Respiration Physiology
VAGAL
North-Holland Publishing Company, Amsterdam
(1975) 23, 133-146;
MODULATION
OF RESPIRATORY
CONTROL
DURING
LAHIR12, SARAH S. ME1 and FREDERICK
F. KAO
EXERCISE’
SUKHAMAY
Department of Physiology, Downstate Medical Center, State University of New New York, U.S.A.
Abstract.
Vagal modulation
15 anesthetized
mongrel
both,
ventilation
increased
the intact
dogs.
After
of chemical dogs.
bilateral
approached
both
vagotomy response
its maximal
of ventilation
chemical
by increasing
little by rate. The ventilatory volume
control
Arterial
stimuli-
during
hypoxic,
rate and depth
chemical
drive
to the chemical
value at a relatively
rest and exercise hypercapnic
of breathing
increased
breath
was studied
during
mostly
reached
by depth
a plateau
frequency.
Muscular
when
exercise
could
the volume activated
through
between
related
to influence
vagal
a mechanism
tidal volume
reflex. During
the relationship
not
and breath exercise,
independent
Breathing Control
shared
by
cycle during another
the
chemical
chemical
mechanism,
control
in and
tidal
exercise,
largely restored frequency response in the vagotomized animals. Since the rate response stimuli but not to exercise was impaired by vagotomy, we concluded that hyperpnea occur
of
rest and exercise
however, chemical
The relationship
in
or a combination
ventilation
drive, therefore, unchanged
York at Brooklyn.
to of
of ventilation.
stimulation
was modulated
by
presumably
bulbo-pontine,
is
of the lung volume.
pattern
Exercise
of breathing
Vagus nerve
Recently Phillipson et al. (1970) and Bouverot (1973) examined the role of vagal afferents in the regulation of breathing in awake dogs during muscular exercise. Phillipson et al. concluded that the ventilatory response to mild exercise was not dependent on intact vagus whereas Bouverot reported that in the absence of the vagal afferents the ventilatory response to exercise was diminished. Several years ago we investigated the effect of acute bilateral vagotomy on chemical control of ventilation during exercise in anesthetized dogs and reported briefly (Lahiri et al., 1967) that when ventilation became limited under conditions of hypercapnia or hypoxia or a combination of both, exercise could overcome this limitation partially Accepted for publication 16 October 1974. ’ Supported
in part by grants
from the National
Institute
of Health
HL-04032
and HL-08805.
’ Present address: Cardiovascular-Pulmonary Division, Department of Medicine of Physiology, University of Pennsylvania, Philadelphia, Pa. 19104, U.S.A. 133
and
Department
134
S. LAHIRI,
S. ME1 AND F. F. KAO
and could cause a further increase in ventilation by increasing both depth and frequency of breathing. At a constant level of exercise, however, the effects of hypercapnia and hypoxia in vagotomized dogs on ventilation were again limited. These results, which afford more information on vagal modulation of respiratory control during exercise, are presented here. Methods
Male mongrel dogs weighing 2&23 kg were anesthetized with sodium pentobarbital (30 mg/kg intravenously). The animal was tracheotomized, and a plastic tube of internal diameter similar in size to the animal’s trachea was inserted and connected with a Lloyd breathing valve (Warren E. Collins, Inc., Braintree, Mass.). The expired ventilation was measured breath by breath by means of a potentiometercoupled gas meter (Instrumentation Associates, New York, N.Y.). Inspired gas mixtures were made instantaneously and continuously from gas cylinders containing air, lOOo/ O,, lOOO/;COZ and lOOo,bN,. End-tidal Pco2 was monitored continuously by a calibrated infrared COP analyzer (Godart capnograph, Instrumentation Associates, New York, N.Y.). Arterial blood pressure was monitored from a brachial artery by means of a blood pressure transducer (Statham Instruments, Oxnard, Calif). All these measurements were recorded continuously on a Visicorder (Honeywell, Denver, Colorado). Arterial samples (about 3 ml) were collected anaerobically under given conditions, and the pH. Pcoz and PO1 were measured with Astrup, Severinghaus and Clarke electrodes (Radiometer, Copenhagen, Denmark) which were calibrated at 38 “C. PROCEDURE
