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Ann. Rev. PhysioL 1983. 45:393-413

Copyright © 1983 by Annual Reviews Inc. All rights reserved

VENTILATORY CONTROL
DURING EXERCISE IN HUMANS
Annu. Rev. Physiol. 1983.45:393-413. Downloaded from www.annualreviews.org

Brian 1. Whipp
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Division of Respiratory Physiology and Medicine, Department

of Medicine, Harbor-UCLA Medical Center, Torrance, California 90509
and Departments of Physiology and Medicine, UCLA School of Medicine,
Los Angeles, California 90024

Exercise entails an increased transformation rate of substrate free energy

into the mechanical energy of muscle contraction, with ventilatory control
functioning to regulate the composition of the fluid milieus of the force­
generating cells. Analysis of ventilatory control during exercise therefore
requires gas exchange as a crucial frame of reference. Although recent
publications will be addressed primarily in this review, they will be consid­
ered within the context of prevailing control theories, even though these are
based, in humans, almost entirely upon exercise performed under rigidly
controlled, and arguably unnatural, laboratory conditions.
Ventilatory Response Characteristics
MODERATE EXERCISE Although an abrupt increase in ventilation
(VE) occurring at the first respiratory cycle following the transition from
rest to constant-load exercise was described by Krogh & Lindhard in 1913
(63), the pattern of the immediate ventilatory response and its determinants
remain of considerable experimental interest. For example, Paulev (84),
Whipp et al (120), and Jensen et al (54) have all demonstrated that the
response, as evidenced by the start of a systematic change in the profile of
respiratory airflow, begins in virtual synchrony with the onset of the work
and can occur in either the inspiratory or expiratory phase of the respiratory
cycle. This typically results in an increment of ventilation that is relatively
constant, irrespective of the work rate (25, 53), and lasts for some 15-20
sec; if cued by a preparatory warning, the ventilatory changes may even
precede the exercise (100). The dynamics of the early VE response depends,
393
0066-4278/83/0315-0393 $02.00
 394 WHIPP

howc�ver, upon whether the constant-load work is imposed from a back­

ground of rest or of mild exercise, a more slowly developing hyperpnea
being evident for work-to-work transitions (13, 16, 69, 85, 124).
R(:cently, dynamic work-rate forcing techniques and computer analysis
have detailed the response characteristics of this phase of the hyperpnea,
which precedes altered mixed venous gas tensions (i.e. phase 1 or �1). Thus
Whipp et al (124) utilized multiple repetitions of constant-load exercise
performed either from rest or from a background of mild work. Fujihara
et al (37, 38) employed not only the square wave but also its integral and
differential (i.e. the ramp and impulse functions respectively). Bennett et al
Annu. Rev. Physiol. 1983.45:393-413. Downloaded from www.annualreviews.org

(10) chose pseudorandom binary sequences of work rate, while Bakker et

al (5) and Swanson (95) utilized sinusoidal forcing functions. The common
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feature of these studies [but not of the sinusoidal studies of Wigertz (125)
and Casaburi et al (15)] is that a rapid VE component was evident against
a background of prior mild exercise. This component evidenced quite differ­
ent kinetic characteristics from the subsequent nonsteady-state component
of the response (i.e. phase 2 or �2). Thus while both components are
adequately described by the first-order transfer function:

Ae-sT l/(l+sor) 1.

(where s is the Laplace transformation variable, A is the steady-state ampli­

tude and or and T are the time constant and delay parameters, respectively),
the �:arly response has a time constant of some 7 sec but that for the
subst:quent response is 40--50 sec. No statistical criteria were established to
determine whether the �1 response was, in fact, first-order.
Several groups have demonstrated that the ¢1 hyperpnea is typically not
associated with the increase in the gas exchange ratio (R) and end-tidal
P02 and the decrease in end-tidal PC02 characteristic of hyperventilation
(16,54,69, 75, 85,109,124). Others, however, have reported that hyperven­
tilation is a consistent finding at exercise onset (2, 117). It has been sug­
gested that such hyperventilation only results from more erratic breathing
responses, often with evidence of VE and airflow overshooting in �1 (119).
R<lLther, there appear to be proportional increas�s in the ventilatory and
cardiac output responses in ¢1, at least as inferred from: (0) the constancy
of alveolar gas tensions and R, and (b) V02 and VC02 both changing in
concert with VE during ¢ l , abruptly for rest-to-work transitions but
markedly more slowly from a background of mild exercise (16, 69, 124).
The latter, however, is complicated by functional residual capacity nor­
mally decreasing at the onset of constant-load exercise (69, 103), requiring
correction for changes in the lung gas stores of O2 and CO2 (9, 96).
 VENTILATORY CONTROL IN EXERCISE 395

