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The effect of limb movements on the regulation of depth and rate of breathing
Respiration PhysioIogy (1916) 21, 33-52; North-Holland Publishing Company, Amsterdam
THE EFFECT OF LIMB MOVEMENTS ON THE REGULATION OF DEPTH AND RATE OF BREATHING’
EMIL10 AGOSTONI and EDGARDO D’ANGELO Istituto di Fisiologia Umana (Ia Cattedra), Universitri di Milano, Milan, Italy
Abstract. In anesthetized dogs and rabbits passive or active limb movements (1) shifted to the left the relationship between tidal volume (VT) and inspiratory time (I?), (2) lowered the relationship between expiratory time (fe) and Ti and decreased its slope, and (3) increased the output to the inspiratory muscles (W/I?). These effects increased with increasing the frequency of movements. Similar effects were obtained after vagotomy. When the stimulus was started during expiration, Te was shortened in spite of the previous unatTected Ti. Arterial Pco, during exercise was similar (active movements) or below (passive movements) control value. Since other chemical and physical humoral factors do not seem involved, the whole increase of ventilation should be produced by neurogenic stimuli. The time course of Te, Ti and Vr/Ti at the onset and at the offset of limb movements indicates an abrupt and a .slow component in the neurogenic drive. A single contraction of the limb during expiration or inspiration affected the timing and the VTpi of 3-g breaths. Control of breathing Expiratory time Inspiratory time Muscular exercise
Neurogenic stimuli to ventilation Output to inspiratory muscles Vagotomy
It has been known for many years that passive (Harrison et al., 1932; Comroe and Schmidt, 1943; Dejours et al., 1956) and active involuntary (Krogh and Lindhard, 19 17 ; Comroe and Schmidt, 1943 ; Asmussen and Nielsen, 1948 ; Kao, 1963 ; Rodgers, 1968) movements of the limbs produce an increase of ventilation. This reflex increase of ventilation originate from stimulation of joint receptors (Comroe and Schmidt, 1943; Flandrois et al., 1966) and of muscle spindles (Bessou et al., 1959; Gautier et al., 1964). Harrison et al. (1932) pointed.out that in some dogs the increase of ventilation produced by passive limb movements persists for 2-3 min after cessation of the movements. In line with this observation is the persistence of the hyperventilatory effect Accepted for publication 4 February 1976.
1 This research was supported by the National Research Council of Italy. 33
34
E. AGGSTONIANDE. D’ANGELO
of gastrocnemius-soleus nerve stimulation (Senapati, 1966) and of limb muscle squeezing (Eldridge, 1974) after cessation of the stimulus. Analogous to this persistence may be considered the persistence of hyperpnea after cessation of carotid sinus nerve (CSN) stimulation (Gesell et al., 1942; Eldridge, 1974). Eldridge (1972, 1974) also reported that CSN stimulation for only one breath has no effect on subsequent breaths. Von Euler et al. (1970) and Clark and von Euler (1972) have provided new insights into the control of breathing as far as depth and rate regulation are concerned. They showed the following features : (1) Inspiratory duration (Ti) is set by a vagal feedback system linked to the increase of lung volume (the Hering-Breuer reflex) with a threshold mechanism decreasing with time from the onset of inspiration (i.e. the VT-I? relationship). (2) After vagotomy Ti is independent of changes in tidal volume and depends essentially upon the bulbo-pontine pacemaker. (3) Expiratory duration depends on the preceding Ti (Te-Ti relationship), and Ti and Te within each breath are independent of the preceding breaths. The purpose of our research is to determine the following points. (1) The influence of the respiratory stimuli produced by passive or active limb movements on the VT-Ti relationship, the Te-Ti relationship, the bulbo-pontine pacemaker, the output to the inspiratory muscles (in terms of VT/l?). (2) The time course of Ti, Te and VT/Ti at the onset and at the offset of the limb movements. (3) The effect of a single limb movement performed during expiration or inspiration on the breath during which it is elicited and on the subsequent breaths.
Methods Experiments were performed on 8 dogs (7-19 kg b.wt) and 8 rabbits (1.7-3.2 kg b.wt) in the supine posture and anesthetized with intravenous injections of sodium pentobarbital (30 mg/kg), and of a mixture of sodium pentobarbital (20 mg/kg) and urethane (0.5 g/kg), respectively. After the vagi were isolated in the neck, a T cannula was tightly inserted into the trachea a few rings below the larynx and connected to a pneumotachograph and to a Statham P 23 BB pressure transducer. In some experiments a thermistor was advanced into the chest through the jugular vein. Signals from the transducers and the thermistor were fed into a Sanbom oscillograph; that from the pneumotachograph was electrically integrated to give tidal volume changes. A polyvinyl catheter connected through a 3-way stopcock to a syringe (dead space 0.06 ml) was inserted into the carotid artery; samples of blood (0.5 ml in rabbits and 1 ml in dogs) were analyzed for Pco2 and PO2 by means of a Radiometer blood gas analyzer (BMS 3MK2 and PHM 71MK2). Passive exercise was induced by manually moving the animal’s hind limbs at an approximate frequency of 1 Hz. The leg was alternatively flexed and extended relative to the thigh and the latter to the trunk : the angle between the two parts was made to change by about 70” in both joints. Active exercise was induced by stimuli delivered
BREATHING
CONTROL DURING
LIMB MOVEMENTS
35
through two needles inserted subcutaneously in the medial side of the thigh and connected to a Grass S 4 stimulator. Stimulating pulses were square waves of g-l 5 V, 50 msec of duration, delivered at a frequency of either 1 or 3 cycles per sec. Each type of exercise lasted about 3 min and was performed at least once by all animals before and after bilateral cervical vagotomy. Complete airway occlusion at end expiration was performed 3-5 times both before and during exercise after a steady pattern of breathing had been established; occlusions lasted one complete cycle as monitored by tracheal pressure and were separated by 4-5 unoccluded breaths. Blood samples were drawn before the exercise and during its steady state. From the spirographic tracing recorded at a chart speed of 10 or 25 mm+ and from the alveolar pressure (Palv) during occluded breaths, the duration of inspiration and expiration, tidal volume and peak tracheal pressure (during occlusion) were measured breath by breath. In addition as an index of the central drive to the respiratory muscles the mean inspiratory flow (VT/Ii) was computed for each breath. It may be argued that VT/Ii is not a good index of the central drive because it may be affected by mechanical factors such as elastance and flow-resistance. Within the range of VT occurring in our experiments, however, the changes of Palv/Ti during occlusion were proportional to those of VT/Ti; hence VT/Ti may be considered a good index of the central drive. In order to avoid variance due to different values of the various parameters among individual animals, data obtaining for exercise were expressed relative to corresponding control values at rest; these were obtained by averaging data of ten consecutive breaths recorded before the onset of each type of exercise. The average ratios and their SE thus obtained were multiplied by the corresponding average value obtaining for all animals of a given species at rest. In four dogs and three rabbits experiments were performed also while the animals were breathing 3 % CO, in air from a spirometer connected to the inspiratory port of a two-way valve attached to the pneumotachograph. Passive and active (3 Hz) exercise were induced after a steady pattern of breathing in response to CO, at rest had been established. Moreover, in these animals the effect of tetanic stimulation of the hind limbs maintained for 2-3 min was studied during air breathing; stimulation frequencies of 50-60 Hz were used. Finally, the effect of a single contraction of the hind limbs induced either during inspiration or expiration was studied in four dogs and three rabbits before and after bilateral vagotomy.
Results and dIscussion STEADY STATE
The effect of passive and active hind limb movements on the relationship between tidal volume and inspiratory duration (VT-Ii) and between expiratory and inspiratory
36
E. AGOSTONI AND E. D’ANGELO
duration (Te-Ti) is shown in figs. 1 and 2 for dogs and rabbits, respectively. The corresponding values and percent changes of ventilation, breathing frequency and VT/% are given in table 1. Limb movements displaced the VT-l? relationship to the left, the percent decrease of Ti being nearly the same both at control VT and at VT = 0. The effect of passive movements at about 1 Hz was nearly equal to that of active movement at 1 Hz; the effect of active movements at 3 Hz was greater. Comparable shifts of the VT-Ti relationship have been obtained by increasing body temperature
68 ? 8 ‘i:
5-
0
control
0
passive
0 /+
:
exer.
/I
0 active exer. 1 Hz 0 active exer. 3Hz
/I
a 4% II
/I
II
$$i
/I
/
:
0 5 ‘$
0 i3:
,&”
2 *, P 1
/
*/Q
,$J I
I
1
I
I
O.=1
inspiratory
durationsec
Fig. 1. Lower d@ram : Approximate relationship between tidal volume and inspiratory duration in dogs obtained from unloaded breaths and the first inspiratory effort after closure of the airways. The data refer to control conditions, passive movements of the hind limbs at about 1 Hz, active movements at 1 or 3 Hz. Each symbol is the average from 8 dogs, the data for each animal were normalized as indicated under Methods. The horizontal and vertical bars indicate the SE. Closed symbols = after vagotomy. Upper diagram: Relationship between expiratory and inspiratory duration in dogs under the above mentioned conditions. Since the closed symbols refer to data obtained after vagotomy, the broken line joining them shows the effect of limb movements on the bulbo-pontine timing. The broken line joining the open symbols shows the effect of limb movements on the bulbo-pontine timing under the tonic vagal influence.
BREATHING CONTROL DURING LIMB MOVEMENTS
31
0 control
0 passive
exer. 1l-k
active
exer. 3Hz
A
50
exer.