Experiments were performed on 15 dogs. Light anesthesia was maintained throughout the duration of experiment, of about four hours, by giving repeated small doses of pentobarbital. A stable resting alveolar PCoL and a similar slope of ventilatory response curve to CO, (Vn-Pa,,,) under a given experimental condition were taken as the criteria of stability. The first arterial sample was taken when the animal showed a steady-state ventilation on room air. Subsequent arterial samples were collected when the animal attained a steady-state on a given inspired gas mixture. The steady-state was achieved in 5-7 min. The ventilation was related to Paco2 to construct a \iE-Pa,,, response curve. Usually 2-5 %-Pa coZ points were obtained at a given level of Pao,. Two levels of Pao, (50, and * 200 mm Hg) were used. The infra-nodose cervical vagi were infiltrated with procaine before sectioning. The central cut ends were kept painted with procaine. In about l&15 min after vagotomy, ventilation, arterial blood gases and pressure of the animal became stable. As before, another set of VE-PacoZ response curves were determined. Exercise was induced in both hind legs of the dog by means of a sine-wave stimulator (Kao and Suckling, 1963). The frequency of stimulation was 2/set, and the current strength was 30 m. A steady-state of 0, uptake and ventilation was achieved in about
VAGUS
IN EXERCISE
135
HYPERPNEA
4 min. The 7irE-Paco2 response curves during exercise were again determined as described before (in 6 dogs). Oxygen uptake was determined by closed circuit spirometry (Warren E. Collins, Inc., Braintree, Mass.) during steady-states of rest and exercise. Since vagotomy also removed a part of the peripheral chemoreceptor drive (from the aortic bodies), it was relevant to determine if the peripheral chemoreflex contributed significantly to the pattern of ventilatory response to CO, and exercise. Thus the carotid body chemoreceptors were denervated by sectioning carotid sinus nerves in three experiments before vagotomy. The ventilatory response to CO, and exercise was determined while Pao2 was maintained around 200 mm Hg. Metabolic acidosis was also used as a mode of chemical stimulation to ventilation. Dilute acid solution (0.3 N HCl) was infused through a cephalic vein at the rate of one drop per set initially, and at a slower rate thereafter to maintain arterial pH at a constant level. In three such preparations ventilatory response to CO, was examined before and after vagotomy. Results
The mean expired ventilation, tidal volume and respiratory frequency of the anesthetized dogs breathing room air were 5.6 l/min (BTPS), 330 ml (BTPS) and 17/min, respectively. The corresponding arterial Po2, Pco2 and pH were 8 I,32 and 7.32, respectively. Clearly the animals were in a state of mild metabolic acidosis in the beginning of the experiment. VENTILATORY
RESPONSE
TO CHEMICAL
STIMULI
IN INTACT
ANIMALS
The relationship between VE and Pacer at a given Paoz was linear within the limits of our observations (Pa,, ,:3&68 mm Hg). The increase in by was accomplished by increases both in tidal volume and respiratory frequency. The arithmetic mean ( +S.E.) of the slopes of these bE-Pace, curves in the absence of hypoxia was 0.71 kO.13 l/min x mm Hg Paco2. Arterial hypoxia (Pa,, of about 50 mm Hg) increased ventilation and lowered Paco2. The effects of hypoxia on ventilatory response curves to CO2 were as follows: (a) the response curves were set at a higher ventilation than during hyperoxia at a given Pace, and (b) the slope of the response curves increased in 80% of the experiments. In the remaining 20’/&the slopes did not change. The mean slope at Pa,, of 50 mm Hg was 1.03 20.19, the increase from the normal level being significant (P < 0.01). EFFECT
OF VAGOTOMY
Bilateral cervical vagotomy generally increased minute ventilation and tidal volume but decreased respiratory frequency. Arterial Pco2 decreased from 32 to 28 mm Hg on the average. The %‘E-Pacol response curves during hyperoxia changed in the following ways: (1) they were shifted to a higher ventilation at a lower Paco2, (2) the slope, over the lower range of Paco2, was increased but (3) decreased at a
136
S. LAHIRI,
SREATHS/min
S. MEI’AND
F. F. KAO
20
t IO t
0 20-
\tE L/min .STPS
IO-
$0
I
I
I
I
30
40
50
60
pace**mm Fig. 1. Effects of bilateral
cervical
hypercapnia
The open symbols
and hypoxia.
