therefore suggest that there is a separate ne twork of neurons in which activity builds up during a period of stimulation (from a variety of sources) and decays slowly on its cessation. The exact location of this network must, at the present time, remain a matter of speculation. We have suggested* that the reticular activating system (RAS) is a good candidate (4) but there are no direct studies of the RAS to support this idea. Likewise, no firm conclusions can be drawn as to whether the output of the network is tonic or has a rhythmic component not related to the usual inspiratory-expiratory switching circuits. Since the time courses of decay as well as the magnitudes of the poststimulus augmentation of inspiration were unaffected by vagal inhibition applied during the last part of a facilitatory stimulus or at various times during recovery process, it can be concluded that the network of neurons that sustain this process do not receive input from the pulmonary stretch receptors. A following conclusion is that the inputs from these two sources to the inspiratory-expiratory cycling mechanism must be entering parallel to each other. It was noted earlier that vagal influences had a questionable effect of shortening the time constant of the afterdischarge, the association being present in one study (4) but not in another (3). At the present time, the existence of such an effect must remain uncertain. Even if it is real, however, the results of the present study indicate that it must be due to vagal afferents other than those from stretch receptors. One of the more striking findings of the study is that of Fig. 3, which shows that activity in the postulated neuronal network increases during stimulation. of the carotid sinus nerve in this case, dzspite the absence of inspiratory activity or cycling of respiration brought about by vagal inhibition. This provides support for a conclusion that at least part of the innut from such external stimuli goes directly to this network, which is then responsible for the observed afterdischarge. At the same time, it supports an additional conclusion that the input from inspiratory neurons (i.e., the central inspi-
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ratory activity, postul .ated by von Euler and associates (6) to be important in the off-switch mechani sm) is not required to activate the network. Karczewski et al . (7) have reported that following vagal stimulation there appears to be a short-term (5 10 s) “memory” of the inhibitory effect on phrenic activity. This effect was seen in some but not all of the animals studied here. Although it is of considerable interest that a reverberating mechanism, one with a
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quite short tim .e constant, may exist in the vagal offswitch circu its, the differen .ce in duration .me ans that a different neuron pool must be responsible for vagal memory than for the long recovery process. The authors express their appreciation to Kay for their excellent technical assistance. This study was supported by Public Health
Ga 11 man
Vaughn
and to Eve
Service
Research
11 April
1978.
Grants~~7689 and ~~1132. Received
5 December
1977; accepted
in final
form
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F. L. Central neural respiratory stimulatory effect of respiration. J. AppZ. PhysioZ. 37: 723-735, 1974. 3. ELDRIDGE, F, L. Relationship between respiratory nerve and muscle activity and muscle force output. J. Appl. Physiol. 39:
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F. L. Central neural stimulation of respiration in unanesthetized decerebrate cats. J. Appl. Physiol. 40: 23-28, 1976. 5. ELDRIDGE, F. L. Maintenance of respiration by central neural feedback mechanisms. Federation Proc. 36: 2400-2404, 1977. 6. EULER, C. VON, I. MARTILLA, J. E. REMMERS, AND T. TRIPPENBACH. Effects of lesions in the parabrachial nucleus on the mechanisms for central and reflex termination of inspiration in the cat. Acta Physiol. Stand. 96: 324-337, 1976. 7. KARCZEWSKI, W. A., K. BUDZINSKA, H. GROMYS, R. HERCZYNSKI, AND J. R. ROMANIUK. Some responses of the respiratory complex
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to stimulation of its vagal and mesencephalic inputs. In: Respiratory Centers and Afferent Systems, edited by B. Duron. Paris: INSERM, 1976, vol. 59, p. 107-115. LOESCHCKE, H. H., J. DELATTRE, M. E. SCHLAEFKE, AND C. 0. TROUTH. Effects on respiration and circulation of electrically stimulating the ventral surface of the medulla oblongata. Respiration PhysioZ. 10: 184-197, 1970. SMITH, D. M., R. R. MERGER, AND F. L. ELDRIDGE. Servo control of end-tidal CO, in paralyzed animals. J. Appl. Physiol.: Respint. Environ, Exercise Physiol. 45: 133-136, 1978. SWANSON, G. D., D. S. WARD, AND J. W. BELLVILLE. Posthyperventilation isocapnic hyperpnea, J. Appl. PhysioZ. 40: 592-596, 1976. TAWADROUS, F. D., AND F. L. ELDRIDGE. Posthyperventilation breathing patterns after active hyperventilation in man. J. AppZ. PhysioZ. 37: 353-356, 1974. TRENCHARD, D, Role of pulmonary stretch receptors during breathing in rabbits, cats and dogs. Respiration Physiol. 29: 231246, 1977.