0 active
*fr
RABBIT
I
1
II
6
i
t
I
I
I
I
,k., 0
II
I I
I
I
0.2
0.4
0.6
inspiratory
0.8
1.0
duration,sec
Fig. 2. Lower diugrum: Approximate relationship between tidal volume and inspiratory duration in rabbits obtained from unloaded breaths and the first inspiratory effort after closure of the airways. The data refer to control conditions, passive movements of the hind limbs at about 1 Hz, active movements at 1 or 3 Hz. Each symbol is the average from 8 rabbits. For further explanations see legend to fig. 1. Upper diagram: Relationship between expiratory and inspiratory duration in rabbits under the above mentioned conditions. For further explanations see legend to fig. 1.
by 2 to 3.5 “C both in cats (Grunstein et al., 1973a; Bradley et al., 1974b) and in rabbits (D’Angelo and Agostoni, 1975b); in our animals, however, body temperature was essentially the same during exercise and at rest. Changes of the VT-Ti relationship have been obtained also by increasing Pkol in cats by Miserocchi and MilicEmili (1975) and in dogs, cats and rabbits by D’Angelo and Agostoni (1975a). This change, however, is mainly due to an increase of slope of the relationship, i.e. Ti of occluded breaths (Ti”) is shortened relatively more than Ti at VT control. Indeed, when Bradley et al. (1974b) determined the volume threshold curve in cats only above VT control, no appreciable effect was found even when Ph, was 15 mm Hg
Active 3Hz A%
Active 1Hz A%
**
1.66
+55
+219
2.59
+104
Mean of 8 animals &SE. *** A not significant
* ATPS
2
3
f16
f8
+3
1.26
Passive about 1 Hz A%
+44
k16
0.81+ 0.04
$343
13.83
+116
6.73
0.49**
Control
A%
Active 3 Hz
Active 1 Hz A%
f8
5.43
Passive about 1 Hz A%
+74
3.12f
Control
ir 1*/min
+141
106.9
+79
79.5
+51
67.1
9
3
+13
* 9
f
4.0
+24
f12
f
44.4*
+212
51.7
f87
31.0
+71
28.3
16.6& 1.9
f c/min
+33
25.6
+15
22.2
f
f2
3
1.4***
1.9
+ 2
+2.7*
19.8
1.0***
+ 1
19.3f
+41
265.6
+15
216.9
+2.1*
192.7
188.8+ 16.9
ml*
VT
1.17
1.52
+2
0.33
-65
0.33
-52
-40
0.58
+2
f2
+2
0.97 f0.08
-70
f4
+4
2.77 kO.30
0.84
-68
-45
Te set
f3
f2
-44
0.25
-26
0.33
-20
0.36
f2
&2
f0.3
0.45 f0.05
-68
0.47
-31
0.77
+2
1.12f0.08 0.80 -29
Ti set
+137
105.5
+56
69.2
+28
57.0
7
3
+ 7
f
+ 1
3.4
k35
f
+ 4
44.5j,
+256
628.2
+68
297.2
+44
253.7
176.4k22.1
VT/Ti ml*/sec
TABLE 1 Values of ventilation@), breathing frequency (f), tidal volume (VT), expiratory duration (Te), inspiratory duration (Ti) and mean inspiratory flow (VT/Ti) during control condition and during steady state passive or active movements of the hind limbs
b z?
z m
3
z
BREATHINGCONTROLDURING
LIMB MOVEMENTS
39
above control value. According to previous observations in rabbits and dogs @‘Angelo and Agostoni, 1975a) an increase of 15 mm Hg of Pa,, does not shorten Ti and VT control as much as during passive exercise, whereas it moves Ti” to a point nearly midway between Ti” during passive exercise and Ti” during active exercise at 3 Hz. Hence the effect of CO, on the VT-l? relationship is essentially different from that of the stimuli from the moving limbs. In any case, in our experiment Pacoz was similar to control value during active limb movements and decreased by 3-4 mm Hg during passive limb movements. Movements of the limbs lowered the Te-Ti relationship: since Te was shortened more than Ti, the slope of the relationship decreased progressively as the frequency of movements increased. The percent changes of Te and Ti are reported for convenience in table 1. The output to inspiratory muscles, expressed by the average inspiratory flow (VT/T?), was increased by limb movements (table 1). One may compute from the data obtained when breathing CO, (table 3) that the increase of the output to the inspiratory muscles produced by passive movements was similar to that caused at rest by an increase in Pace, of about 5 mm Hg in dogs and 8 mm Hg in rabbits, while that produced by active exercise at 3 Hz was similar to that caused at rest by an increase of PacOz of about 15 mm Hg in dogs and 18 mm Hg in rabbits. It appears from table 1 that the effect produced by limb movements on the various parameters is greater in dogs than in rabbits, except for the increase of VT during active movements at 1 Hz which is similar. The increase of ventilation brought forth by passive movements was mainly due to an increase in breathing frequency; this is in line with the results obtained in man and dogs by Harrison et al. (1932) and in dogs by Comroe and Schmidt (1943), whereas in man these authors found a comparable increase of frequency and VT. On the other hand, hyperpnea produced by passive (Comroe and Schmidt, 1943) and active (Comroe and Schmidt, 1943 ; Rodgers, 1968) limb movements in cats is mainly due to an increase of VT and hence of the output to the inspiratory muscles. These findings indicate that there are species difference about the quantitative aspects of the effects produced by limb movements on the VT-% relationship and on the output to inspiratory muscles. The effect of vagotomy is also shown in figs. 1 and 2 (closed symbols). Under this condition the timing of breath depends only on the b~bo-pontine pacemaker. Since airways occlusion at end expiration in intact animals abolishes the vagal modulation during inspiratory effort (Richardson et al., 1973), comparison of the effects of limb movements on the timing of breathing between intact and vagotomized animals should be made on occluded breaths. In order to facilitate this comparison in figs. 1 and 2 Te and Ti data points obtaining for occluded breaths at rest and during the various types of exercise in intact animals are joined by a dashed line; similarly the points referring to vagotomized animals are joined by a dashed line. The data at rest confirm the marked influence of tonic vagal impulses (increase of Ti”) and the lack of influence on Te” at FRC found in dogs, cats and rabbits (D’Angelo and Agostoni,
2 4 er:
? 9
**
*
+217
2.27
+84
Mean of 8 animals +SE.
ATPS
A%
Active 3Hz
A%
+ll
k5
1.32
Active 1 Hz
+46
k28
0.72+ 0.05
+396
13.65
+175
7.58
0.33**
Control
A%
Active 3Hz
A%
Active 1 Hz
A%
*lo
4.61
Passive about 1 Hz
+67
2.75 f
Control
V l*/min
+122
42.5
+56
29.9
8
0.5
* 9
k4
1.4
+28
k17
f
19.2*
+214
23.4
+116
16.1
+53
11.4
7.4*
f c/min
+43
54.2
+18
44.6
f
3
&2
f
1
1
1.9
+ 8
f
37.8*
+58
579.5
+26
460.9
+9
400.5
-65
-43
-74
-61
0.73 kl
*2
-38
-22 0.75
&2
+1
+132
73.7
+52
+ 9
&4
1.4
k31
48.3
+243
*20
0.94
k3
487.1
+100
1.16
1.81
*4
+ 5
31.8*
-52
-35
285.7
+36
192.9
1.2lkO.08
+2
+3
1.78
&2
during
142.3* 18.7
Vr/Ti ml*/sec
(VT/%)
2.05 kO.21
1.44
2.18
-19
2.21
3.32 +4
2.72kO.19
Set
Ti
5.57kO.39
-40
StX
ml* 366.1 k30.0
Te
VT
TABLE 2 Values of ventilation 0, breathing frequency (f), tidal volume (VT), expiratory duration ne), inspiratory duration (Ti) and mean inspiratory flow control conditions and during steady state passive or active movements of the hind limbs in vagotomized animals
$
a”
.m
B
.” *
%
BREATHNGCONTROL
DURING LIMB MOVEMENTS
41
1975a), at variance with Grunstein et aE. (1973b) who never found an increase of Ti” after bilateral cervical vagotomy. Moreover, the tonic vagal effect on Ti” persisted during limb movements. As observed in intact animals limb movements produced a marked decrease of Ti and Te set by the bulbo-pontine pacemaker (figs. 1 and 2). Indeed, when expressed as percent of the control values, the changes caused by limb movements in vagotomized animals (table 2) were similar to those occurring in intact animals (table 1). This is in line with the results obtained by Phillipson et al. (1970) and Bouverot (1973) in conscious dogs and by Lahiri et al. (1975) in anesthetized dogs : once expressed relative to control values their data show that the increase of breathing frequency produced by active limb movements was the same before and after vagotomy. Indeed in our dogs active limb movements at 3 Hz brought the breathing frequency of vagotomized dogs to a value higher than that in the control intact dog, and in vagotomized rabbits to a value similar to that of control intact rabbits (tables 1 and 2). Since also VT was increased by limb movements, VT/% was increased by limb movements after vagotomy. On the other hand, both at rest and during limb movements VT/Ti after vagotomy was smaller than before vagotomy. There is general agreement that vagotomy either abolishes or markedly reduces the CO, effect on the breathing frequency (Lahiri et al., 1975). Vagotomy, however, does not change the effect of hyperthermia on the breathing frequency (Grunstein et al., 1973a; Widdicombe and Winning, 1974) nor that of stimuli from the moving limbs. This further supports the similarity between the effects produced by limb movements and hyperthermia, and the difference between these effects and those produced by CO,. The effect of giving 3% CO, in air to breath to intact dogs is illustrated in fig. 3. Similar results were obtained in intact rabbits. It appears that both at rest and during limb movements the VT-Ii relationship is not appreciably affected by the consequent increase of 4-5 mm Hg in Pacol. This confirms our data on resting dogs, cats and rabbits (D’Angelo and Agostoni, 1975a) and those of Grunstein et al. (1973b) on cats, showing that only marked increases of Pacol are able to produce a significant change of the VT-Ti relationship. On the other hand, Miserocchi and Milic-Emili (1975) in lightly anesthetized cats found that an increase of Paco2 by 5 mm Hg was sufficient to produce a significant shortening of Ti”. Moreover, the results obtained by all these authors as well as by Clark and von Euler (1972) and by Bradley et al. (1974a) in cats, showed that an increase of CO, does not affect the Te-Ti relationship at rest. Our results show that this is true also during limb movements. Hence, at least within the range of Paco2 values occurring during spontaneous exercise, an increase of CO, acts only by increasing the output to the inspiratory muscles, i.e. by increasing VT/Ti, leaving the time-related characteristics of the respiratory centers unaffected. The comparison of the value of d(VT/Ti)/dPaco, and of dV/dPaco, at rest and during limb movement suggests that the action of the CO, stimulus is additive, because these values are not significantly changed by limb movements in either dogs or rabbits (table 3). Similar results, as far as A?/AP.+o, is concerned, were reported
E. AGOSKNI ANDE. D’ANGELO
42
0.5
I
I
I
1
I
I
I
I
PaconmHg 0 37.5 0 41.5 a41.8 0 34.1 m 38.7 6 36.6
1.3
1.5
1.7
1.9
: I
inspiratory duration , set
Fig. 3. Lower d@ram: Approximate relationship between tidal volume and inspiratory duration in dogs obtained from unloaded breaths and the first inspiratory effort after closure of the airways. Half-closed symbols = animals breathing 3 % CO, in air ; star = tetanic stimulation of the hind limb for about 2 min, brdathing air. For key to the other symbols and further explanations see fig. 1. Upper diagram: Relationship between expiratory and inspiratory duration in dogs under the above mentioned conditions.
also for man during voluntary exercise (Dejours et a[ 1960; Cunningham et al., 1966; D’Angelo and Torelli, 1971). The same conclusion was drawn by Kindermann and Pleschka (1973), who recorded phrenic nerve activity in cats during stretching the triceps surae with different chemical stimulation backgrounds. When the hind limbs were stimulated by a frequency high enough to produce a tetanic contraction, neither the VT-Ti nor the TeTi relationship was modified (fig. 3); Ti” moved a little to the left but not significantly. Indeed under this condition joint receptors and muscle spindles should not be stimulated except at the onset and at the offset of the stimulus. Since the stimulation was maintained for a few minutes Pa,,* increased and the point moved up nearly along the resting VT-l? relationship and down along the resting Te-Ti relationship (fig. 3). The ensuing hyperpnea could be entirely explained by the increase of Pacoz, because the value of A7j/APaco2 during tetanic stimulation was similar to that during CO, breathing at rest. The similarity of the ventilatory effects obtained during passive and active movements at the same frequency as well as the fact that the ventilatory effects during
BREATHINGCONTROLDURINGLIMBMOvFMENTs
43
tetanic stimulation were only related to the CO, increase show that during electrical stimulation of the hind limbs the possible stimulation of receptors not involved by normal exercise did not appreciably affect ventilation.