vagotomy
on the responses describe
symbols
Hg
of ventilation
the relationship
before
and breath vagotomy
frequency
to
and the closed
after vagotomy.
higher level of Pa,02 often giving rise to a plateau. An example of these changes is shown in fig. 1. As in the normal intact animals, hypoxia shifted the curve to a higher ventilation and increased the slope of the %-Pa,,, curve. However, the curve reached the same plateau as in hyperoxia. This plateau was, however, reached at a lower Pace, than in hyperoxia. The chemical stimulation of ventilation increased breath frequency only slightly after vagotomy. EFFECT OF VAGOTOMY
IN ANIMALS
WITH
SEVERED CAROTID
SINUS NERVES
To eliminate the carotid body chemoreflex and to examine the effect of vagotomy on ventilatory drive from the central CO2 chemoreflex, the carotid sinus nerves were cut bilaterally in 3 dogs. It was assumed that the stimulatory effect of hypercapnia on aortic bodies in the presence of hyperoxia was minimal, and the subsequent vagotomy was not expected to cause any important change in the peripheral chemoreflex. This assumption seemed reasonable in view of the observation of Phillipson et al. (1970) that vagal blockade did not produce any consistent effect on apneic threshold Paco2 implying that aortic chemoreflex due to CO2 provided little ventilatory stimulation. Thus the ventilatory response to CO2 in the carotid sinus denervated dog was presumably due to central CO2 drive, and therefore the
VAGUS IN EXERCISE HYPERPNEA
BREATHS/mi
n
0
20
I
I
1
I
30
40
50
60
Pace,,
3
mm&!
and breath frequency responses to hypercapnia in a bilaterally carotid chemoand sinus denervated dog. before ( A) and after (H) bilateral vagotomy.
Fig. 2. Ventilatory
allowed measurement of the effect of vagotomy on ventilatory drive from the central chemoreflex. The ventilatory responses to changes in Paco2 before and after vagotomy in one animal are shown in fig. 2. The 7iiTE-Paco,relationship during hyperoxia in the carotid sinus denervated preparation was linear. Bilateral vagotomy changed the response curve in the same way as was seen in animals with intact carotid sinus nerves (cf. fig. 1). That is, the ventilatory response increased at lower levels of PdcOz but reached a plateau at higher levels of Pacoz. The respiratory frequency after vagotomy remained relatively constant between 25-27 breaths/min in the lower range of Pacoz, and ventilation increased primarily by the increases in tidal volume. At high levels of Paco2 ventilation did not change but breath frequency declined. Examination of each breath showed that during hypercapnia the decrease in breath frequency was primarily due to an increase in the inspiratory duration.
preparation
EFFECT OF VAGOTOMY
AmER
METABOLIC
ACIDOSIS
The results of one of the 3 experiments is shown in fig. 3. Three %-Pa,,, curves during hyperoxia were obtained in the following sequence: normal (0) during acute metabolic acidosis ( x ) and after vagotomy (0). The ventilatory response to a given Pa,oL during metabolic acidosis was greater than in control. Thus acidosis,
138
S. LAHIRI,
S. MEI AND F. F. KAO
4030BREAlHS/min 20IOOARTERIAL pH = x
7.294-7.399
30-
20-
. VE L/min BTPS IO-
‘4 7.300-7.430
0
OL IO
h
20
30
Pace,, Fig. 3. Effect of bilateral capnia
during
vagotomy
acute metabolic
on the responses acidosis
(control:
0;
)
mm h
of ventilation acidosis:
x
and
breath
; vagotomy
frequency
during
to hyper-
acidosis:
0).