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ELDRIDGE,FREDERIC L., AND PRITAM GILL-KUMAR. Lack of effect of vagal afferent input on central neural respiratory afterdischarge. 3. Appl. Physiol.: Respirat. Environ. Exercise Physiol. 45(3): 339-344, 1978. -The effect of respiratory inhibition caused by vagal stimulation or lung inflation on the central neural mechanism that maintains respiration after cessation of a facilitatory stimulus was studied in anesthetized cats. Phrenic activity was increased by carotid sinus nerve stimulation or by squeezing or stretching calf muscle. On cessation of stimulation there was an immediate decrease in respiratory output followed by a slow decrease (afterdischarge) over a period of 5 min. Vagal stimulation or lung inflation, which caused marked inhibition of inspiration, had no effect on the development of the afterdischarge or on the course of the subsequent recovery process. The mechanism causing afterdischarge is probably a buildup of activity in a neural network in the medulla and pons. Since its activity is unaffected by vagal inhibition of respiration, it can be concluded that the network is separate from inspiratory output neurons and those involved in phase switching and that it is not dependent on increased central inspiratory neuron activity. regulation of respiration; neural control; nonchemical respiratory stimuli; neural feedback; poststimulation respiration; vagus nerve; lung inflation; phrenic activity; cat
mechanism that has the property of maintaining an increased but slowly declining respiratory activity for some minutes after cessation of a primary stimulus (2, 5). A variety of stimuli, including electrical stimulation of the carotid sinus nerve and chemical stimulation of the carotid body (Z), squeezing of the calf muscles (Z), electrical stimulation of the ventral surface of the medulla (8), and voluntary hyperventilation (10, 11) have been shown to activate the process. The level of the C02-H+ stimulus, if constant, does not affect the declining pattern resulting from the process (Z), but changes do interact with it (1). Anesthesia, or lack of it, and a number of ablative procedures, including decerebration (4), decerebellation (5), spinal cord section at CT-T, (2)) and carotid sinus nerve or vagal section (2) have not had obvious effects on the process. Changes in circulation do not appear to be causal (1, 2). The various findings have led to a conclusion that the mechanism involved is neural and located in the pontomedullary region of the brain, and that it probably acts through the medium of neural positive-feedback circuits THERE
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Copyright
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which produce an afterdischarge, or reverberation, in some neuronal network. This activity in turn results in the continuing but slowly decaying stimulation of respiration. Although such activity could be in the respiratory feedback loops involved in inspiratory-expiratory cycling, several pieces of evidence suggest that it lies outside these areas. First, the reverberatory process may take some time to become fully activated, even though the tidal phrenic output has already reached its maximum (2). Second, a large augmented breath, or sigh, occurring during the slow recovery period in vagally intact animals does not affect the process (4). Although the earlier studies showed that the vagus nerves did not have much effect beyond a questionable shortening of the slow recovery process, the specific effect of inhibitory vagal stretch receptor input was not tested. If the mechanism which causes respiration to be sustained lies outside the networks of inspiratory and expiratory output neurons and those concerned with respiratory phase switching, one would expect that even severe inhibition of inspiration by vagal input would have little or no effect on the process. The purpose of the present study was to test this hypothesis. METHODS