The onset of phase 2 is signalled by altered gas composition in the mixed

venous blood entering the pulmonary capillaries, accelerating the rates of
transfer of O2 and CO2 across the gas exchange interface. This results in an
increase in PE-rC02and a simultaneous decrease of PE'f02 and R (69, 75, 85,
109). However, the question of whether this secondary increase of ventila­
tion actually occurs on the same breath as the increased rates of pulmonary
gas exchange (i.e. suggesting intrapulmonary mediation) or whether the
c/>2 hyperpnea begins some two breaths or so later [i.e. reflecting the lung-to­
carotid body transit delay (51, 86) and suggesting mediation by the conven­
tional chemoreceptors] remains to be resolved.
Annu. Rev. Physiol. 1983.45:393-413. Downloaded from www.annualreviews.org

Several investigators have applied a simple first-order or mono-exponen­

tial model (equation I) to the VE response to exercise instituted from prior
mild exercise and estimate the time constant to be about 70 sec. More
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recently, however, more discriminating work-rate forcings and the applica­

tion of systems-analytic techniques for model discrimination have resulted
in the formulation of model structures more appropriate to the response
characteristics of the exercise hyperpnea. The current consensus thus favors
models that incorporate two compartments rather than one.
Fujihara et al (37, 38) used square-wave, ramp, and impulse forcings of
work rate and concluded that the transient behavior of the exercise hyperp­
nea was best described by the additive interaction of two simple, first-order
components operating in parallel, the response characteristics of the first
being early and rapid and those of the second delayed and slow:

A e-sT 1I(I+ST1) + Be-sT 1I(I+ST2) 2.

where A and B are the steady-state amplitudes of the c/>I and c/>2 response
components, and 71, 72 and T" T2 are the corresponding time constant and
delay parameters. These authors elected to modify this model structure by
including an additional time constant parameter (T3) in the slow c/>2 com­
partment, whose action was to "filter" its response:

3.

And while it provided a statistically better fit to their data, these authors
do not indicate whether this additional term is merely a mathematical
expedient or has any physiological significance. Using pseudo-random bi­
nary sequences of work rate, Bennett et al (10) found that the modified
model of Fujihara et al [(37, 38); equation 3] also provided a better descrip­
tion of their ventilatory data than did the simpler models (equations I &
2). Again, however, the physiological significance of the third time constant
parameter was not discussed. Both Fujihara et al (37, 38) and Bennett et
 396 WHIPP

al (10) reported similar values for the cp2 delay parameter, T2 (some 15-20
sec), and the two time constant parameters (some 40-60 sec and 16-19 sec,
respectively).
Whipp et al (124), however, argued that the cp2 data resulting from
multiple square-wave forcings of work rate were so well described by a
mOIllo-exponential that the incorporation of additional dynamic compo­
nents appeared unwarranted. Furthermore, the cp2 time constant was not
discernibly affected by whether the prior control condition was rest or mild
exercise, a value of about 55 sec being obtained in both cases.
A fundamentally different model structure was used by Bakker et al (5).
Annu. Rev. Physiol. 1983.45:393-413. Downloaded from www.annualreviews.org

Based upon the results of sinusoidal and impulse work-rate forcings, a

second-order model was selected in which the two simple, first-order com­
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poncmts were placed in series rather than in parallel:

4.
Altbough the authors do not detail the physiological basis of this model,
it would be compatible with the ventilatory response dynamics reflecting the
serial washout of two intervening compartments or, perhaps, the washout
of a single compartment followed by a receptor mechanism responding with
first-·order kinetics. Furthermore, as the fit of the data to this model in­
dicated the operation of a critically damped system (i.e. relative damping
coefficient � 1), these authors raised the possibility that the system might
include feedback pathways in addition to the two components in the for­
ward path.
Investigators have also attempted to relate the phase 2 VE response
dynamics to those of O2 uptake and CO2 output. Satisfactory descriptions
of the cp2 gas exchange responses have been obtained from simple, first­
orde:r models (Le. equation 1). The time constants of the V02 and Ve02
responses, however, are appreciably different, that for VOz being some
35-40 sec and that for Veoz some 50-60 sec (69, 75, 124). The slower
kinetics of Ve02 relative to V02 reflects the considerable capacity for
tissue storage of COz (57, 109).
Clearly, the ventilatory response cannot "track" both Voz and Veoz. It
is with Ve02 that VE is most closely related during this nonsteady-state
phase (15, 16, 75, 109, 118). Consequently, a transient fall in Pa02 should
be evident, and the slightly slower time course of VE than Veoz should also
elicit a small transient rise in Pae02. Experimental evidence of such a
transient arterial hypoxemia has been established (79, 123, 127). During
sinusoidal work-rate forcing (6 min period; work rate below the anaerobic
threshold), Whipp and associates (123) also demonstrated a significant
sinusoidal variation of Pae02 ("" ±1 torr, mean to peak), the peak occurring
when both VE and Ve02 were high, reflecting the small dynamic decoupling
between these variables.
 VENTILATORY CONTROL IN EXERCISE 397