TIME COURSE AT THE ONSET AND OFFSET OF STIMULATION
The spirographic tracings in fig. 4 show the effect at the onset and at the offset of st~ulation at 3 Hz in a dog before and after bilateral vagotomy. When the stimulus was started during expiration Te was shortened: i.e. the stimuli coming from the moving limbs cut down the expiratory duration set by the previous inspiration according to the Te-Ti relationship (see below under : Stimulus during a single expiration or inspiration). ,
a
t
4 a2
0.1
0
0.6
-_ 0.4 )s a2 01 ! /
1 i j 1 -ivj’i I-
.._
i.
/ / j
j i j i- /‘/ / / /
/ / i j / / /
j
/
i
‘.1...:
? :
1 i : :
Fig. 4. Spirographic tracings taken at slow speed to illustrate the changes occurring at the onset and at the offset of stimulation of the hind limbs at 3 Hz. The period of stimulation is indicated on the time scale. Upper tracing: intact dog. Lower tracing (slower paper speed): vagotomized dog. Time in sec.
The time course of Te, Ti and VT/T? at the onset and at the offset of passive or active limb movements in dogs is illustrated by fig. 5. Since the time course with st~u~ation at 1 Hz was nearly the same as that with stimulation at 3 Hz, we reported only the latter. Both at the onset and at the offset there was a sudden change followed by a slower one. Both during passive and active movements the time course was slower at the offset than at the onset. During active movements the time course was slower than during passive movements. Similar results were obtained after vagotomy. The time course of Te, Ti and VT/% at the onset and at the offset of passive and active limb movements‘in rabbits is ihustrated by fig. 6. Under our experimental conditions rabbits showed a paradoxical phenomenon both during active and passive movements. The first inspiration since the beginning of stimulation (independently of the respiratory phase during which the stimulus started) was longer and deeper than the control one, with a slight increase of VTfTi. The first inspiration often looked like a sigh, but it did not always disappear after vagotomy. The time course of ali parameters both at the onset and at the offset was faster in rabbits than in dogs.
44
E. AGGSTDNI AND E. D’ANGELG
DOG ACTIVE
PASSIVE
time,sec Fig. 5. Time course of Te, Ti and VT/Ti at the onset and at the offset of passive or active hind limb movements in dogs. The closed circles refer to the first breath, the open circles refer to the average of all breaths occurring within each 10 set interval from the onset or the offset. Each symbol refers to 6 dogs. The vertical bars indicate the SE. The changes of each parameter are taken as fraction of the change attained at equifibrium. The frequency of active movements was 3 Hz, that of passive ones was about 1 Hz.
The time course of the changes of Te, Ti and VT/n at the offset of limb movements found by us in dogs lasted l-2 min; this agrees in general with the data on hyperventilation at the offset of exercise found by Harrison et al. (1932) and Senapati (1966) in dogs and by Comroe and Schmidt (1943), Rodgers (1968) and Eldridge (1974) in cats. The faster time course in rabbits is probably related to a species difference, because Eldridge (1974) found that the time course was essentially the same with different types of anesthesia. Eldridge’s experiments (1974) were performed under isocapnic conditions; hence the slow decay of hyperventilation after cessation of the stimulus could not be explained by hypercapnia. Eldridge, following the suggestion of Gesell et al. (1942), related the slow decay to the phenomenon of the afterdischarge: i.e. the stimuli coming from CSN or the limbs activate reverberating circuits acting on the respiratory centers. In our experiments Paa, during active movements was close to control values, whereas during passive movements it was lover (table 3). The values of Pa,, and of body temperature during limb movements were similar to control
BRi3ATHING CONTROL DURING LB%?3MOANS
4s
RABBIT
time,sec Fig. 6. Time course of Te, Ti and VT/Ti at the onset and at the offset of passive or active hind limb movements in rabbits. The closed circles refer to the first breath. The open circles refer to the average of all breaths occurring within each 2 set interval from the onset and within each 4 see interval from the offset, Each symbol refers to 6 rabbits. The vertical bars indicate the SE. The changes of each parameter are taken as fraction of the change attained at equilibrium. The frequency of active movement was 3 Hz, that of passive ones was about 1 Hz.
ones. Both in dogs and in rabbits, blood pressure decreased at the onset of passive or active mov~~nts~ but recovered partially during the period of movements; at the offset it returned to control value with a time course roughly similar to that of the respiratory changes. Similar results were also obtained by Comroe and Schmidt (1943). Although a marked increase of biood pressure in the carotid sinus decreases ventilation, whereas a marked decrease increases ventilation (Heymans and Bouckaert, 1930), the respirator changes observed during Iimb movements are not secondary to the changes of blood pressure because of the following findings: (1) The respiratory effects during limb movements when both carotid arteries were clamped were similar to those occurring with open carotid arteries, as previously shown by Rodgers (1968) and in spite of the fact that at rest closure of the carotid arteries produced an increase of v~ti~ation as expected. (2) The decrease of blood pressure after f&20 set of limb movements was greater than that after 60 set, whereas the respiratory changes after 1O-20set were similar to or smaller
46
E. AGWT0Nl AND E. D’ANGEI.0
TABLE3 Effects
L; ii
of CO, on the ontput to the ~s~rato~
.g . $
* **
d~T~~/d~~,
and on
air
0”3~~0,020
5.66+0.46
34.1.k0.8
78.4+2,0
3% CD,
0,466+0.045
9.05+0.45
38.7rtO.5
77*o+o.ti
3% CO,
0.$14~0.038
$ .r( i
mu&es,
17.95&-1.29 43.510.8
ventilation, d~/d~x,
at rest,
0.036~0.~
0.77&0.11
0.032~0.004
0.75 ltO.05
78.2&0.8
ATPS
SE.
4.>” 3 D+ 2I 1
time,
Fig. 7. Time course of ventilation at the onset and the offset of passive (open circles] or active (closed circles) hind limb movements in dogs and rabbits. Each symbol refers to 6 dugs and 6 rabbits. The frequency of active movements was 3 Hz, that of passive movements was about 1 Hz. The numbers within brackets along the line indicate the values of Pacol at rest and during passive or active limb movements. At the offset data were ROlonger plotted after they bad reached the control values.
than those after 60 sec. It seems therefore that both the respiratory and vascular changes are parallel effects produced on the bulbo-betide cemtersby the stimuli coming from the moving limbs. Hence, the st~dy~s~t~ respiratory changes seem essentiallydue to the stimuli from the moving limbs. If so, also the slow decay of the hyperventilation observed at the end of limb movements should be largely due to
47
BWATHING CONTROL DURING LIMB MOVE
luring
passive and active (3 Hz) exercise, in 4 dogs and 3 rabbits
Rabbit VT/T~
pa,* (mm Hg)
(ml*/sec) 45.6k2.5
856.7_+ 35.3
pao,
A\jlAPam2
(mm Hg)
(ml*/m~
33.3kO.3
71.Ok2.5
66.3k1.7
1328.3f
17.0
39.OkO.3
72.2k2.2
61.5&6.3
f420.Q
28.6
29.3 kO.9
72.3k2.6
86.9k1.9
195o.oi: 59.0
35.2 kO.9
71.2k2.4
112.7+7.0
2874.3 _t 87.5
32.5 f0.9
12.7$2.7
137.6+4.6
3430.0+ 162.6
39.5 f 1.o
13.2k2.2
*mm Hg)
3.7kO.l
83.555.4
4.5212
92.75 12.3
3.620.4
79.2& 0.7
the afterd~scharge. In this caption, however, one must consider that owing to the marked and abrupt fall in ventilation occurring at the end of exercise Ph, during the recovery period should increase relative to the exercise value. Hence, the slow decay of all parameters at the offset should be affected by the relative increase of Pam,. From the data of the phrenic nerve minute output at the offset of both CSN stimulation and calf squeezing obtained in cats by Eldridge (1974) under isocapnic conditions it seems that the slow component contributes about 50 % of the whole neurogenic drive. Our data are represented in terms of ventilation in fig. 7 for both dogs and rabbits. It appears that in anesthetize animals at the offset of both passive and active limb movements the slow component accounts for about 30 % of the whofe ne~ogenic drive in dogs and for about 50 % in rabbits.
SINGLE STIMULUS DURING EXPIRATION OR INSPIRATION
The effects of a single stim~us to the hind limbs during expiration or ~~iration on Te, Ti and Vr/Ti, relative to their control values, are illustrated in figs. 8 and 9. The overall data obtained on the first 3 expirations or insp~mtions since the single stimulus are reported in table 4. At variance with the continuous stimulation at steady state, the single stimulus produced a greater effect in rabbits than in dogs. Like continuous stimulation the single stimulus, either given during expiration or inspiration, pro-
E. AGGSTGNI AND E. D’ANGELO
48
DOG
t 0.d
f, = 13.2Imin
Te,.