Studies were performed on 10 healthy adult cats. They were anesthetized with ether and then given chloralose (40 mg/kg) and urethan (250 mg/kg) via a foreleg vein. Femoral arterial pressure was measured by means of a strain gauge. Temperature was monitored with a rectal thermistor and maintained at 3738°C by a heating lamp. The trachea was cannulated through a neck incision and continuous sampling of airway carbon dioxide partial pressure (Pco2) was accomplished by means of a catheter placed in the airway with analysis by an infrared CO, analyzer (Beckman LB 2). Following these preparations the animal was placed supine on a table with a rigid head mount. Both carotid sinus nerves were exposed and crushed near the carotid body; one was then placed on bipolar platinum electrodes for stimulation. One phrenic nerve root (C5) was also exposed in the neck, cut, desheathed, and placed on platinum recording electrodes. All nerves were submersed in pools of mineral oil. The animal was then attached to a volume cycled
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340
F,
ventilator (Phipps & Bird) and paralyzed with gallamine triethiodide, 3 mg/kg iv initially, with additional doses given as needed to prevent muscular activity. To prevent significant changes in end-tidal and arterial PCO~ secondary to changes of cardiac output and venous return to the lungs, the DC voltage on the ventilator’s motor could be controlled by the animal’s end-tidal Pco2 (PET& level through an electronic circuit (9). The pump rate of the ventilator was thereby servo controlled to maintain PET co2 within 2 0.5 Torr of the desired level, which was set to yield a phrenic activity value in the normal quiet breathing range for that cat. The purpose of the experiments was to examine the effect of vagally induced inhibition of respi ration on the neural mechanism responsible for the afterdischarge. Two ways of increasing respiratory output were used. of the The first was continuous electrical stimulation carotid sinus nerve; frequency was 25 Hz and duration 0.5 ms for each pulse but voltages were varied (0.1-0.6 V) as necessary to obtain a satisfactory neural output response. The second was manual squeezing of calf muscles (1) or stretching of them by maintained manual flexion of the ankles. Two methods of stimulating pulmonary stretch receptor afferents were used in separate groups of animals. Electrical stimulation of vagus rterve. The vagosympathetic trunks were cut in the neck. The central cut end of the vagus on the right side was carefully separated from the sympathetic trunk, desheathed, and placed on bipolar platinum electrodes for stimulation. Frequency of stimulation was 100 Hz and pulse duration 0.1 ms, The voltage used was the lowest that would produce maximal inhibition of inspiration and was usually not far above the threshold for inhibitory effects. Lung inflation. The vagi remained intact in this group of animals and natural stimulation of bpul monary stretch receptors was achieved by increasing the volume of air in the lungs while containing ventilation. This was accomplished by means of applying positive airway pressure throughout expiration by connecting the expiratory tube to an underwater port. The positive expiratory pressure could be varied; it ranged between 7.5 and 10 cmH,O. The value to be used for a given experiment was selected to cause maximal inhibition of inspiration without serious impairment of circulation, as reflected by the arterial pressure. Experimental protocol After attaining a fixed PETITE were and stable respiratory output , base conditions recorded. Respiration was then increased by stimulation of carotid sinus nerve (CSN) or calf muscle afferents for 1 min. After withdrawal of the stimulus, recovery was recorded for another 5 min. This represented the control experimental run, After again reaching the stable base state, the CSN or calf muscle stimulus was repeated under the same conditions, with the exception that a vagal stimulation or lung inflation causing high grade inhibition of inspiratory output was given during the last 15-20 s of the facilitatory stimulation. Recovery was again followed for 5 min. Subsequent runs were the same except that vagal stimulation or l
L, ELDRIDGE
AND
P, GILL-KUMAR
lung inflation was applied during the first 15-20 s of recovery or at a later time in recovery. Data obtained included arterial pressure, airway PcoZ, phrenic nerve impulses, a marker for the CSN or for vagal muscle stimul ation, and a second marker stimula .tion or lung in *flation, all of w *hich were recorded on magnetic tape and photographically by means of a galvanometer recorder. The peak 0.1-s value of integrated phrenic activity was determined by means of an integrating digital voltmeter as previously described (3). It has been shown that this value is a satisfactory index of neural respiratory (tidal) output for each breath (3). Breath-by-breath neural minute output was calculated as the product of this tidal value and respiratory frequency. For purposes of comparing the time courses of the several recovery runs in the same cat and in different cats, respiratory minute output for each breath during a recovery was calculated and the differences between all recovery breaths and final recovery level determined. These differences were plotted against time on a logarithmic scale, with the first recovery breath assigned a value of 100% and the final recovery level a value of 0%. 1 The resulting plot is exponential in form (2) . RESULTS