in animals with intact vagi, stimulated ventilation. After vagotomy the character of this response changed dramatically. Without COz inhalation the ventilation was greater but the plateau of ventilatory response to CO2 stimulation was reached at lower levels of PaLcoI. The limitation of response was primarily due to a limitation of breath frequency. With the increases in Pa,-o, the breath frequency actually decreased. Severe acidosis (pH = 7.0 at Pacoz = 17.0) as seen in another vagotomized animal, decreased breath frequency more dramatically and thus diminished ventilatory response to CO2 further. EFFECT OF VAGOTOMY
ON HYPERPNEA
OF EXERCISE
Electrically stimulated muscular movements of the hind limbs increased oxygen uptake, on the average, from 140 to 420 ml/min (STPD). After vagotomy the
139
VAGUS IN EXERCISE HYPERPNEA
corresponding values were 143 and 414 ml/min. The increases in ventilation during hyperoxic exercise as a multiple of resting ventilation are shown in fig. 4. These ratios are shown instead of the actual values because of the scatter in the observations between the animals. It appears that vagotomy decreased the increment in ventilation
0 - 3.0
0 VR
FR 2.0
Y I.oo
-2.0
I:
/ 0.2
0.4
f0,.
0 L/min
. 0.2
I .o
STPD
Fig. 4. Effect of bilateral vagotomy on the ventilatory responses ventilation between exercise and rest, and F, represents breath vagotomy:
0.4
to exercise. V, represents frequency ratio (control
ratio
of
:0; after
0).
during exercise but the difference was not significant. Also, the increment in the breath frequency (expressed as a multiple of the resting frequency, F,J was similar to that in the intact animal. Thus the frequency governor seemed to respond to exercise stimulus even after vagotomy unlike the response to chemical stimuli. EFFECT OF VAGOTOMY
ON ~E--Paco2
RESPONSE
IN MUSCULAR
EXERCISE
VE-Pacoz response curves were constructed during hyperoxic exercise in all the six experiments. The results from one such experiment is shown in fig. 5. Ventilatory response to CO2 (at low levels) during exercise increased after vagotomy just as in rest. After vagotomy, however, the breath frequency response to CO2 was practically abolished both in rest and during exercise. But the breath frequency response to exercise per se was little affected (see fig. 5). The data for hypoxic exercise were less complete, and the details of these results are not presented. However, basically a similar pattern of response of respiratory depth and frequency emerged from the two more complete experiments. That is, exercise increased respiratory frequency as ventilation was stimulated but the superimposed hypoxic and hypercapnic stimuli produced little increase in the breath frequency and all the increases in ventilation were accomplished by the increases in tidal volume. When tidal volume approached the maximal value with increased chemical stimuli, a plateau in the ventilatory response appeared.
BREATHS/min
20_
IO-
I 30
0
1
40
Pacer.
Fig.
5.
mm
1
I
30
40
wp
Effect of exercise on ventilatory response to hypercapnia before (open symbols: (closed symbols: R,, E,) bilateral vagotomy (R= rest; E=exercise)
R, E) and after
30-
20-
IO-
QE L/min BTPS
O-
20-
IO-
O0
I
IO
I
I
20
30
BREATHS Fig, 6. Effect of vagotomy
/ min
on the relationship between breath frequency and tidal volume during exercise and hypercapnia. Two examples are shown here. The relationship between VE and breath frequency is approximately linear under each experimental condition: hypercapnia at rest (0) and exercise (A) before vagotomy; hypercapnia at rest (0) and exercise ( A) after vagotomy.