2.48
MC
1
J
WTITi),=
t ime,
90.3
mllsec
set
Fig. 8. Effect in dogs of a single stimulus to the hind limbs given during expiration (left) or inspiration (right) on expiratory duration (Te), inspiratory duration (Ti) and mean inspiratory flow (VT/Ti), relative to their control values. The arrows indicate the moment of the stimulus. White and black rectangles refer to expiration and inspiration, respectively. The horizontal broken lines indicate the confidence limits of the average control value at 95 %, computed by multiplying the SE of the mean of 6 control values preceding the stimulus by the value oft at P = 0.05 and 5 degrees of freedom. The control values at the 3 parameters, plus those of breathing frequency are inserted.
duced a greater effect on Te than on Ti. A single contraction of the hind limbs not only affected the timing of the respiratory phase during which it occurred, but it significantly affected the timing of the following 3 to 8 breaths. On the other hand Eldridge (1972, 1974) found that carotid sinus nerve stimulation for only one breath had no significant effect on poststimulation breaths. Since it seems unlikely that a single short contraction of muscles would significantly change any of the humoral factors affecting ventilation, our findings suggest that the stimuli elicited by limb movements are more powerful than those of the CSN in activating the reverberating circuits acting on the respiratory centers (see above). As already shown in a previous paper dealing with the tonic vagal influences on depth and rate of breathing (D’Angelo and Agostoni, 1975a) and as could be expected, there is not a single Te-Ti relationship, but a family of such relationships. Indeed, also the stimuli from the moving limbs modify the control TeTi relationship (figs. 1 and 2). It seems, therefore, that stimuli from the vagus or from propioceptors may affect the circuit setting Te according to Ti by changing its ‘gain’, i.e. by changing the slope of the Te-Ti relationship. When a single stimulus is given during
BREATHING CXNTROL DURING LIMB MOVEMENTS
49
RABBIT
2
4
6
6
10
12
time, set
Fig. 9. Effect in rabbits of a single stimulus to the hind limbs given during expiration (left) or inspiration (right) on Te, Ti and VT/Ti relative to their control values. For further explanations see legend to fig. 8.
expiration it could change the ‘gain’ of the above-mentioned circuit or act directly anticipating the beginning of inspiration. The same considerations apply probably to the findings of Knox (1973). He showed that Te could be shortened or lenghtened, by lung deflation or inflation, respectively, during expiration, without influencing Ti. Knox was working on the vagal feedback and this effect disappezrsd with the stimulus, i.e. Te and Ti of the following breaths were not influenced. As a matter of fact there is no evidence that lung volume related vagal stimuli activate reverberating circuits. The paradoxical effect in rabbits occurred also with the single stimulus during inspiration (fig. 9 and table 4). In spite of this, the following Te was shortened and the timing of the following breaths was the same as that occurring when the stimulus was given during expiration (table 4). Although the data reported in table 4 refer only to stimuli given during a time corresponding to the central period of control expiration or inspiration, stimuli were also given in the first part of expiration or inspiration. We found that even if the stimulus to the hind limbs was given only 0.1 set after the beginning of expiration or inspiration there was qualitatively the usual effect both in dogs and in rabbits.
-
0.91 +0.03
1.12
0.59 i-O.03
0.88 f0.02
1.21
W%
Wi,
CVWi)
.~
2 d
1.10 kO.03
kO.03
0.97 * 0.02
1.53 *0.09 1.15 +0.03
0.82 kO.02
0.65 +0.06
1.18
1.13 +0.02
0.63 +0.07
0.89 +0.01
0.81 +0.01
2
0.98 *0.01
0.81 +0.01
1
1.12 f 0.02
0.86 Jco.01
0.77 f0.03
f0.02
1.12
0.92 fO.O1
0.89 to.02
3
Stimulus during inspiration -
0.77
1.11 +0.01
0.90 +0.01
0.61 kO.03
1.20 kO.03
+0.01
0.90
*to.04
1
1.06 50.01
0.95 to.003
0.83 rto.02
1.18 *0&l
0.92 fO.02
0.72 f0.06
2
1.04 kO.02
0.97 +0.01
0.92 -to.02
1.15 +0.04
0.93 +0.02
0.76 +0.06
3
Stimulus during expiration
Vagotomixed
1.oz” +o - .04***
1.03 *0&F**
0.80 f0.02
1.18 kO.03
0.89 f0.02
0.72 to.03
1
1.07 +0.04
0.91 kO.02
1.18 kO.03
0.84
1.09 j, 0.02
0.93 kO.01
1.03 kO.02
0.98 rto.01
0.98 +0.02***
0.93 to.02
lto.01
0.85 +0.05
3 0.76 kO.04
2
Stimulus during inspiration
** SE. *** Not signikative.
* The data refer to 4 dogs and 3 rabbits. The stimulus was applied between 30 and 40 y0 of Te control and between 25 and 55 o/oof Ti control. When the stimulus was applied during the expiration the first Te is that during which the stimulus was applied and the first Ti is that following, viceversa when the stimulus was applied during inspiration. To visualize the valuescorresponding to the respiratory phase during which the stimulus was applied they are typed boldface.
kO.04
0.94 kO.02
0.73 kO.05
0.69
kO.02
+0.06
1.13
WTi) -____ (Vr/Ti ,)
+0.02
0.94 +0.01
1.18
0.91 +0.01
0.92 kO.01
0.83 +0.02
+0.01
0.80 +0.02
0.79 *0.03**
3
-
1.18
2
1
Stimulus during expiration
Intact
TABLE 4 Values of expiratory duration CJe), inspiratory duration (Ti) and mean inspiratory flow (Vr/Ti), relative to control values, during and after a single stimulus to the hind limbs applied during expiration or inspiration*
g !z
$ m
z
B
.m *
8
BREATHING CGNTROL DURING LIMB MOVEMENT8
51
Though the quanti~tive relationship was not systemati~ly studied, it seems that in dogs, when the stimulus was given during the second quarter of Te control, the shortening was similar to that occurring when the stimulus was given during the first quarter. This suggests that the first discharges from the propioreceptors, reaching the respiratory centers at the very beginning of expiration, are without effect (probably because the ~r~hold for starting inspiration is high) and only those coming later through longer or reverberating circuits produce an effect. On the other hand, when the stimulus is given during the second quarter of the control phase both fast and slow stimuli would be threshold and expiration is ended within a shorter time from the stimulus.
References Asmussen, E. and M. Nielsen (1948)Studies on the initial changes in respiration at the transition from rest to work and from work to rest. Actu Physiol. &and. 16: 270285. Bessou, P., P. Dejours and Y. Laporte (1959). Effets venti~toires reflexes de la stimulation de fibres alT&entes de grand diametre d’origine musculaire chez le Chat. C. R. Sot. BioI. 153: 477-481. Bouverot, P. (1973). Vagal afferent flbres from the lung and regulation of breathing in awake dogs. Respir. Physiol. 17: 325-335.
Bradley, G. W., C. von Euler, I. Marttila and B. Roos (1974a). Transient and steady state effects of CO, on mechanisms determining rate and depth of breathing. Actu Physiol. Stand. 92: 341-350. Bradley, G. W., C. von Euler, I. Marttila and B. Roos (1974b). Steady state effects of CO, and temperature on the ~lationship between lung volume and inspiratory duration (Hering-Breuer threshold curve). Acta Physiol. Stand. 92: 351-363. Clark, F. J. and C. von Euler (1972). On the regulation of depth and rate of breathing. J. Physiol. (London) 222
: 267-295.
Comroe, J. H. Jr. and F. C. Schmidt (1943). Reflexes from the limbs as a factor in the hyperpnea of muscular exercise. Am. J. Physiol. 138: 536-547.
~onn~gh~, D. J. C., B:B. Lloyd and D. Spurr (1966). The relationship between the increase of breathing during the first respiratory cycle in exercise and the prevailing background of chemical stimulation. J. Physiol. (London) !85: 73-75P.
D’Angelo, E. and G. Torelli (1971). Neural stimuli increasing respiration during different types of excercise. J. Appl. Physiol. 30: 116121. D’Angelo, E. and E. Agostoni (1975a). Tonic vagal influences on inspiratory duration. Respir. Physiol. 24: 287-302.
D’Angelo, E. and E. Agostoni (1975b). Immediate response to expiratory threshold load. Respir. PhysioE. 25 : 269-284.
Dejours, P., A. Teillac, Y. Labrousse and J. Raynaud (1956). Etude du mecanisme de la regulation cardioventilatoire au debut de l’exercice musculaire. Reu. Franc. Ef. Clin. Biol. 1: 504-517. Dejours, P., R. Lefrancois, R. Flandrois and A. Teillac (1960). Autonomie des stimulus ventilatoires, oxygene, gaz carbonique et neurogenique de l’exercice musculaire. J. Physiol. (Paris) 52: 63-64. Eldridge, F. L. (1972). The importance of timing on the respiratory effects of i~te~ittent carotid sinus nerve stimulation. J. Physiof. (London) 222: 297-318. Eldridge, F. L. (1974). Central neural respiratory stimulatory effect of active respiration. J. Appl. PhysioE. 37: 723-735.
Euler, C. von, F. Herrero and I. Wexler (1970). Control mechanisms determining rate and depth of respiratory movements. Respir. Physiol. 10: 93-108.
E. AGGSTONI AND E. D’ANGELO
52
Flandrois, R., J. R. Lacour, J. I. Maroquin et J. Charlot (1966). Essai de mise en evidence d’un stimulus neurogtnique articulaire de la ventilation lors de l’exercice musculaire chez le chien. J. Physiol. (Paris) 58: 222-223.
Gautier, H. A., Lacaisse, P. Pasquis and P. Dejours (1964). Reaction ventilatoire a la stimulation des fuseaux neuro-musculaires par la succinylcholine chez le Chat. J. Physiol. (Paris) 56: 560-561. Gesell,R., C. R. Brassfield and M. A. Hamilton (1942). An acid-neurohumoral mechanism of nerve cell activation. Am. J. Physiol. 136: 604-608. Grunstein, M. M., W. M. Fisk, L. A. Leiter and J. Milic-Emili (1973a). Effect of body temperature on respiratory frequency on anesthetized cat. J. Appl. Physiol. 34: 154159. Grunstein, M. M., M. Younes and J. Milic-Emili (1973b). Control of tidal volume and respiratory frequency in anesthetized cats. J. Appl. Physiol. 35: 463473. Harrison, W. G. Jr., J. A. Calhoun and T. R. Harrison (1932). Afferent impulses as a cause of increased ventilation during muscular exercise. Am. J. Physiol. 100: 68-73. Heymans, C. and J. J. Bouckaert (1930). Sinus caroticus and respiratory reflexes. I. Cerebral Blood flow and respiration. Adrenaline apnoea. J. Physiol. (London) 69 : 254-266. Kao, F. F. (1963). An experimental study of the pathway involved in exercise hypcrpnea employing crosscirculation techniques. In: The Regulation of Human Respiration, edited by D. J. C. Cunningham and B. B. Lloyd. Oxford, Blackwell, pp. 461-502. Kindermann, W. and K. Pleschka (1973). Phrenic nerve response to passive muscles stretch at different arterial CO, tensions. Respir. Physiol. 17: 227-237. Knox, C. K. (1973). Characteristics of inflation and deflation reflexes during expiration in the cat. J. Neurophysiol. 36 : 284-295.