Carotid sinus nerve stimulation and calf muscle squeezing both led to an increase in inspiratory neural output (Figs. lA, 3A, and 4A). The calf muscle stimulation led to a different respiratory response, characterized by a much higher respiratory frequency, than did the CSN. Nevertheless, the poststimulus recovery patterns were similar in form. The off-transients consisted of two components, immediate decreases in respiratory output with the first poststimulus inspiration, but not to control levels, and then slow decreases to control over a period of minutes (Figs. lA, 3A, and 4A). The decline of the second component took the form of an exponential function, with a time constant of 58 s in the cat shown in Figs. IA and 2A. These findings are similar to those reported earlier (2). Stimulation of the inhibitory, Vagal stimulation. presumably stretch receptor, fibers of the vagus nerve always led to prompt inhibition of inspiratory neural output. Used alone in an animal during quiet breathing, there were often no significant effects on respiraoutput beyond the immedi ate inhibitory effect (Fig. although occasionally the first poststimulus breath showed slight residual effects of the preceding inhibition. During the slow recovery process caused by a preceding facilitatory stimulus (CSN or calf muscle), vagal inhibition had no lasting effect on its course once the immediate inhibitory effects had ended. All six animals ’ Note that in the experimental runs shown in Figs. ZC and 6C, the first breaths of recovery were under the influence of vagal stimulation or lung inflation. For the purpose of plotting these graphs, therefore, the magnitudes of the first recovery breaths (the 100% values) were assumed to be the same as those in runs not affected by vagal afferent stimulation,
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CENTRAL
NEURAL
RESPIRATORY
341
AFTERDISCHARGE
When calf muscle stimulation was used to produce increased respiratory output, the poststimulus recovery pattern was similar in form to that after CSN stimulaB. VAGAL STIMULATION FOR IO0 ‘:::.. .+, 20 set PRECEDING RECOVERY k, - - ..>* . . ‘...‘.
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, “::$&.&::., ‘. This lack of effect of vagal inhibition applied before (Fig. 2B), at the onset (Fig. 2C), or during recovery (Fig. W) on the exponential form of the recovery is shown more conclusively when changes of breath-by-breath minute neural output are plotted semilogarithmically. The time constant of the control run (Fig. 2A) is 58 s. If the breaths occurring during vagal stimulation are not included, the time constants of the three vagal stimulation runs are 56 s (Fig. 2B), 64 s (F ig. ZC), and 55 s (Fig. W). The 95% confidence intervals for the regression lines for all four overlap, so it can be concluded that they are not significantly different from each other. Even when the inspiratory response to carotid sinus nerve stimulation and inspiratory-expiratory cycling was totally inhibited by simultaneous stimulation of the vagus nerve (Fig. 3B), a slowly waning afterdischarge similar to that of the control (Fig. 3A) occurred.
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RECOVERY
FIG. 1. Respiratory outputs (integrated phrenic activity) in 5 experimental runs in 1 cat, showing base-line levels at left of each recording, facilitatory effect of 60 s of carotid sinus nerve (CSN) stimulation and slow recovery process (afterdischarge) following cessation of stimulation. A: control experiment. B: vagal stimulation during final 20 s of CSN stimulation. C: vagal stimulation during first 23 s of recovery. D: vagal stimulation during 22-42 s of recovery. E: vagal stimulation alone. Note that although vagal stimulation causes marked inhibition of inspiration, its effect does not long outlast its exhibition and it does not affect slow recovery process.