While the hyperpnea of moderate exercise appears to comprise elements

whose characteristics are linear and first-order (or approximately so), few
investigators have systematically addressed the question of linearity. For
example, it is not known whether the time constant of the phase 2 VE
response is affected by the range of work rates over which the forcing
function is applied. But since V02 exhibits static linearity (Le. equal incre­
ments of power educe equal increments of V02 in the steady state) and also
dynamic linearity (i.e. the same time constant obtains for different square­
wave increments of power) and'since the gas exchange ratio appears to have
quite complex kinetics in q,2 (Le. in response to a square-wave increment of
Annu. Rev. Physiol. 1983.45:393-413. Downloaded from www.annualreviews.org

power, it does not remain constant, change monotonically, or change in­

stantaneously to a new value at the onset of q,2, but rather undershoots
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transiently), the presence of nonlinearities in the cp2 response of Veoz and,

therefore, VE should perhaps be expected. Indeed, Bakker et al (5) have
reported the behavior o( Voz to be linear, but that of Ve02 and VE to be'
quasi- or nonlinear. Further complicating the Vcoz and VE kinetics in-,this
phase is the influence of the transient increase in blood lactate that occurs
below the anaerobic threshold, this being especially prominent at the upper
reaches of ,moderate-intensity exercise.
The steady-state or phase 3 ventilatory response is thought to represent
the sum of the steady-state responses of the phase' 1 and phase 2 compo­
nents. It is generally conceded (19, 55, 107) that in the steady state both
alveolar and minute ventilation increase as a linear function of Ve02 (rather
than V02) and, consequently, Pae02 is regulated at or very close to its
resting value. The linear VrVC02 relationship passes through the origin:

5.

but the VE - VC02 relationship has a positive intercept on the VE axis of

some 3-5 liters per min (25, 105):

VE = (863 VCOz/Pac02) + V0 6.

or, alternatively:

7.

where V0 is the dead space ventilation and VoiVT is the physiological dead
space fraction of the breath. Consequently, the ventilatory response to
exercise is systematically greater when Pac02 is caused to be low (58, 82)
or Vo and VOiVT high (89, 105, 106).
Jones (56) has recently demonstrated that as Veoz was decreased in the
steady state of moderate exercise by physical training (owing to a lowering
 398 WHIPP

of the R.Q.) VE also decreased as a consequence and with an identical

proportionality to that predicted by the VE-VC02 relationship originally
induced by exercise prior to the training. Furthermore, both Jones et al (58)
and Oren et al (82) have altered the regulated level of resting Paco2 by
means of sustained diet-induced metabolic acidosis and alkalosis. In these
studies, VE was changed during moderate exercise precisely as predicted for
regulation of Paco2 with an altered "set point" (i.e. equations 6 & 7).
Dempsey and his co-workers (29), however, have rightly cautioned that
strict isocapnia during moderate exercise may be more a laboratory phe­
nomenon than a manifestation of spontaneous exercise, the latter involving
Annu. Rev. Physiol. 1983.45:393-413. Downloaded from www.annualreviews.org

a much greater behavioral or supra-bulbar control of VE' To support their

cont<ention, these authors have actually measured a sustained respiratory
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alkallosis during prolonged, moderate running. Furthermore, in longer-term

exercise (cycling for about 1 hr), Martin et at (73) found that VE evidenced
a continuous, slow drift that was not apparent in V C02' The estimated
Paco2, however, remained constant, suggesting that the drift was a function
of alterations in VD of unknown origin. This was thought not to be related
to the increased body temperature, although a good correlation was ob­
served between the magnitude of the VE increase and the plasma norepi­
nephrine concentration.

HEA VY AND SEVERE EXERCISE There has been less emphasis on ana­
lyzing VE during heavy and severe exercise, owing largely to the nonlineari­
ties in its response. These stem predominantly from the lactic acidosis that
characterizes these work rates (72, 80, 111); but increased body temperature
(29), catecholamines (73), and even, in some apparently normal but highly
fit subjects, arterial hypoxemia (29) are also likely to contribute.
It has been shown recently that when an incremental exercise test is
performed in which work rate is increased each minute or less, a range is
observed above the anaerobic threshold within which VE rises as a function
of VC02 (109) in the same direct proportionality as below the threshold.
This observation is supported by the results of studies in which sinusoidal
fluctuations of work rate encroached above the anaerobic threshold by a
small amount (16). This range of work rates has been termed the range of
"isocapnic buffering," although direct support for arterial isocapnia, rather
than mere PErC02 constancy (109), remains to be established. Conse­
quently, there appears to be no respiratory compensation for the metabolic
acidosis in this range (i.e. lowering of Paco2)' It is not clear at present why
the ventilatory control system sensors do not "see" the decreased arterial
pH in the phase of isocapnic buffering, while they do apparently respond
if the work rate increment is prolonged to 4 min or more (108, 111)j the
carotid bodies, which are thought to mediate the compensatory hyperventi-
 VENTILATORY CONTROL IN EXERCISE 399