Krogh, A. and J. Lindhard (1917). A comparison between voluntary and electrically induced muscular work in man. J. Physiol. (London) 51: 182-201. Lahiri, S., S. S. Mei and F. F. Kao (1975). Vagal modulation of respiratory control during exercise. Respir. Physiol. 23
: 133-146.
Miserocchi, G. and J. Milic-Emili (1975). Contribution of hypercapnic stimuli and vagal afferents to the timing of breathing in anesthetized cats. Respir. Physiol. 25: 71-88. Phillipson, E. A., R. F. Hickey, C. R. Bainton and J. A. Nadel(l970). Effect of vagal blockade on regulation of breathing in conscious dogs. J. Appl. Physiol. 29: 475479. Richardson, P. S., G. Sant’Ambrogio, J. Mortola and R. Bianconi. (1973). The activity of lung afferent nerves during tracheal occlusion. Respir. Physiol. 18: 273-283. Rodgers, S. H. (1968). Ventilatory response to ventral root stimulation in the decerebrate cat. Respir. Physiol. 5: 165-174.
Senapati, J. M. (1966). Effect of stimulation of muscle afferents on ventilation .of dogs. J. Appl. Physiol. 21: 242-246.
Widdicombe, J. G. and A. Winning (1974). EtTects ophypoxia, hypercapnia and changes in body temperature on the pattern of breathing in cats. Respjr. Physiol. 21: 202221.
THE EFFECT OF LIMB MOVEMENTS ON THE REGULATION OF DEPTH AND RATE OF BREATHING’
EMIL10 AGOSTONI and EDGARDO D’ANGELO Istituto di Fisiologia Umana (Ia Cattedra), Universitri di Milano, Milan, Italy
Abstract. In anesthetized dogs and rabbits passive or active limb movements (1) shifted to the left the relationship between tidal volume (VT) and inspiratory time (I?), (2) lowered the relationship between expiratory time (fe) and Ti and decreased its slope, and (3) increased the output to the inspiratory muscles (W/I?). These effects increased with increasing the frequency of movements. Similar effects were obtained after vagotomy. When the stimulus was started during expiration, Te was shortened in spite of the previous unatTected Ti. Arterial Pco, during exercise was similar (active movements) or below (passive movements) control value. Since other chemical and physical humoral factors do not seem involved, the whole increase of ventilation should be produced by neurogenic stimuli. The time course of Te, Ti and Vr/Ti at the onset and at the offset of limb movements indicates an abrupt and a .slow component in the neurogenic drive. A single contraction of the limb during expiration or inspiration affected the timing and the VTpi of 3-g breaths. Control of breathing Expiratory time Inspiratory time Muscular exercise
Neurogenic stimuli to ventilation Output to inspiratory muscles Vagotomy
It has been known for many years that passive (Harrison et al., 1932; Comroe and Schmidt, 1943; Dejours et al., 1956) and active involuntary (Krogh and Lindhard, 19 17 ; Comroe and Schmidt, 1943 ; Asmussen and Nielsen, 1948 ; Kao, 1963 ; Rodgers, 1968) movements of the limbs produce an increase of ventilation. This reflex increase of ventilation originate from stimulation of joint receptors (Comroe and Schmidt, 1943; Flandrois et al., 1966) and of muscle spindles (Bessou et al., 1959; Gautier et al., 1964). Harrison et al. (1932) pointed.out that in some dogs the increase of ventilation produced by passive limb movements persists for 2-3 min after cessation of the movements. In line with this observation is the persistence of the hyperventilatory effect Accepted for publication 4 February 1976.
1 This research was supported by the National Research Council of Italy. 33
34
E. AGGSTONIANDE. D’ANGELO
of gastrocnemius-soleus nerve stimulation (Senapati, 1966) and of limb muscle squeezing (Eldridge, 1974) after cessation of the stimulus. Analogous to this persistence may be considered the persistence of hyperpnea after cessation of carotid sinus nerve (CSN) stimulation (Gesell et al., 1942; Eldridge, 1974). Eldridge (1972, 1974) also reported that CSN stimulation for only one breath has no effect on subsequent breaths. Von Euler et al. (1970) and Clark and von Euler (1972) have provided new insights into the control of breathing as far as depth and rate regulation are concerned. They showed the following features : (1) Inspiratory duration (Ti) is set by a vagal feedback system linked to the increase of lung volume (the Hering-Breuer reflex) with a threshold mechanism decreasing with time from the onset of inspiration (i.e. the VT-I? relationship). (2) After vagotomy Ti is independent of changes in tidal volume and depends essentially upon the bulbo-pontine pacemaker. (3) Expiratory duration depends on the preceding Ti (Te-Ti relationship), and Ti and Te within each breath are independent of the preceding breaths. The purpose of our research is to determine the following points. (1) The influence of the respiratory stimuli produced by passive or active limb movements on the VT-Ti relationship, the Te-Ti relationship, the bulbo-pontine pacemaker, the output to the inspiratory muscles (in terms of VT/l?). (2) The time course of Ti, Te and VT/Ti at the onset and at the offset of the limb movements. (3) The effect of a single limb movement performed during expiration or inspiration on the breath during which it is elicited and on the subsequent breaths.
Methods Experiments were performed on 8 dogs (7-19 kg b.wt) and 8 rabbits (1.7-3.2 kg b.wt) in the supine posture and anesthetized with intravenous injections of sodium pentobarbital (30 mg/kg), and of a mixture of sodium pentobarbital (20 mg/kg) and urethane (0.5 g/kg), respectively. After the vagi were isolated in the neck, a T cannula was tightly inserted into the trachea a few rings below the larynx and connected to a pneumotachograph and to a Statham P 23 BB pressure transducer. In some experiments a thermistor was advanced into the chest through the jugular vein. Signals from the transducers and the thermistor were fed into a Sanbom oscillograph; that from the pneumotachograph was electrically integrated to give tidal volume changes. A polyvinyl catheter connected through a 3-way stopcock to a syringe (dead space 0.06 ml) was inserted into the carotid artery; samples of blood (0.5 ml in rabbits and 1 ml in dogs) were analyzed for Pco2 and PO2 by means of a Radiometer blood gas analyzer (BMS 3MK2 and PHM 71MK2). Passive exercise was induced by manually moving the animal’s hind limbs at an approximate frequency of 1 Hz. The leg was alternatively flexed and extended relative to the thigh and the latter to the trunk : the angle between the two parts was made to change by about 70” in both joints. Active exercise was induced by stimuli delivered
BREATHING
CONTROL DURING
LIMB MOVEMENTS
35
through two needles inserted subcutaneously in the medial side of the thigh and connected to a Grass S 4 stimulator. Stimulating pulses were square waves of g-l 5 V, 50 msec of duration, delivered at a frequency of either 1 or 3 cycles per sec. Each type of exercise lasted about 3 min and was performed at least once by all animals before and after bilateral cervical vagotomy. Complete airway occlusion at end expiration was performed 3-5 times both before and during exercise after a steady pattern of breathing had been established; occlusions lasted one complete cycle as monitored by tracheal pressure and were separated by 4-5 unoccluded breaths. Blood samples were drawn before the exercise and during its steady state. From the spirographic tracing recorded at a chart speed of 10 or 25 mm+ and from the alveolar pressure (Palv) during occluded breaths, the duration of inspiration and expiration, tidal volume and peak tracheal pressure (during occlusion) were measured breath by breath. In addition as an index of the central drive to the respiratory muscles the mean inspiratory flow (VT/Ii) was computed for each breath. It may be argued that VT/Ii is not a good index of the central drive because it may be affected by mechanical factors such as elastance and flow-resistance. Within the range of VT occurring in our experiments, however, the changes of Palv/Ti during occlusion were proportional to those of VT/Ti; hence VT/Ti may be considered a good index of the central drive. In order to avoid variance due to different values of the various parameters among individual animals, data obtaining for exercise were expressed relative to corresponding control values at rest; these were obtained by averaging data of ten consecutive breaths recorded before the onset of each type of exercise. The average ratios and their SE thus obtained were multiplied by the corresponding average value obtaining for all animals of a given species at rest. In four dogs and three rabbits experiments were performed also while the animals were breathing 3 % CO, in air from a spirometer connected to the inspiratory port of a two-way valve attached to the pneumotachograph. Passive and active (3 Hz) exercise were induced after a steady pattern of breathing in response to CO, at rest had been established. Moreover, in these animals the effect of tetanic stimulation of the hind limbs maintained for 2-3 min was studied during air breathing; stimulation frequencies of 50-60 Hz were used. Finally, the effect of a single contraction of the hind limbs induced either during inspiration or expiration was studied in four dogs and three rabbits before and after bilateral vagotomy.
Results and dIscussion STEADY STATE
The effect of passive and active hind limb movements on the relationship between tidal volume and inspiratory duration (VT-Ii) and between expiratory and inspiratory
36
E. AGOSTONI AND E. D’ANGELO
duration (Te-Ti) is shown in figs. 1 and 2 for dogs and rabbits, respectively. The corresponding values and percent changes of ventilation, breathing frequency and VT/% are given in table 1. Limb movements displaced the VT-l? relationship to the left, the percent decrease of Ti being nearly the same both at control VT and at VT = 0. The effect of passive movements at about 1 Hz was nearly equal to that of active movement at 1 Hz; the effect of active movements at 3 Hz was greater. Comparable shifts of the VT-Ti relationship have been obtained by increasing body temperature
68 ? 8 ‘i:
5-
0
control
0
passive
0 /+
:
exer.
/I
0 active exer. 1 Hz 0 active exer. 3Hz
/I
a 4% II
/I
II
$$i
/I
/
:
0 5 ‘$
0 i3:
,&”
2 *, P 1
/
*/Q
,$J I
I
1
I
I
O.=1
inspiratory
durationsec
Fig. 1. Lower d@ram : Approximate relationship between tidal volume and inspiratory duration in dogs obtained from unloaded breaths and the first inspiratory effort after closure of the airways. The data refer to control conditions, passive movements of the hind limbs at about 1 Hz, active movements at 1 or 3 Hz. Each symbol is the average from 8 dogs, the data for each animal were normalized as indicated under Methods. The horizontal and vertical bars indicate the SE. Closed symbols = after vagotomy. Upper diagram: Relationship between expiratory and inspiratory duration in dogs under the above mentioned conditions. Since the closed symbols refer to data obtained after vagotomy, the broken line joining them shows the effect of limb movements on the bulbo-pontine timing. The broken line joining the open symbols shows the effect of limb movements on the bulbo-pontine timing under the tonic vagal influence.