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200
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FIG. 2. Plots of breath-by-breath neural minute respiratory outputs for runs A, B, C, and D of the cat shown in Fig. 1, during recovery from carotid sinus nerve stimulation. Oblique lines in A indicate range of breath-by-breath variation; this range is smaller than the 95% confidence limits calculated from the regressions. Dotted areas in B, C, and D denote control range. Note inhibition of inspiration by vagal stimulation has no significant subsequent effect on recovery slopes. PHRENIC
CSN
STIMULATION
PHRENIC
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-
3. Phrenic nerve recording and respiratory output in 2 runs in 1 vagotomized cat. A: control run, showing base-line activity at left, effect of CSN stimulation of 30 s duration, and recovery. B: showing base-line activity, effect of combined CSN and vagal stimulation, and recovery. Although inspiration is almost completely inhibited during combined stimulation, poststimulation respiratory activity is augmented in almost the same way as in control run and decays with approximately the same course. Note that base-line phrenic activity is less in B than in A. This accounts for differences in frequency and neural output between 2 recordings but should not affect conclusions to be drawn from figure. FIG.
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342
F. L. ELDRIDGE
60 set
2 c
VAGUS MUSCLE
VAGUS MUSCLE.
FIG. 4. Respiratory outputs in 3 runs in 1 cat showing base lines, facilitatory effect of squeezing calf muscle for approximately 1 min, and recovery. A : control run showing poststimulation augmentation of respiratory output. B: vagal stimulation during last 15 s of calf squeezing. C: vagal stimulation during first 15 s of recovery. Vagal inhibition of inspiration has no significant effect on recovery pattern.
CSN
5 -
LUNG
LUNG
P. GILL-KUMAR
tion (Fig. 4A). Again, vagal stimulation causing inhibition of inspiration had no effect on the poststimulation recovery pattern or time course whether it was applied during the last part of muscle squeezing (Fig. 4B) or during the early portion of recovery (Fig. 4C). In this group of cats, the end-tidal CO, was servo controlled so changes of less than 1 Torr occurred, regardless of the experimental intervention. Arterial pressure changes were generally small and, as noted before (2, 4), showed no consistent relationship to the afterdischarge pattern whether or not vagal stimulation was used. Lung inflation. Because the vagi were intact in these animals and the ventilator’s cycle was usually out of phase with the animal’s own neural respiration, vagal stretch reflexes caused greater breath-to-breath variability of phrenic discharge than in the vagotomized animals. Nevertheless, the findings in the four animals were essentially the same as with electrical stimulation of the vagus. The volume of sustained lung inflation was not measured but positive expiratory pressures of 7.5-10 cmH,O were sufficient to produce marked inspiratory inhibition, In the example shown in Fig. 5, the control run (Fig. 5A) shows the typical poststimulation slow recovery after a minute of CSN stimulation. Lung inflations causing inspiratory inhibition during the last part of the CSN stimulation (Fig. 5B), during the first part of recovery (Fig. 5C), or later recovery (Fig. So), again
STIM
CSN STIM. INFLATION
-
CSN STIM. IN FLATION
-
40
80
120
RECOVERY LUNG
tNFLATtON
-
5. Respiratory outputs in 5 runs in 1 cat, showing base lines at left, facilitatory effect of 60 s of CSN stimulation, and slow recovery following cessation of stimulation. A : control experiment. B: lung inflation during final 17 s of CSN stimulation. C: lung inflation during 1st 17 s of recovery. D: lung inflation during 16-31 s of recovery. E: lung inflation alone. FIG.
AND
I60
40
TIME,
80
120
160
seconds
FIG. 6. Plots of breath-by-breath neural minute respiratory outputs for runs A, B, C, and D of cat (Fig+ 51, during recovery from CSN stimulation, Oblique lines in A indicate range of breath-bybreath variation; approx the same as 95% confidence limits calculated from regression. Dotted areas in 23, C, and D denote control range. Inhibition of inspiration by lung inflation has no significant subsequent effect on slow recovery slopes.