lation (112, 122), have a time constant of response to exogenous H+ of less

than 1 sec [in the cat, at least (87)].
A further complication at very high work rates is that of mechanical
limitation to air flow generation. While this is not a usual finding in normal
subjects (66, 78), the extremely high work rates attainable by fit subjects
render them more likely to encroach upon the mechanical limits for expira­
tory airflow during high-intensity, exhaustive exercise. Griroby et al (42)
and Olaffson & Hyatt (78) have shown that highly fit subjects achieved
expiratory airflows that reached their volume-specific maximum during
high-intensity exercise. Furthermore, Follinsbee et al (35) demonstrated
Annu. Rev. Physiol. 1983.45:393-413. Downloaded from www.annualreviews.org

that such highly fit athletes reached a maximum exercise ventilation that
was, on average, some 95% of their resting maximum voluntary ventilation,
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in contrast to the 60--70% normally attained in less fit subjects. Conse­

quently, as athletes become more and more "fit," a greater requirement for
optimum pulmonary mechanics is likely to be a determinant of successful
performance.

Altered Control
PERIPHERAL NEUROGENIC DRIVE Jaeger-Denavit et al (50) induced
"passive movement of the knees" through 90° at a frequency of I Hz
repeatedly in healthy subjects and in subjects with paraplegia resulting from
clinically complete spinal-cord lesions at T l2. The hyperpnea that normally
occurred on the first "exercise" 1l10vement was absent in the paraplegic
subjects. In a further group of parJtplegics having only partial loss of sensa­
tion and movement in the knee region, the first-breath hyperpnea was
significantly reduced compared to control. These authors concluded that
afferents from the limbs play a determining role in the initial ventilatory
response associated with movement. Unfortunately, the simultaneous gas
exchange and alveolar gas tension responses were not reported in this study.
Weissman et al (114) have demonstrated that if exercise is induced in
normal subjects who constrain their VE at the resting level, then alveolar
gas tensions immediately change (PE]'C02 increasing and PE'f02 decreasing)
to reflect the increased pulmonary blood flow without concomitant ventila­
tory response. Such measurements would have ruled out the possibility that
the neurological deficit also altered cardiovascular reflexes.
Adams et al (1) have studied the VE response to electrically induced limb
movement in subjects with complete spinal transection at T3; but they also
determined VCO2 and PE]'C02' They found that VE increased on the first
complete respiratory cycle following "exercise" onset similarly to normal
subjects, PE]'C02 being unchanged in both cases. Subsequently, however,
VE rose more slowly to the steady state in the cord-transected subjects. But
 400 WHIPP

as "COz dynamics were similarly slowed, the authors concluded that the
effe:::t of spinal-cord transection on the early VB response to the "exercise"
was a consequence of the slower rate of CO2 delivery to the lungs, rather
than a direct effect of impaired neurogenesis per se. In addition, Asmussen
:et al (4) had previously demonstrated that the VE and PEJC02 responses to
steady-state exercise were normal in a tabetic subject who evidenced com­
plete loss of proprioceptive reflexes from the legs and lower trunk.
Jammes et al (52) administered high-frequency mechanical vibration
unilaterally to the tendons of the biceps or triceps brachialis muscles in
nonnal resting subjects, this technique having been shown to stimulate
Annu. Rev. Physiol. 1983.45:393-413. Downloaded from www.annualreviews.org

preferentially muscle spindle afferents both in animals and humans. These

authors found that VE increased on the first or second breath following the
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ons(�t of the period of vibration and that PEJC02 fell. No a�ptation of the
response was apparent. Since the hyperventilation ,occurred even though
cardiac rhythm did not change, the authors concluded (contrary to other
investigators) that actual contraction of the muscle is not a prerequisite for
evoking the VE effects induced by muscle afferent stimulation. However,
unlike the initial hyperpnea1of.moderate dynamic exercise in humans, the
responses to such high-frequency vibration resulted in hypocapnia. Further­
more, Hornbein et al (47) could not document significant effects on VE in
exercising humans of selectively blocking the 'Y-efferent system to the legs
(without significant impairment to the a-fibers).
Tibes et al (99) correlated the nonsteady-state changes in VE with those
in the concentrations of various putative chemical mediators of the exercise
hyp.,"Ipnea
neously exercising subjects. Because [K+] correlated better with VE than did
femoral-venous Po2, PC02, pH, lactate, or osmolarity, these authors con­
cluded that [K+] in the interstitial fluid was likely to be stimulating the
small-diameter type III and IV muscle afferents. In contrast, Comroe &
Schmidt (17) were unable to induce hyperpnea when venous blood collected
from the exercising limbs of dogs was infused into the arterial supply of limb
muscle.

CENTROGENIC DRIVE

Corticogenic drive There is some evidence in humans suggestive of a corti­

cal c:ontribution to the exercise hyperpnea. Hyperventilation occurred in the
the steady state of exercise in situations where the degree of conscious effort
required to -accomplish a specified motor task was greater than normal­
e.g. following partial muscle paralysis by.curarization (3, 77), by simulta­
neous activation of antagonist musculature'(40),'or by hypnotic suggestion
(23, 76). Conversely, the use of hypnotic suggestion to abolish the percep-
 VENTILATORY CONTROL IN EXERCISE 401

tion of muscular effort during exercise led to a slight reduction in the

magnitude of the exercise hyperpnea (23).