VAGUS
IN EXERCISE
A similar effect of exercise on ventilation denervated animals during hyperoxia. EFFECT
OF VAGOTOMY
ON THE FREQUENCY
HYPERPNEA
was found in the carotid
AND DEPTH
141
chemo-
OF BREATHING
The relationship between respiratory frequency and depth under various experimental conditions was examined. Two sets of data relating bE to breath frequency are shown in fig. 6. It can be seen that the increases in ventilation in the intact animals (open symbols) was accompanied by the increases in breath frequency both during rest and exercise. After vagotomy breath frequency did not increase (upper panel) or increased little (lower panel) as ventilation increased as a result of increased chemical stimuli during rest (closed circles). That is, much of the ventilation increase was achieved by the increase in tidal volume. A given level of exercise. however, greatly changed the effect of vagotomy on the relationship between \jE and breath frequency. The upper panel of fig. 6 shows that the increase in ventilation during exercise was accompanied by a normal increase in breath frequency (28/min) which far exceeded the limited frequency (12/min) found during chemical stimulation in the resting animal. Chemical stimulation during exercise, however, increased ventilation by tidal volume alone. It seemed that the level of exercise set the frequency governor at a higher level. The lower panel in fig. 6 shows that breath frequency response to chemical stimulation was still present after vagotomy, and that it improved during exercise. Discussion
This study showed that bilateral infra-nodose cervical vagotomy in the anesthetized dog dramatically decreased the response of breath frequency to hypercapnic and hypoxic stimuli at rest whereas the frequency response to exercise stimulus was less impaired. The ventilatory response to exercise was similar before and after vagotomy. Phillipson et al. (1970) also reported that cold block of the cervical vagal nerves in the awake dogs did not impair the ventilatory response to mild exercise. Bouverot (1973) on the other hand, observed that chronic lung denervation decreased ventilatory response in the awake dogs during a similar degree of exercise. However, both Phillipson et al. (1970) and Bouverot (1973) reported increases in breath frequency during exercise even in the absence of vagal influence, although the response was less than in the intact animals. This study also showed that at a given exercise level the effect of chemical stimuli on the frequency response remained diminished in the vagotomized animal. That is, whereas exercise per se practically restored the relationship between ventilation and breath frequency to normal, it did not alter the abnormal response to superimposed chemical stimuli. The effect of exercise on breath frequency in the vagotomized animals was presumably not related to the effect of temperature because vagotomy did not change the rectal temperature. It is known that an increase in arterial temperature increases breath frequency even in the absence of vagal influence
142
S. LAHIRI,
S. ME9 AND F. F. KAO
(e.g., Phillipson et al., 1970). Our results, therefore, bear on two aspects of vagal modulation of ventilatory control, namely chemical and neural. VAGAL MODULATION
OF* CHEMICAL CONTROL OF VENTILATION
Our results on the anesthetized dogs are in conformity with the earlier observations of Scott (1908) on the anesthetized rabbits, in that after vagotomy hypercapnia stimulated ventilation primarily by tidal volume response. The net result was that the ventilatory response to CO,, within a limited range, increased. It is important to emphasize that it is within this normal range of Pa,-oI that the control of ventilation need be considered (see Dejours et al., 1965). Thus we found, unlike Richardson and Widdicombe ( 1969), that the normal chemical control of ventilation was usually enhanced in the absence of vagal influence. Richardson and Widdicombe reported that vagotomy diminished ventilatory sensitivity to CO, during hyperoxia and hypoxia in the rabbits. Our data would show such a smaller slope constant after vagotomy if a single line is drawn through all the experimental points. Von Euler et al. (1970) also reported a diminished ventilatory response to CO2 in their cats after vagotomy. They used a rebreathing technique for the determination of the CO, response. This technique may not provide a suitable index of ventilatory response to Pace, at levels below the mixed venous Pcoz because of the lack of equilibrium between Paco2 and the central CO, sensors (Read, 1967). It was within this range of Pace* that we found, employing the steady-state technique, that the ventilatory response was usually enhanced in the vagotomized dogs. We also found that the effects of hypoxic stimulus and those of a combination of hypoxic and hypercapnic stimuli on ventilation were similarly influenced by vagotomy during rest and exercise. This apparent enhanced response to mild chemical