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CENTRAL
NEURAL
RESPIRATORY
had no significant effect on the subsequent recovery patterns which were sim .ilar to the control. This is also is plotted semilogashown in Fig. 6 where recovery rithmically. The time constant of the control run (Fig. 6A) is 43 s in this cat. Those of three lung inflation runs are 49 s (Fig. 6B), 43 s (Fig, 6C), and 46 s (Fig. 6D), again not significantly different from the control or each other. Lung inflation alone (Fig. 5E) did not cause aftereffects like those of CSN or calf muscle stimulation, although again there were slight residual inhibitory effects for several breaths after the lungs were allowed to deflate. Some inspiratory activity often did occur during simultaneous CSN stimulation and lung inflation, This can be seen in Fig. 7B where the poststimulation augmentation of respiratory output is similar to that of the control run (Fig. 7A). Figure 7C shows that several brief CSN stimulations, causing the same number of large inspirations as in the vagally inhibited run (Fig. 7B), produced a much smaller afterdischarge. Thus, the continuous CSN stimulation of the vagally inhibited run activated the mechanism caus #ing the afterdischarge despite the few actual inspirations. Again, arterial pressure changes were generally small despite the lung inflation and showed no consistent relationship to the afterdischarge pattern. DISCUSSION
This study reaffirms the existence of a mechanism which is located in the central nervous system and which maintains respiration for a significant time after cessation of an external stimulus. It also shows that
LUNG
INFLATION
343
AFTERDISCHARGE
C
I I 1
CSNSTIMFIG. 7. Respiratory outputs in 3 runs in 1 cat. A: control, showing base line at left, facilitators effect of continuous CSN stimulation and recovery. k effect oflcombined CSN stimulation and lung inflation, foilowed by slow recovery. C: effect of 3 brief CSN stimulations alone. Note continuous CSN stimulation activates slow recovery process despite vagal inhibition (B), whereas 3 similar inspirations due to CSN stimulation alone (0 cause onlv minimal activation of slow recovery mechanism.
this process is unaffected by inhibition caused by stimstretch recepulation of vagal afferents or pulmonary tors. Although it might be argued that electrical stimulation of the vagus nerve does not necessarily produce pure stretch receptor fiber activation, it has been shown that it can satisfactorily mimic the effects of natural stimulation of stretch receptors (12). In any case the finding that lung inflation yielded the same results as vagal stimulation makes any difference unimportant from the point of view of the conclusions of this study. It was suggested earlier that the mechanism causing the afterdischarge involves a buildup of activity in some neuronal network in the medulla and pons (2, 4). We originally suggested that the networks of inspiratory and expiratory output neurons might be the locus of the feedback activity. However, since augmented inspirations (4), as well as inhibition of inspiratory neurons (this study) leave the process unaffected, we can conelude that neither the inspiratory-expiratory networks nor any of those involved in the switching mechanisms are the seat of the poststimulus activity. Our findings therefore suggest that there is a separate ne twork of neurons in which activity builds up during a period of stimulation (from a variety of sources) and decays slowly on its cessation. The exact location of this network must, at the present time, remain a matter of speculation. We have suggested* that the reticular activating system (RAS) is a good candidate (4) but there are no direct studies of the RAS to support this idea. Likewise, no firm conclusions can be drawn as to whether the output of the network is tonic or has a rhythmic component not related to the usual inspiratory-expiratory switching circuits. Since the time courses of decay as well as the magnitudes of the poststimulus augmentation of inspiration were unaffected by vagal inhibition applied during the last part of a facilitatory stimulus or at various times during recovery process, it can be concluded that the network of neurons that sustain this process do not receive input from the pulmonary stretch receptors. A following conclusion is