Hypothalamus Eldridge et al (33) have recently demonstrated that elec­

trical stimulation of the "hypothalamic motor area" in the cat induced
rapid ventilatory and gas exchange responses. However, these results ap­
pear qualitatively unlike those obtained in studies of volitional exercise in
humans, of "exercise" induced by stimulation of peripheral nerve or muscle
in cat and dog (65, 115, 116), or even of "fictive locomotion" (33). That is,
a profound and rapid hyperventilation ensued, possibly consequent to
Annu. Rev. Physiol. 1983.45:393-413. Downloaded from www.annualreviews.org

stimulation of extra-pyramidal pathways to the respiratory muscles. How­

ever, Eldridge'S experiments provide a useful reminder to consider similari­
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ties between the role of the hypothalamus (and other limbic structures) in
the integrative response to exercise as a "state," and its known and detailed
role in the induction of rage, arousal, defence etc.

Central neural "reverberation" Eldridge (32) has also suggested that cen­
tral neural mechanisms may be important in determining the cf>2 kinetics
of the exercise hyperpnea. Specifically, he has demonstrated that the "res­
piratory centers" themselves have neural dynamics capable of sustaining an
hyperpnea despite the removal of the causal stimulus. Rather than an
immediate step-decrease in respiratory activity after abrupt removal of a
carotid body or hindlimb stimulus, an early and abrupt fall was followed
by a slower decline; the mechanism of this slower component was isolated
to the brain stem (32). A similar phenomenon has also been described in
resting humans following the abrupt cessation of a bout of isocapnic voli­
tional hyperventilation (97, 98). These findings may be significant for the
cf>2 VE kinetics of exercise, although the on-off symmetry of the cf>2 time
constant in humans is not as evident in the "reverberatory experiments" in
the cat.

CAROTID BODY DRIVE The peripheral chemoreceptors do not normally

appear to influence significantly the magnitude of the cf>1 hyperpnea in
humans. Consequently, the abrupt cf>1 hyperpnea did not differ appreciably
from normal in a group of subjects who had undergone surgical resection
of their carotid bodies (112). Neither was this response significantly affected
in normal subjects by hypoxia, hyperoxia, or by sustained or acute hyper­
capnia (20, 27, 102). However, the parameters of the distribution of the cf>
1 VE response and its reproducibility remain to be established, and so
judgments regarding the normalcy of a particular response are often based
upon less than rigorous criteria.
 402 WHIPP

S(:veral lines of evidence in humans, however, implicate the carotid bod­

ies in 1>2 ventilatory control. Cunningham et al (22) demonstrated that
breathing pure O2 to inactivate the carotid bodies markedly delayed the
onset of the 1>2 hyperpnea and appreciably slowed its kinetics, compared
with the responses during hypoxia, a result supported by Linnarsson (69).
Extending this approach, Griffiths et al (41) and Whipp & Wasserman (122)
have: demonstrated that the 1>2 time constant was inversely proportional to
carotid body responsiveness. Increased central chemoreceptor drive, how­
ever" does not appear to speed the ¢2 kinetics (104).
Intriguingly, the ¢2 hyperpnea appears to retain its exponentiality, re­
Annu. Rev. Physiol. 1983.45:393-413. Downloaded from www.annualreviews.org

gardless of the time constant of the response or the proportional role of the
carotid bodies. It is difficult to envision how the ventilatory response of a
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simple additive control system can remain exponential as the carotid body
component assumes progressively greater prominence. Consequently, the
carotid body drive in ¢2 may dictate the speed with which the fundamental
proc,ess (likely within the brainstem respiratory centers) operates, while not
dismpting its underlying exponentiality.
Furthermore, Oren et al (83) determined the influence on the 1>2 VB
kinetics of metabolic acid-base changes induced by the ingestion of am­
monium chloride (metabolic acidosis), sodium bicarbonate (metabolic al­
kalosis), and calcium carbonate (control), each for three days. The
metabolic acidosis significantly reduced the ¢2 time constant, whereas the
metabolic alkalosis increased it. Because the carotid bodies in humans
appear to be largely responsible for the VE response to relatively acute
metabolic acidosis, and because the ¢2 time constant was lengthened in all
thre(: acid-base states to the same absolute value by hyperoxia, these investi­
gators also believe that the carotid bodies in humans are important in
establishing the VE kinetics in ¢2 of exercise.
Subjects who had undergone bilateral carotid body resection evidenced,
on average, appreciably slower than normal kinetics for the 1>2 response to
moderate exercise, despite the magnitUde of the ¢1 and ¢2 components
being unaltered (112). As a consequence, an appreciable respiratory acidosis
resulted during 1>2. Although this is persuasive evidence, more precise
quantification of the actual exponentiality (or the lack of it) of the 1>2
ventilatory reponse and the influence of hyperoxia in such subjects would
be most useful.
There is evidence, too, that the carotid bodies may also contribute to
ventilatory control in ¢3 of moderate exercise. Utilizing the abrupt and
surreptitious substitution of O2 for air, investigators found that the contri­
bution of the carotid bodies to the ¢3 hyperpnea appears to be somewhat
greater than at rest (26, 93, 118). However, subjects who had previously
undergone bilateral carotid body resection evidenced a 1>3 response no
 VENTILATORY CONTROL IN EXERCISE 403