stimuli could, in part, be related to the removal of tonic and inspiratory vagal inhibition (see Bartoli et al., 1973) as a result of vagotomy. The release from the vagal inhibition could cause increased central response to a given chemical stimulus. The lack of tonic inhibition could give rise to a tonic increase in the activity of inspiratory neurones, and the lack of inspiratory inhibition could result in an increase in the rate and duration of inspiratory activity. It has been shown that inthe absence of volume-related vagal reflex, inspiration is prolonged without any appreciable increment in the rate of inspiratory activity (e.g. Clark and von Euler, 1972). That is. sensitivity of the respiratory neuronal assembly is not increased by vagotomy. Given this condition, an alternative mechanism for the increased ventilation per minute would be to increase the total duration of inspiratory flow at the expense of the expiratory duration. Our data do not allow precise analysis of the various phases of respiratory cycles but the observations of Clark and von Euler (1972) appear to suggest that the latter is a likely mechanism in the chemical regulation of ventilation (see also von Euler et al., 1970). It is pertinent to raise the point that vagal denervation also removed the influence of aortic chemoreceptors on ventilation. However, absence of the aortic chemoreflex presumably did not modify the vagal influence since bilateral denervation of the
VAGUS
IN EXERCISE
HYPERPNEA
143
carotid chemoreceptors, the primary source of respiratory peripheral chemoreflex, did not alter the basic effect of vagotomy on ventilatory response to CO, at rest and during exercise in steady-state conditions. The denervation of the peripheral chemoreceptors presumably decreased the ventilatory drive. But the vagal modulation of the remaining central chemical drive was not altered appreciably. Also, moderate metabolic acidosis in the normal as well as carotid chemodenervated dogs stimulated ventilation but did not change the response pattern of vagotomy. Thus, the \a$~l modulation of chemical control of ventilation was basically similar irrespective of the source of afferent input from the peripheral or central chemoreceptors. In severe acidosis arterial pH = 7.0), however, ventilation was depressed after vagotomy because of impaired tidal volume as well as breath frequency. The reason for this dual depression after vagotomy is not apparent. VAGAL
MODULATION
OF VENTILATION
DURING
EXERCISE
Since the effect of exercise on the ventilatory pattern in the vagotomized dogs could not be produced by hypercaphic and hypoxic stimuli, one immediate conclusion is that the exercise stimulus to ventilation does not consist merely of metabolic and chemical changes(with respect to C02-H+ and hypoxia) or other changes, such as an increased cardiac output, which might lead to transient increases in arterial chemical stimuli (Wasserman et al., 1974). Wasserman et al. (1974), however, reported that the effect of increased blood flow was independent of the peripheral chemoreceptors. Also, Davies and Lahiri (1973) showed that the mean activity of carotid chemoreceptor in cats was not increased during exercise. Thus, at least a part of the ventilatory response during exercise stemmed from a reflex independent of the chemical stimuli. The role of neural effect in exercise hyperpnea in anesthetized dogs has been demonstrated by Kao (1963). The neural effect in exercise hyperpnea is also incorporated in the neuro-humoral theory of Dejours (1959).. The idea that a neurally mediated reflex is involved in exercise hyperpnea is also supported by our observation that the first contraction of the limb muscles was simultaneously accompanied by a shortening of the breath period in the intact as well as in vagotomized animals. It must be noted, however, that even during exercise breath frequency in the vagotimized animals was somewhat less than that in the control at a given ventilation. This effect of exercise on breath frequency is similar to those in awake dogs with vagal blockade (Phillipson et al., 1970) and with denervated lungs (Bouverot, 1973). Clearly muscular exercise activated a mechanism which decreased the duration of a breath cycle independent of the volume-related pulmonary vagal reflex. Muscular exercise involved hind-limb movement which may have influenced the respiratory frequency. This control of the breath cycle was apparently related directly to the intensity of muscular exercise and was presumably mediated through a neural reflex involving the bulbo-pontine center. The contention that the vagal modulation of chemical hyperpnea is in some way distinct from that of exercise hyperpnea could be more fully appreciated by expressing tidal volumes as a function of the duration of breath cycles. The effects of exercise
144
S. LAHIRI,
S. MEI AND F. F. KAO
.6-
.4 /
/ .2-
/
“1
/
I
I
1
I
I 3
I 4
1 5
I 6
1
’
ON’
L 1.2-
I.O-
.8-
.6 / /
.4 -
/ / /
.2-
/ /
0”
I
’
2
0
BREATH Fig.