that the inputs from these two sources to the inspiratory-expiratory cycling mechanism must be entering parallel to each other. It was noted earlier that vagal influences had a questionable effect of shortening the time constant of the afterdischarge, the association being present in one study (4) but not in another (3). At the present time, the existence of such an effect must remain uncertain. Even if it is real, however, the results of the present study indicate that it must be due to vagal afferents other than those from stretch receptors. One of the more striking findings of the study is that of Fig. 3, which shows that activity in the postulated neuronal network increases during stimulation. of the carotid sinus nerve in this case, dzspite the absence of inspiratory activity or cycling of respiration brought about by vagal inhibition. This provides support for a conclusion that at least part of the innut from such external stimuli goes directly to this network, which is then responsible for the observed afterdischarge. At the same time, it supports an additional conclusion that the input from inspiratory neurons (i.e., the central inspi-
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ratory activity, postul .ated by von Euler and associates (6) to be important in the off-switch mechani sm) is not required to activate the network. Karczewski et al . (7) have reported that following vagal stimulation there appears to be a short-term (5 10 s) “memory” of the inhibitory effect on phrenic activity. This effect was seen in some but not all of the animals studied here. Although it is of considerable interest that a reverberating mechanism, one with a
AND
P. GILL-KUMAR
quite short tim .e constant, may exist in the vagal offswitch circu its, the differen .ce in duration .me ans that a different neuron pool must be responsible for vagal memory than for the long recovery process. The authors express their appreciation to Kay for their excellent technical assistance. This study was supported by Public Health
Ga 11 man
Vaughn
and to Eve
Service
Research
11 April
1978.
Grants~~7689 and ~~1132. Received
5 December
1977; accepted
in final
form
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F. L. Posthyperventilation and passive hyperventilation,
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F. L. Central neural respiratory stimulatory effect of respiration. J. AppZ. PhysioZ. 37: 723-735, 1974. 3. ELDRIDGE, F, L. Relationship between respiratory nerve and muscle activity and muscle force output. J. Appl. Physiol. 39:
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F. L. Central neural stimulation of respiration in unanesthetized decerebrate cats. J. Appl. Physiol. 40: 23-28, 1976. 5. ELDRIDGE, F. L. Maintenance of respiration by central neural feedback mechanisms. Federation Proc. 36: 2400-2404, 1977. 6. EULER, C. VON, I. MARTILLA, J. E. REMMERS, AND T. TRIPPENBACH. Effects of lesions in the parabrachial nucleus on the mechanisms for central and reflex termination of inspiration in the cat. Acta Physiol. Stand. 96: 324-337, 1976. 7. KARCZEWSKI, W. A., K. BUDZINSKA, H. GROMYS, R. HERCZYNSKI, AND J. R. ROMANIUK. Some responses of the respiratory complex
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to stimulation of its vagal and mesencephalic inputs. In: Respiratory Centers and Afferent Systems, edited by B. Duron. Paris: INSERM, 1976, vol. 59, p. 107-115. LOESCHCKE, H. H., J. DELATTRE, M. E. SCHLAEFKE, AND C. 0. TROUTH. Effects on respiration and circulation of electrically stimulating the ventral surface of the medulla oblongata. Respiration PhysioZ. 10: 184-197, 1970. SMITH, D. M., R. R. MERGER, AND F. L. ELDRIDGE. Servo control of end-tidal CO, in paralyzed animals. J. Appl. Physiol.: Respint. Environ, Exercise Physiol. 45: 133-136, 1978. SWANSON, G. D., D. S. WARD, AND J. W. BELLVILLE. Posthyperventilation isocapnic hyperpnea, J. Appl. PhysioZ. 40: 592-596, 1976. TAWADROUS, F. D., AND F. L. ELDRIDGE. Posthyperventilation breathing patterns after active hyperventilation in man. J. AppZ. PhysioZ. 37: 353-356, 1974. TRENCHARD, D, Role of pulmonary stretch receptors during breathing in rabbits, cats and dogs. Respiration Physiol. 29: 231246, 1977.
Downloaded from www.physiology.org/journal/jappl at Lunds Univ Medicinska Fak Biblio (130.235.066.010) on February 14, 2019.