different from normal with respect to VB or arterial blood gas tensions (70,
112). One explanation for this is that other (presumably central chemore­
ceptor) mechanisms "take over" the normal carotid body component. It is
not clear, however, what "takes over" the reduced carotid body drive in the
carotid body resected subject, although the possibility that the resection
removed a hyperventilatory component (which is commonly observed in
subjects with bronchial asthma) may not be ruled out at present. Further
complicating ready interpretation of the role of the carotid bodies is the
fact that a group of Japanese who had undergone carotid body resection
did evidence a reduction of the hyperpnea of moderate exercise (46), al­
Annu. Rev. Physiol. 1983.45:393-413. Downloaded from www.annualreviews.org

though they also showed evidence of significantly impaired pulmonary

mechanics.
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The carotid bodies have also been shown to mediate the. respiratory
compensation for the acute metabolic acidosis of heavy and severe exercise;
subjects who had undergone bilateral carotid body resection evidenced no
such compensation (112, 122). It would be interesting to know if subjects
with little or no carotid-body sensitivity to hypoxemia, such as high-altitude
natives (64), also have reduced responses to acute changes of [H+) and,
consequently, less complete respiratory compensation during heavy and
severe exercise.

CENTRAL CHEMORECEPTOR DRIVE The failure to discern a recogniz­

able stimulus in the cerebrospinal fluid during rp3 of moderate exercise, at
least in animals (12, 61, 67), has led to the belief that central chemoreceptor
mechanisms are not involved in the ventilatory control process. However,
there is a preliminary report that blocking Region "S" on the ventral
medullary surface actually abolished the exercise hyperpnea in cats whose
carotid sinus nerves had been sectioned (92). This observation suggests
either that central chemoreceptor afferents (thought to course through
Region "S") play a significant role in the exercise hyperpnea or that some
other afferent or efferent excitatory activity can be inhibited by this regional
block. Further consideration must, however, await detailed report of these
experiments.
During heavy and severe exercise, the central chemoreceptors presum­
ably exert a restraint upon the hyperpnea, from the supposed alkaline shift
in the cerebrospinal fluid resulting from the arterial hypocapnia [demon­
strated to date only in the pony, however (12») and also possibly by sup­
pressing carotid body afferent drive as has been demonstrated when the
efferent activity in Hering's nerve is increased [as it has been shown to do
in the cat when the cerebrospinal fluid becomes alkaline (71)]. Since no such
evidence is available in humans, these considerations remain only plausible
suppositions.
 404 WHIPP

CARDIODYNAMIC DRIVE Noting the stability of alveolar gas tensions

characteristic of <PI, Wasserman and his associates (109, 110) questioned
whether the implicit tight coupling of the pulmonary blood flow and VE
responses 'in this phase of the wo rk might be causal rather than coincident.
They t herefore hypothesized that a primary change in cardiac output (Q)
might itself trigger the rapid hyperpnea. Any such increase that was not
matched by an appropriate increase in VA would necessarily result in a
downstream error signal in pH, Pcoz, and P02 that could be sensed by a
"rap idly res pond ing chemore�eptor," t hereby providing a humoral stimu­
Annu. Rev. Physiol. 1983.45:393-413. Downloaded from www.annualreviews.org

lus to the early hyperpnea of exercise.

To test this hypothesis, these investigators (110) increased Q in awake
and anesthestized dogs either by electrically "pacing" the right atrium or
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by small intravenous bolus injections of the ,8-stimulant isoproterenol.

When Q rose (and not before), VE increased consequently with little or no
change in PEJC02 or Paco2' The term "cardiodynamic hyperpnea" was
proposed for such a mechanism.
Mediation of the cardiodynamic component of the exercise h yperpnea,
however, is not likely to require "downstream " chemoreception via th�
peripheral or central chemoreceptors directl y, based upon their known
transit delays from the lun gs, the likely change in the error signal, and the
chemoreflex gains. Furthermore, Wasserman et al showed that in humans
the magnitude of the <PI component of the exercis e hyperpnea was not
systematically different in subjects who had u n derg one bilateral carotid
body resection and in control subjects (112).
Huszkczuk et al (48) recently proposed that the cardiodynamic hyperp­
nea may result from an afferent signal deriving f r om the heart itself . Under
conditions in which right ventricular moving-average pressure (p�)-a
functional analog of RV work-was altered in the dog either by altered
peripheral resistance and venous return or partial inflation of a balloon
in the RV outflow tract, the ven tilatory changes were highly correlated with
both the magnitude and the time course of the changes in PIW.
Q
However, changes in that are solely or predominatly induced by heart
rate rather than by both rate and stroke volume do not appear to induce
abrupt changes in VE- Thus work-to-work transitions in the upright posi­
tion (13, 16,124) or rest-to-work transitions in the supine position (60, 113)
(i.e. with stroke volume already elevated to, or close to, its exercise level
prior to the work) are not associated with a rapid cpl h yperpnea. Further­
more, Jones et al (59) performed a more definitive study, inducing incre ases
in heart rate in patients with permanent, demand-type pacemakers (placed
for the management of atrioventricular block). When heart rate was
abruptly increased from some 50 min- I to 80 min- I , there was no si gnificant
VE respon se for approximately 20 sec on average, despite Pm<'02 having
 VENTILATORY CONTROL IN EXERCISE 405