BREATHING CONTROL DURING LIMB MOVEMENTS
31
0 control
0 passive
exer. 1l-k
active
exer. 3Hz
A
50
exer.
0 active
*fr
RABBIT
I
1
II
6
i
t
I
I
I
I
,k., 0
II
I I
I
I
0.2
0.4
0.6
inspiratory
0.8
1.0
duration,sec
Fig. 2. Lower diugrum: Approximate relationship between tidal volume and inspiratory duration in rabbits obtained from unloaded breaths and the first inspiratory effort after closure of the airways. The data refer to control conditions, passive movements of the hind limbs at about 1 Hz, active movements at 1 or 3 Hz. Each symbol is the average from 8 rabbits. For further explanations see legend to fig. 1. Upper diagram: Relationship between expiratory and inspiratory duration in rabbits under the above mentioned conditions. For further explanations see legend to fig. 1.
by 2 to 3.5 “C both in cats (Grunstein et al., 1973a; Bradley et al., 1974b) and in rabbits (D’Angelo and Agostoni, 1975b); in our animals, however, body temperature was essentially the same during exercise and at rest. Changes of the VT-Ti relationship have been obtained also by increasing Pkol in cats by Miserocchi and MilicEmili (1975) and in dogs, cats and rabbits by D’Angelo and Agostoni (1975a). This change, however, is mainly due to an increase of slope of the relationship, i.e. Ti of occluded breaths (Ti”) is shortened relatively more than Ti at VT control. Indeed, when Bradley et al. (1974b) determined the volume threshold curve in cats only above VT control, no appreciable effect was found even when Ph, was 15 mm Hg
Active 3Hz A%
Active 1Hz A%
**
1.66
+55
+219
2.59
+104
Mean of 8 animals &SE. *** A not significant
* ATPS
2
3
f16
f8
+3
1.26
Passive about 1 Hz A%
+44
k16
0.81+ 0.04
$343
13.83
+116
6.73
0.49**
Control
A%
Active 3 Hz
Active 1 Hz A%
f8
5.43
Passive about 1 Hz A%
+74
3.12f
Control
ir 1*/min
+141
106.9
+79
79.5
+51
67.1
9
3
+13
* 9
f
4.0
+24
f12
f
44.4*
+212
51.7
f87
31.0
+71
28.3
16.6& 1.9
f c/min
+33
25.6
+15
22.2
f
f2
3
1.4***
1.9
+ 2
+2.7*
19.8
1.0***
+ 1
19.3f
+41
265.6
+15
216.9
+2.1*
192.7
188.8+ 16.9
ml*
VT
1.17
1.52
+2
0.33
-65
0.33
-52
-40
0.58
+2
f2
+2
0.97 f0.08
-70
f4
+4
2.77 kO.30
0.84
-68
-45
Te set
f3
f2
-44
0.25
-26
0.33
-20
0.36
f2
&2
f0.3
0.45 f0.05
-68
0.47
-31
0.77
+2
1.12f0.08 0.80 -29
Ti set
+137
105.5
+56
69.2
+28
57.0
7
3
+ 7
f
+ 1
3.4
k35
f
+ 4
44.5j,
+256
628.2
+68
297.2
+44
253.7
176.4k22.1
VT/Ti ml*/sec
TABLE 1 Values of ventilation@), breathing frequency (f), tidal volume (VT), expiratory duration (Te), inspiratory duration (Ti) and mean inspiratory flow (VT/Ti) during control condition and during steady state passive or active movements of the hind limbs
b z?
z m
3
z
BREATHINGCONTROLDURING
LIMB MOVEMENTS
39
above control value. According to previous observations in rabbits and dogs @‘Angelo and Agostoni, 1975a) an increase of 15 mm Hg of Pa,, does not shorten Ti and VT control as much as during passive exercise, whereas it moves Ti” to a point nearly midway between Ti” during passive exercise and Ti” during active exercise at 3 Hz. Hence the effect of CO, on the VT-l? relationship is essentially different from that of the stimuli from the moving limbs. In any case, in our experiment Pacoz was similar to control value during active limb movements and decreased by 3-4 mm Hg during passive limb movements. Movements of the limbs lowered the Te-Ti relationship: since Te was shortened more than Ti, the slope of the relationship decreased progressively as the frequency of movements increased. The percent changes of Te and Ti are reported for convenience in table 1. The output to inspiratory muscles, expressed by the average inspiratory flow (VT/T?), was increased by limb movements (table 1). One may compute from the data obtained when breathing CO, (table 3) that the increase of the output to the inspiratory muscles produced by passive movements was similar to that caused at rest by an increase in Pace, of about 5 mm Hg in dogs and 8 mm Hg in rabbits, while that produced by active exercise at 3 Hz was similar to that caused at rest by an increase of PacOz of about 15 mm Hg in dogs and 18 mm Hg in rabbits. It appears from table 1 that the effect produced by limb movements on the various parameters is greater in dogs than in rabbits, except for the increase of VT during active movements at 1 Hz which is similar. The increase of ventilation brought forth by passive movements was mainly due to an increase in breathing frequency; this is in line with the results obtained in man and dogs by Harrison et al. (1932) and in dogs by Comroe and Schmidt (1943), whereas in man these authors found a comparable increase of frequency and VT. On the other hand, hyperpnea produced by passive (Comroe and Schmidt, 1943) and active (Comroe and Schmidt, 1943 ; Rodgers, 1968) limb movements in cats is mainly due to an increase of VT and hence of the output to the inspiratory muscles. These findings indicate that there are species difference about the quantitative aspects of the effects produced by limb movements on the VT-% relationship and on the output to inspiratory muscles. The effect of vagotomy is also shown in figs. 1 and 2 (closed symbols). Under this condition the timing of breath depends only on the b~bo-pontine pacemaker. Since airways occlusion at end expiration in intact animals abolishes the vagal modulation during inspiratory effort (Richardson et al., 1973), comparison of the effects of limb movements on the timing of breathing between intact and vagotomized animals should be made on occluded breaths. In order to facilitate this comparison in figs. 1 and 2 Te and Ti data points obtaining for occluded breaths at rest and during the various types of exercise in intact animals are joined by a dashed line; similarly the points referring to vagotomized animals are joined by a dashed line. The data at rest confirm the marked influence of tonic vagal impulses (increase of Ti”) and the lack of influence on Te” at FRC found in dogs, cats and rabbits (D’Angelo and Agostoni,
2 4 er:
? 9
**
*
+217
2.27
+84
Mean of 8 animals +SE.
ATPS
A%
Active 3Hz
A%
+ll
k5
1.32
Active 1 Hz
+46
k28
0.72+ 0.05
+396
13.65
+175
7.58
0.33**
Control
A%
Active 3Hz
A%
Active 1 Hz
A%
*lo
4.61
Passive about 1 Hz
+67
2.75 f
Control
V l*/min
+122
42.5
+56
29.9
8
0.5
* 9
k4
1.4
+28
k17
f
19.2*
+214
23.4
+116
16.1
+53
11.4
7.4*
f c/min
+43
54.2
+18
44.6
f
3
&2
f
1
1
1.9
+ 8
f
37.8*
+58
579.5
+26
460.9
+9
400.5
-65
-43
-74
-61
0.73 kl
*2
-38
-22 0.75
&2
+1
+132
73.7
+52
+ 9
&4
1.4
k31
48.3
+243
*20
0.94
k3
487.1
+100
1.16
1.81
*4
+ 5
31.8*
-52
-35
285.7
+36
192.9
1.2lkO.08
+2
+3
1.78
&2
during
142.3* 18.7
Vr/Ti ml*/sec
(VT/%)
2.05 kO.21
1.44
2.18
-19
2.21
3.32 +4
2.72kO.19
Set
Ti
5.57kO.39
-40
StX
ml* 366.1 k30.0
Te
VT
TABLE 2 Values of ventilation 0, breathing frequency (f), tidal volume (VT), expiratory duration ne), inspiratory duration (Ti) and mean inspiratory flow control conditions and during steady state passive or active movements of the hind limbs in vagotomized animals
$
a”
.m
B
.” *
%
BREATHNGCONTROL
DURING LIMB MOVEMENTS
41
1975a), at variance with Grunstein et aE. (1973b) who never found an increase of Ti” after bilateral cervical vagotomy. Moreover, the tonic vagal effect on Ti” persisted during limb movements. As observed in intact animals limb movements produced a marked decrease of Ti and Te set by the bulbo-pontine pacemaker (figs. 1 and 2). Indeed, when expressed as percent of the control values, the changes caused by limb movements in vagotomized animals (table 2) were similar to those occurring in intact animals (table 1). This is in line with the results obtained by Phillipson et al. (1970) and Bouverot (1973) in conscious dogs and by Lahiri et al. (1975) in anesthetized dogs : once expressed relative to control values their data show that the increase of breathing frequency produced by active limb movements was the same before and after vagotomy. Indeed in our dogs active limb movements at 3 Hz brought the breathing frequency of vagotomized dogs to a value higher than that in the control intact dog, and in vagotomized rabbits to a value similar to that of control intact rabbits (tables 1 and 2). Since also VT was increased by limb movements, VT/% was increased by limb movements after vagotomy. On the other hand, both at rest and during limb movements VT/Ti after vagotomy was smaller than before vagotomy. There is general agreement that vagotomy either abolishes or markedly reduces the CO, effect on the breathing frequency (Lahiri et al., 1975). Vagotomy, however, does not change the effect of hyperthermia on the breathing frequency (Grunstein et al., 1973a; Widdicombe and Winning, 1974) nor that of stimuli from the moving limbs. This further supports the similarity between the effects produced by limb movements and hyperthermia, and the difference between these effects and those produced by CO,. The effect of giving 3% CO, in air to breath to intact dogs is illustrated in fig. 3. Similar results were obtained in intact rabbits. It appears that both at rest and during limb movements the VT-Ii relationship is not appreciably affected by the consequent increase of 4-5 mm Hg in Pacol. This confirms our data on resting dogs, cats and rabbits (D’Angelo and Agostoni, 1975a) and those of Grunstein et al. (1973b) on cats, showing that only marked increases of Pacol are able to produce a significant change of the VT-Ti relationship. On the other hand, Miserocchi and Milic-Emili (1975) in lightly anesthetized cats found that an increase of Paco2 by 5 mm Hg was sufficient to produce a significant shortening of Ti”. Moreover, the results obtained by all these authors as well as by Clark and von Euler (1972) and by Bradley et al. (1974a) in cats, showed that an increase of CO, does not affect the Te-Ti relationship at rest. Our results show that this is true also during limb movements. Hence, at least within the range of Paco2 values occurring during spontaneous exercise, an increase of CO, acts only by increasing the output to the inspiratory muscles, i.e. by increasing VT/Ti, leaving the time-related characteristics of the respiratory centers unaffected. The comparison of the value of d(VT/Ti)/dPaco, and of dV/dPaco, at rest and during limb movement suggests that the action of the CO, stimulus is additive, because these values are not significantly changed by limb movements in either dogs or rabbits (table 3). Similar results, as far as A?/AP.+o, is concerned, were reported
E. AGOSKNI ANDE. D’ANGELO
42
0.5
I
I
I
1
I
I
I
I
PaconmHg 0 37.5 0 41.5 a41.8 0 34.1 m 38.7 6 36.6
1.3
1.5
1.7
1.9
: I
inspiratory duration , set
Fig. 3. Lower d@ram: Approximate relationship between tidal volume and inspiratory duration in dogs obtained from unloaded breaths and the first inspiratory effort after closure of the airways. Half-closed symbols = animals breathing 3 % CO, in air ; star = tetanic stimulation of the hind limb for about 2 min, brdathing air. For key to the other symbols and further explanations see fig. 1. Upper diagram: Relationship between expiratory and inspiratory duration in dogs under the above mentioned conditions.