7. Relationship
Exercise
always
hypercapnia exercise achieve
between
shortened
showed
the
tidal
CYCLE volumes
duration
and
DURATION, duration
of breath
cycle
little or no effect on the duration
SEC.
of breath as tidal
of breath
cycles volume
in vagotomized was
dogs.
increased
whereas
cycle. The two ventilatory
stimuli,
and hypercapnia. produced different combinations of tidal volume and breath frequency to the same ventilation as shown by the isoventilation lines (dashed diagonals). The large symbols
represent
ventilation
without
hypercapnia,
and small symbols
with hypercapnia.
and hypercapnia on the relationship (VT-cycle duration) in the vagotomized dogs are shown in fig. 7. These data are taken from the same experiments which are shown in fig. 6. The upper panel shows that during exercise the duration of respiratory cycle shortened as the tidal volume increased (large triangle). The hypercapnic stimulation, on the other hand, increased tidal volume without any appreciable change in the duration of breath cycles. The lower panel of fig. 7 shows a basically similar effect of exercise on the relationship between tidal volume and cycle
145
VAGUS IN EXERCISE HYPERPNEA
duration after vagotomy. Hypercapnic stimulation of ventilation did not produce the same relationship as did exercise. Hypercapnia, however, in this instance unlike the previous one, decreased the duration of breath cycle along with the increase in the tidal volume both at rest and during exercise. The foregoing analysis provides further evidence to the effect that exercise influences the tidal volume-cycle duration relationship differently from that during chemical stimulation for the same ventilatory effect in the vagotomized dogs. The intensity of muscular exercise seemed to determine the set point for the combination of tidal volume and cycle duration independent of the chemical stimuli. It is of interest to note in this context that exercise decreases the Pacoz threshold for ventilation during hypoxia (see Masson and Lahiri, 1974). Conclusion
The effect of vagotomy on the chemical regulation of ventilation in the anesthetized dogs both in rest and during exercise is profound. The breath frequency regulation during chemical stimulation is lung volume related and is dependent on vagal afferent impulses from the lungs. The vagal modulation of the control of ventilation by the peripheral and central chemoreflex is similar, and is likely to occur at the same neuronal level of the brain stem. On the other hand, regulation of breath frequency during muscular exercise alone is not critically dependent on.the vagal reflex. It is presumably directly linked to neural drive from the exercising limbs and is activated through the bulbo-pontine mechanism. The bulbo-pontine mechanism often showed little modulation of breath frequency during chemical drive. There are thus important differences between the control of ventilation during chemical drive and that during muscular exercise. The effects peculiar to exercise add to the body of evidence that a mechanism, other than chemical (hypoxia, CO,-H+ ), comes into play during exercise in the regulation of ventilation. References Bartoli,
A., E. Bystrzycka,
A. Guz.
S. K. Jain,
M. I. M. Noble
of the pulmonary vagal control of central respiratory movements. .I. Pkpsiol. (London) 230: 4499465. Bouverot. P. (1973). Vagal afferent Respir. Physiol. 17: 325-335.
R. 0. and S. Lahiri (1973). Absence
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S. LAHIRI, S. MEI AND F. F. KAO
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Respir. Physiol. 7: 122-135. factors
hyperpnea:
in the regulation hyperpnea
secondary
of