increased by a mean of 2.5 torr [and by some 4 torr in their subject example:
Figure 1 in (59)], at which time PE'J02 had fallen by about 8 torr and the
gas exchange ratio R by about 0.1. Because these changes were associated
with increased VC02 and VC02, there was clear evidence of increased Q
without hyperpnea. Subsequent increases in VE, beginning approximately
20 sec after the induced tachycardia, were observed and presumably re­
sulted from humoral stimulation of the peripheral and central chemorecep­
tors by the altered arterial blood-gas composition.
Diversion of a portion of the normal venous return from the venae cavae
into the aorta has been undertaken by several groups in the dog, (the
Annu. Rev. Physiol. 1983.45:393-413. Downloaded from www.annualreviews.org

returning blood being "arterialized" by a gas exchanger). Despite method­

ological differences, these studies had a strikingly similar result. Blood flow
by University of Melbourne on 04/29/13. For personal use only.

through the heart and lungs was reduced, either at rest (39, 88, 94) or in
the steady state of exercise (49, 81), hypopnea developed, even inducing
apnea with sufficient thoracic hypoperfusion.
Brown et al (14) examined the role of such a cardiodynamic mechanism
in the steady state of moderate exercise in humans by infusing propranolol
to block ,a-adrenergic receptors. A fall in VE was observed consequent to
the fall in Q; the hypopnea only persisted, however, until mixed venous
CO2 content rose sufficiently to return the pulmonary CO2 flux to normal
(i.e. VC02 was restored to its control exercise level). Consequently, a cardio­
dynamic mechanism for a component of the steady-state exercise hyperpnea
appears likely, involving both feedforward and feedback control elements.

The Search for Humoral Stimuli

The question of whether the hyperpnea of moderate steady-state exercise,
or some proportion of it, is attributable to some change in the chemical or
physical characteristics of the blood or muscle or brainstem interstititial
fluid, and operates through proportional control, remains a central issue.
Since chemoreceptors within the pulmonary artery, capillaries, and veins
have been effectively ruled out, systemic arterial blood has received most
attention in the search for humoral mediation. Although some have as­
serted that arterial PC02 or [H+] is increased systematically in c/>3 of exer­
cise, the experimental evidence overwhelmingly supports the contention
that moderate exercise is isocapnic with respect to carefully established
control values [see (118) for discussion]. Similarly, Pao2 does not change
systematically during c/>3 at these work rates.
Increased body temperature can induce hy:perpnea, mediated' especially
via tachypnea (44); but for the increases of 1°C or less that are typical of
moderate exercise, there appears to be little or no ventilatory stimulation
out of proportion to metabolic rate (28, 43, 121). Furthermore, highly fit
subjects with a wider range of work rates within the moderate intensity
 406 WHIPP

domain, and hence a higher core and muscle temperature at the extreme
of the domain, do not hyperventilate. And unless the thermal stimulatory
effects in such subjects are simply offsetting some reduced ventilatory drive
from other sources, a case for a significant influence from body temperature
at these work rates appears remote.
As neither cerebral blood flow, PaC02 or pHa• cerebral metabolic rate. nor
bulk cerebrospinal fluid pH are thought to change with moderate exercise,
it is supposed that no changes in local pH occur in the brainstem interstitial
fluid composition at the sites of central chemoreception. Thus the search
for al humoral mediator of the steady-state exercise hyperpnea has proven
Annu. Rev. Physiol. 1983.45:393-413. Downloaded from www.annualreviews.org

unslllccessful. Consequently. other COrlinked control mechanisms have

been considered.
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It has been suggested that the restriction of blood carbonic anhydrase to