also for man during voluntary exercise (Dejours et a[ 1960; Cunningham et al., 1966; D’Angelo and Torelli, 1971). The same conclusion was drawn by Kindermann and Pleschka (1973), who recorded phrenic nerve activity in cats during stretching the triceps surae with different chemical stimulation backgrounds. When the hind limbs were stimulated by a frequency high enough to produce a tetanic contraction, neither the VT-Ti nor the TeTi relationship was modified (fig. 3); Ti” moved a little to the left but not significantly. Indeed under this condition joint receptors and muscle spindles should not be stimulated except at the onset and at the offset of the stimulus. Since the stimulation was maintained for a few minutes Pa,,* increased and the point moved up nearly along the resting VT-l? relationship and down along the resting Te-Ti relationship (fig. 3). The ensuing hyperpnea could be entirely explained by the increase of Pacoz, because the value of A7j/APaco2 during tetanic stimulation was similar to that during CO, breathing at rest. The similarity of the ventilatory effects obtained during passive and active movements at the same frequency as well as the fact that the ventilatory effects during
BREATHINGCONTROLDURINGLIMBMOvFMENTs
43
tetanic stimulation were only related to the CO, increase show that during electrical stimulation of the hind limbs the possible stimulation of receptors not involved by normal exercise did not appreciably affect ventilation.
TIME COURSE AT THE ONSET AND OFFSET OF STIMULATION
The spirographic tracings in fig. 4 show the effect at the onset and at the offset of st~ulation at 3 Hz in a dog before and after bilateral vagotomy. When the stimulus was started during expiration Te was shortened: i.e. the stimuli coming from the moving limbs cut down the expiratory duration set by the previous inspiration according to the Te-Ti relationship (see below under : Stimulus during a single expiration or inspiration). ,
a
t
4 a2
0.1
0
0.6
-_ 0.4 )s a2 01 ! /
1 i j 1 -ivj’i I-
.._
i.
/ / j
j i j i- /‘/ / / /
/ / i j / / /
j
/
i
‘.1...:
? :
1 i : :
Fig. 4. Spirographic tracings taken at slow speed to illustrate the changes occurring at the onset and at the offset of stimulation of the hind limbs at 3 Hz. The period of stimulation is indicated on the time scale. Upper tracing: intact dog. Lower tracing (slower paper speed): vagotomized dog. Time in sec.
The time course of Te, Ti and VT/T? at the onset and at the offset of passive or active limb movements in dogs is illustrated by fig. 5. Since the time course with st~u~ation at 1 Hz was nearly the same as that with stimulation at 3 Hz, we reported only the latter. Both at the onset and at the offset there was a sudden change followed by a slower one. Both during passive and active movements the time course was slower at the offset than at the onset. During active movements the time course was slower than during passive movements. Similar results were obtained after vagotomy. The time course of Te, Ti and VT/% at the onset and at the offset of passive and active limb movements‘in rabbits is ihustrated by fig. 6. Under our experimental conditions rabbits showed a paradoxical phenomenon both during active and passive movements. The first inspiration since the beginning of stimulation (independently of the respiratory phase during which the stimulus started) was longer and deeper than the control one, with a slight increase of VTfTi. The first inspiration often looked like a sigh, but it did not always disappear after vagotomy. The time course of ali parameters both at the onset and at the offset was faster in rabbits than in dogs.
44
E. AGGSTDNI AND E. D’ANGELG
DOG ACTIVE
PASSIVE
time,sec Fig. 5. Time course of Te, Ti and VT/Ti at the onset and at the offset of passive or active hind limb movements in dogs. The closed circles refer to the first breath, the open circles refer to the average of all breaths occurring within each 10 set interval from the onset or the offset. Each symbol refers to 6 dogs. The vertical bars indicate the SE. The changes of each parameter are taken as fraction of the change attained at equifibrium. The frequency of active movements was 3 Hz, that of passive ones was about 1 Hz.
The time course of the changes of Te, Ti and VT/n at the offset of limb movements found by us in dogs lasted l-2 min; this agrees in general with the data on hyperventilation at the offset of exercise found by Harrison et al. (1932) and Senapati (1966) in dogs and by Comroe and Schmidt (1943), Rodgers (1968) and Eldridge (1974) in cats. The faster time course in rabbits is probably related to a species difference, because Eldridge (1974) found that the time course was essentially the same with different types of anesthesia. Eldridge’s experiments (1974) were performed under isocapnic conditions; hence the slow decay of hyperventilation after cessation of the stimulus could not be explained by hypercapnia. Eldridge, following the suggestion of Gesell et al. (1942), related the slow decay to the phenomenon of the afterdischarge: i.e. the stimuli coming from CSN or the limbs activate reverberating circuits acting on the respiratory centers. In our experiments Paa, during active movements was close to control values, whereas during passive movements it was lover (table 3). The values of Pa,, and of body temperature during limb movements were similar to control
BRi3ATHING CONTROL DURING LB%?3MOANS
4s
RABBIT
time,sec Fig. 6. Time course of Te, Ti and VT/Ti at the onset and at the offset of passive or active hind limb movements in rabbits. The closed circles refer to the first breath. The open circles refer to the average of all breaths occurring within each 2 set interval from the onset and within each 4 see interval from the offset, Each symbol refers to 6 rabbits. The vertical bars indicate the SE. The changes of each parameter are taken as fraction of the change attained at equilibrium. The frequency of active movement was 3 Hz, that of passive ones was about 1 Hz.
ones. Both in dogs and in rabbits, blood pressure decreased at the onset of passive or active mov~~nts~ but recovered partially during the period of movements; at the offset it returned to control value with a time course roughly similar to that of the respiratory changes. Similar results were also obtained by Comroe and Schmidt (1943). Although a marked increase of biood pressure in the carotid sinus decreases ventilation, whereas a marked decrease increases ventilation (Heymans and Bouckaert, 1930), the respirator changes observed during Iimb movements are not secondary to the changes of blood pressure because of the following findings: (1) The respiratory effects during limb movements when both carotid arteries were clamped were similar to those occurring with open carotid arteries, as previously shown by Rodgers (1968) and in spite of the fact that at rest closure of the carotid arteries produced an increase of v~ti~ation as expected. (2) The decrease of blood pressure after f&20 set of limb movements was greater than that after 60 set, whereas the respiratory changes after 1O-20set were similar to or smaller
46
E. AGWT0Nl AND E. D’ANGEI.0
TABLE3 Effects
L; ii
of CO, on the ontput to the ~s~rato~
.g . $
* **
d~T~~/d~~,
and on
air
0”3~~0,020
5.66+0.46
34.1.k0.8
78.4+2,0
3% CD,
0,466+0.045
9.05+0.45
38.7rtO.5
77*o+o.ti
3% CO,
0.$14~0.038
$ .r( i
mu&es,
17.95&-1.29 43.510.8
ventilation, d~/d~x,
at rest,
0.036~0.~
0.77&0.11
0.032~0.004
0.75 ltO.05
78.2&0.8
ATPS
SE.
4.>” 3 D+ 2I 1
time,
Fig. 7. Time course of ventilation at the onset and the offset of passive (open circles] or active (closed circles) hind limb movements in dogs and rabbits. Each symbol refers to 6 dugs and 6 rabbits. The frequency of active movements was 3 Hz, that of passive movements was about 1 Hz. The numbers within brackets along the line indicate the values of Pacol at rest and during passive or active limb movements. At the offset data were ROlonger plotted after they bad reached the control values.
than those after 60 sec. It seems therefore that both the respiratory and vascular changes are parallel effects produced on the bulbo-betide cemtersby the stimuli coming from the moving limbs. Hence, the st~dy~s~t~ respiratory changes seem essentiallydue to the stimuli from the moving limbs. If so, also the slow decay of the hyperventilation observed at the end of limb movements should be largely due to
47
BWATHING CONTROL DURING LIMB MOVE
luring
passive and active (3 Hz) exercise, in 4 dogs and 3 rabbits
Rabbit VT/T~
pa,* (mm Hg)
(ml*/sec) 45.6k2.5
856.7_+ 35.3
pao,
A\jlAPam2
(mm Hg)
(ml*/m~
33.3kO.3
71.Ok2.5
66.3k1.7
1328.3f
17.0
39.OkO.3
72.2k2.2
61.5&6.3
f420.Q
28.6
29.3 kO.9
72.3k2.6
86.9k1.9
195o.oi: 59.0
35.2 kO.9
71.2k2.4
112.7+7.0
2874.3 _t 87.5
32.5 f0.9
12.7$2.7
137.6+4.6
3430.0+ 162.6
39.5 f 1.o
13.2k2.2
*mm Hg)
3.7kO.l
83.555.4
4.5212
92.75 12.3
3.620.4
79.2& 0.7
the afterd~scharge. In this caption, however, one must consider that owing to the marked and abrupt fall in ventilation occurring at the end of exercise Ph, during the recovery period should increase relative to the exercise value. Hence, the slow decay of all parameters at the offset should be affected by the relative increase of Pam,. From the data of the phrenic nerve minute output at the offset of both CSN stimulation and calf squeezing obtained in cats by Eldridge (1974) under isocapnic conditions it seems that the slow component contributes about 50 % of the whole neurogenic drive. Our data are represented in terms of ventilation in fig. 7 for both dogs and rabbits. It appears that in anesthetize animals at the offset of both passive and active limb movements the slow component accounts for about 30 % of the whofe ne~ogenic drive in dogs and for about 50 % in rabbits.