the interior of the erythrocyte (34. 36. 45) would delay the dehydration of
carbonic acid in the arterial plasma to an extent that could provide a H+
stimulus to the peripheral chemoreceptors. Such a stimulus would not be
evident in equilibrated blood samples. Because the proposed pH stimulus
to the carotid bodies would depend both on mixed venous PC02 and Q. the
"disequilibrium" theory for control of the exercise hyperpnea did meet the
challenge of internal consistency.
Recently, however, the "disequilibrium" theory has undergone two ir­
remediable setbacks. Firstly, the presence of carbonic anhydrase on the
pulmonary capillary endothelial surface and its accessibility to the pulmo­
nary capillary plasma have now been demonstrated ( 30, 62, 66). As a
cons<equence, the dehydration of carbonic acid in plasma is accelerated,
with little or no disequilibrium being discernible at the end of the pulmo­
nary capillary bed. Secondly. Lewis & Hill (68) investigated the conse­
quences on exerciseVE of introducing bovine carbonic anhydrase into the
plasma of dogs (at a level designed to speed the dehydration of carbonic acid
some lOO-fold). However, the expected decrement ofVE that would result
if the proposed disequilibrium were abolished did not occur.
Since the original suggestion by Yamamoto & Edwards (126), investiga­
tors have considered the possibility that the naturally occurring, respirato­
ry-related oscillation of arterial pH and PC02 might contain information
important to the control of the exercise hyperpnea [see (122) for discussion].
This is an attractive proposition because such a mechanism could provide
the ventilatory control system with a COrlinked error signal that could
operate in the absence of a change in mean arterial PC02 or pH. The
presence of these oscillations has been determined from in-line pH measure­
ments in humans (8) and experimental animals (6, 18); both their amplitude
and :rate of change can increase during exercise.
 VENTILATORY CONTROL IN EXERCISE 407

A correspondingly periodic pattern has been discerned in the afferent

discharge from the carotid bodies (7, 11). However, because in humans the
carotid bodies sense arterial oscillations at these frequencies and because
subjects without carotid bodies can achieve the same c/J3 VE at moderate
work rates as normal subjects, signals deriving from such intra-breath
periodicities are presumably not obligatory determinants of a normal
steady-state hyperpnea during exercise. But clearly the slow c/>2 VEkinetics
in carotid body resected subjects (112) are compatible with a role for such
oscillations in the normal c/>2 response. The pH oscillation was virtually
absent (16a) in subjects with chronic obstructive lung disease, suggesting
Annu. Rev. Physiol. 1983.45:393-413. Downloaded from www.annualreviews.org

that the slow ventilatory dynamics in such subjects may reflect the absence
of these oscillations.
by University of Melbourne on 04/29/13. For personal use only.

Saunders, however, has incorporated an ingenious modification of the

"oscillations" theory into a model for the exercise hyperpnea. In simplest
terms, it suggests that the carotid bodies sense not simply the shape but also
the temporal density of the oscillations-i.e. they "count" the number of
peaks per unit time (91). This novel approach would, of course, dispense
with the necessity for a transit delay in the sensing of a cardiodynamically
generated downstream error signal to provide humoral mediation in c/> I of
exercise--ie. increased blood flow itself would be sufficient. However, be­
cause it is by no means certain that carotid artery blood flow actually
increases during exercise in humans, and because the magnitude of the c/>
1 VE increase is not discernibly different in carotid body resected subjects
or when normal subjects breathe hyperoxic gas mixtures, this must be
considered as a stimulating speculation.
It has also been suggested that the intra-breath arterial CO2-H+ oscilla­
tion may also influence VE from its "phase-coupling" to the ongoing respira­
tory cycle (21, 101). This suggestion is based on the demonstration in the
cat (31, 101) that bolus infusion of hypercapnic blood past the carotid
bodies or electrical stimulation of the carotid sinus nerves could elicit
ventilatory response, which was much more striking when applied during
inspiration rather than expiration.
Petersen et at (86), however, have shown that the phase-coupling mecha­
nism does not appear to influence c/>3 VEto any discernible extent through
the spontaneously occurring oscillation; its significance in the c/>1 and c/J2
responses has not yet been investigated. On the other hand, Cross et al (18)
have reported that the influence of the pH oscillation during exercise via
such a phasing mechanism may account for some 17% of the steady-state
ventilatory response to moderate exercise. In addition, Metias et at (74)
recently demonstrated in humans that within-breath fluctuations of alveolar
PC02 (created by an ingenious "plumbing" of the apparatus dead space)
 408 WHIPP

can affect the absolute level of VE, despite an apparently unaltered mean
level.
Finally, Saunders (91) has shown' that one can actually develop a simula­
tion of the exercise hyperpnea using only components of the respiratory­
relatled oscillatory humoral signal, the upstroke of the PC02 oscillation
provilding the important source of afferent information. Saunders's caveat
to his own work (an undisguised reminder to "modelers" of the respiratory
control system) deserves emphasis: "The fact that exercise and C0z- breath­
ing may be neatly stimulated using only components of the oscillating
chemical signal does not imply that it is necessarily an actual source of
Annu. Rev. Physiol. 1983.45:393-413. Downloaded from www.annualreviews.org

information' in real life, or, if actual, the only one."

In conclusion, a vast array of control mechanisms have been postulated
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to account for the exercise hyperpnea in humans, these being apparently

confirmed in most instances by animal experiments. Were they all to operate
in the proposed manner, the perplexity regarding the hyperpnea of moder­
ate exercise would be not why ventilation actually increases but rather why
it normally rises only to a level commensurate with the CO2 output.

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