SINGLE STIMULUS DURING EXPIRATION OR INSPIRATION
The effects of a single stim~us to the hind limbs during expiration or ~~iration on Te, Ti and Vr/Ti, relative to their control values, are illustrated in figs. 8 and 9. The overall data obtained on the first 3 expirations or insp~mtions since the single stimulus are reported in table 4. At variance with the continuous stimulation at steady state, the single stimulus produced a greater effect in rabbits than in dogs. Like continuous stimulation the single stimulus, either given during expiration or inspiration, pro-
E. AGGSTGNI AND E. D’ANGELO
48
DOG
t 0.d
f, = 13.2Imin
Te,.
2.48
MC
1
J
WTITi),=
t ime,
90.3
mllsec
set
Fig. 8. Effect in dogs of a single stimulus to the hind limbs given during expiration (left) or inspiration (right) on expiratory duration (Te), inspiratory duration (Ti) and mean inspiratory flow (VT/Ti), relative to their control values. The arrows indicate the moment of the stimulus. White and black rectangles refer to expiration and inspiration, respectively. The horizontal broken lines indicate the confidence limits of the average control value at 95 %, computed by multiplying the SE of the mean of 6 control values preceding the stimulus by the value oft at P = 0.05 and 5 degrees of freedom. The control values at the 3 parameters, plus those of breathing frequency are inserted.
duced a greater effect on Te than on Ti. A single contraction of the hind limbs not only affected the timing of the respiratory phase during which it occurred, but it significantly affected the timing of the following 3 to 8 breaths. On the other hand Eldridge (1972, 1974) found that carotid sinus nerve stimulation for only one breath had no significant effect on poststimulation breaths. Since it seems unlikely that a single short contraction of muscles would significantly change any of the humoral factors affecting ventilation, our findings suggest that the stimuli elicited by limb movements are more powerful than those of the CSN in activating the reverberating circuits acting on the respiratory centers (see above). As already shown in a previous paper dealing with the tonic vagal influences on depth and rate of breathing (D’Angelo and Agostoni, 1975a) and as could be expected, there is not a single Te-Ti relationship, but a family of such relationships. Indeed, also the stimuli from the moving limbs modify the control TeTi relationship (figs. 1 and 2). It seems, therefore, that stimuli from the vagus or from propioceptors may affect the circuit setting Te according to Ti by changing its ‘gain’, i.e. by changing the slope of the Te-Ti relationship. When a single stimulus is given during
BREATHING CXNTROL DURING LIMB MOVEMENTS
49
RABBIT
2
4
6
6
10
12
time, set
Fig. 9. Effect in rabbits of a single stimulus to the hind limbs given during expiration (left) or inspiration (right) on Te, Ti and VT/Ti relative to their control values. For further explanations see legend to fig. 8.
expiration it could change the ‘gain’ of the above-mentioned circuit or act directly anticipating the beginning of inspiration. The same considerations apply probably to the findings of Knox (1973). He showed that Te could be shortened or lenghtened, by lung deflation or inflation, respectively, during expiration, without influencing Ti. Knox was working on the vagal feedback and this effect disappezrsd with the stimulus, i.e. Te and Ti of the following breaths were not influenced. As a matter of fact there is no evidence that lung volume related vagal stimuli activate reverberating circuits. The paradoxical effect in rabbits occurred also with the single stimulus during inspiration (fig. 9 and table 4). In spite of this, the following Te was shortened and the timing of the following breaths was the same as that occurring when the stimulus was given during expiration (table 4). Although the data reported in table 4 refer only to stimuli given during a time corresponding to the central period of control expiration or inspiration, stimuli were also given in the first part of expiration or inspiration. We found that even if the stimulus to the hind limbs was given only 0.1 set after the beginning of expiration or inspiration there was qualitatively the usual effect both in dogs and in rabbits.
-
0.91 +0.03
1.12
0.59 i-O.03
0.88 f0.02
1.21
W%
Wi,
CVWi)
.~
2 d
1.10 kO.03
kO.03
0.97 * 0.02
1.53 *0.09 1.15 +0.03
0.82 kO.02
0.65 +0.06
1.18
1.13 +0.02
0.63 +0.07
0.89 +0.01
0.81 +0.01
2
0.98 *0.01
0.81 +0.01
1
1.12 f 0.02
0.86 Jco.01
0.77 f0.03
f0.02
1.12
0.92 fO.O1
0.89 to.02
3
Stimulus during inspiration -
0.77
1.11 +0.01
0.90 +0.01
0.61 kO.03
1.20 kO.03
+0.01
0.90
*to.04
1
1.06 50.01
0.95 to.003
0.83 rto.02
1.18 *0&l
0.92 fO.02
0.72 f0.06
2
1.04 kO.02
0.97 +0.01
0.92 -to.02
1.15 +0.04
0.93 +0.02
0.76 +0.06
3
Stimulus during expiration
Vagotomixed
1.oz” +o - .04***
1.03 *0&F**
0.80 f0.02
1.18 kO.03
0.89 f0.02
0.72 to.03
1
1.07 +0.04
0.91 kO.02
1.18 kO.03
0.84
1.09 j, 0.02
0.93 kO.01
1.03 kO.02
0.98 rto.01
0.98 +0.02***
0.93 to.02
lto.01
0.85 +0.05
3 0.76 kO.04
2
Stimulus during inspiration
** SE. *** Not signikative.
* The data refer to 4 dogs and 3 rabbits. The stimulus was applied between 30 and 40 y0 of Te control and between 25 and 55 o/oof Ti control. When the stimulus was applied during the expiration the first Te is that during which the stimulus was applied and the first Ti is that following, viceversa when the stimulus was applied during inspiration. To visualize the valuescorresponding to the respiratory phase during which the stimulus was applied they are typed boldface.
kO.04
0.94 kO.02
0.73 kO.05
0.69
kO.02
+0.06
1.13
WTi) -____ (Vr/Ti ,)
+0.02
0.94 +0.01
1.18
0.91 +0.01
0.92 kO.01
0.83 +0.02
+0.01
0.80 +0.02
0.79 *0.03**
3
-
1.18
2
1
Stimulus during expiration
Intact
TABLE 4 Values of expiratory duration CJe), inspiratory duration (Ti) and mean inspiratory flow (Vr/Ti), relative to control values, during and after a single stimulus to the hind limbs applied during expiration or inspiration*
g !z
$ m
z
B
.m *
8
BREATHING CGNTROL DURING LIMB MOVEMENT8
51
Though the quanti~tive relationship was not systemati~ly studied, it seems that in dogs, when the stimulus was given during the second quarter of Te control, the shortening was similar to that occurring when the stimulus was given during the first quarter. This suggests that the first discharges from the propioreceptors, reaching the respiratory centers at the very beginning of expiration, are without effect (probably because the ~r~hold for starting inspiration is high) and only those coming later through longer or reverberating circuits produce an effect. On the other hand, when the stimulus is given during the second quarter of the control phase both fast and slow stimuli would be threshold and expiration is ended within a shorter time from the stimulus.
References Asmussen, E. and M. Nielsen (1948)Studies on the initial changes in respiration at the transition from rest to work and from work to rest. Actu Physiol. &and. 16: 270285. Bessou, P., P. Dejours and Y. Laporte (1959). Effets venti~toires reflexes de la stimulation de fibres alT&entes de grand diametre d’origine musculaire chez le Chat. C. R. Sot. BioI. 153: 477-481. Bouverot, P. (1973). Vagal afferent flbres from the lung and regulation of breathing in awake dogs. Respir. Physiol. 17: 325-335.
Bradley, G. W., C. von Euler, I. Marttila and B. Roos (1974a). Transient and steady state effects of CO, on mechanisms determining rate and depth of breathing. Actu Physiol. Stand. 92: 341-350. Bradley, G. W., C. von Euler, I. Marttila and B. Roos (1974b). Steady state effects of CO, and temperature on the ~lationship between lung volume and inspiratory duration (Hering-Breuer threshold curve). Acta Physiol. Stand. 92: 351-363. Clark, F. J. and C. von Euler (1972). On the regulation of depth and rate of breathing. J. Physiol. (London) 222
: 267-295.
Comroe, J. H. Jr. and F. C. Schmidt (1943). Reflexes from the limbs as a factor in the hyperpnea of muscular exercise. Am. J. Physiol. 138: 536-547.
~onn~gh~, D. J. C., B:B. Lloyd and D. Spurr (1966). The relationship between the increase of breathing during the first respiratory cycle in exercise and the prevailing background of chemical stimulation. J. Physiol. (London) !85: 73-75P.
D’Angelo, E. and G. Torelli (1971). Neural stimuli increasing respiration during different types of excercise. J. Appl. Physiol. 30: 116121. D’Angelo, E. and E. Agostoni (1975a). Tonic vagal influences on inspiratory duration. Respir. Physiol. 24: 287-302.
D’Angelo, E. and E. Agostoni (1975b). Immediate response to expiratory threshold load. Respir. PhysioE. 25 : 269-284.
Dejours, P., A. Teillac, Y. Labrousse and J. Raynaud (1956). Etude du mecanisme de la regulation cardioventilatoire au debut de l’exercice musculaire. Reu. Franc. Ef. Clin. Biol. 1: 504-517. Dejours, P., R. Lefrancois, R. Flandrois and A. Teillac (1960). Autonomie des stimulus ventilatoires, oxygene, gaz carbonique et neurogenique de l’exercice musculaire. J. Physiol. (Paris) 52: 63-64. Eldridge, F. L. (1972). The importance of timing on the respiratory effects of i~te~ittent carotid sinus nerve stimulation. J. Physiof. (London) 222: 297-318. Eldridge, F. L. (1974). Central neural respiratory stimulatory effect of active respiration. J. Appl. PhysioE. 37: 723-735.
Euler, C. von, F. Herrero and I. Wexler (1970). Control mechanisms determining rate and depth of respiratory movements. Respir. Physiol. 10: 93-108.
E. AGGSTONI AND E. D’ANGELO
52
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