Exp Physiol 91.

1 pp 37–49 37

Experimental Physiology – Neural Control of the Circulation During Exercise

Arterial baroreflex resetting during exercise: a current

perspective
Peter B. Raven, Paul J. Fadel and Shigehiko Ogoh
The Department of Integrative Physiology, University of North Texas, Health Science Center, Fort Worth, TX 76107, USA

Within the past 20 years numerous animal and human experiments have provided supportive
evidence of arterial baroreflex resetting during exercise. In addition, it has been demonstrated
that both the feedforward mechanism of central command and the feedback mechanism
associated with skeletal muscle afferents (the exercise pressor reflex) play both independent
and interactive roles in the resetting of the arterial baroreflex with exercise. A fundamental
alteration associated with baroreflex resetting during exercise is the movement of the operating
point of the reflex away from the centring point and closer to the threshold, thereby increasing the
ability of the reflex to buffer hypertensive stimuli. Recent studies suggest that central command
and the cardiopulmonary baroreceptors may play a role in this movement of the operating
point on the baroreflex–heart rate and baroreflex–blood pressure curve, respectively. Current
research is focusing on the investigation of central neural mechanisms involved in cardiovascular
control, including use of electrophysiological and molecular biological techniques in rat and
mouse models to investigate baroreflex resetting as well as use of state of the art brain imaging
techniques in humans. However, the purpose of this review is to describe the role of the arterial
baroreflex in the regulation of arterial blood pressure during physical activity from a historical
perspective with a particular emphasis on human investigations.
(Received 14 September 2005; accepted after revision 6 October 2005; first published online 6 October 2005)
Corresponding author P. B. Raven: 3500 Camp Bowie Blvd, Fort Worth, TX 76107, USA. Email: praven@hsc.unt.edu

Prior to 1990 it was generally accepted that the arterial
baroreflex control of arterial blood pressure (ABP) was
‘switched off’ during exercise to enable the parallel increase
in heart rate (HR) and ABP. This concept prevailed
despite contrary evidence from both human and animal
investigations (Bevegard & Shepherd, 1966; Coote &
Dodds, 1976; Melcher & Donald, 1981). Bevegard &
Shepherd (1966) asked six subjects to perform supine leg
cycling exercise at heart rates of approximately 90, 110 and
130 beats min−1 while engaging the carotid baroreceptors
with neck suction for 2 min and comparing HR, ABP
and forearm blood flow responses to those obtained at
rest. These investigators reported that ‘during exercise,
stimulation of carotid arterial stretch receptors caused
reductions in HR and ABP of the same absolute magnitude
as at rest’. These data indicated that the arterial baroreflexes
were functional during exercise, at least in response to
simulated hypertension. However, despite these findings,
in a comprehensive symposium on the neural control of
the circulation during static (isometric) exercise in which
the roles of central command and the exercise pressor reflex
were investigated (Mitchell et al. 1981), the consensus
agreement of the symposium’s presenters in explaining the
parallel increase in HR and ABP in the transition from rest
to static exercise was that ‘the arterial baroreflex control of
blood pressure was either “switched off” or “overridden”’.
T. H. Huxley (1894) states that ‘The tragedy of
science. The slaying of beautiful hypotheses by ugly fact.’
Subsequently this hase proven to be correct in light
of the following review of current information. Coote
& Dodds (1976) identified baroreflex resetting during
sustained contraction of the hindlimb in decerebrate
unanaesthetized cats. Subsequently, beginning in 1980,
a series of landmark studies by Donald and coworkers
(Stephenson & Donald, 1980; Melcher & Donald, 1981;
Walgenbach & Donald, 1983), using an isolated carotid
sinus technique in chronically instrumented exercising
dogs, identified an upward shift from rest to exercise of the
baroreflex stimulus–response curve of both HR and ABP
without a change in maximal gain (G max ). Another key
study identifying the importance of the arterial baroreflex
during exercise was performed by Sheriff et al. (1990).
Using chronically instrumented exercising dogs, these
investigators demonstrated that the increase in arterial

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38
pressure evoked by activation of the exercise pressor reflex
became unrestrained following sino-aortic baroreceptor
denervation. Collectively, these data clearly indicated that
arterial baroreflex control of ABP was indeed functional
during exercise and was in fact necessary for the normal
cardiovascular response to exercise.
Methodological considerations for investigating
the arterial baroreflexes
The early recognition of an inverse relationship between
changes in ABP and changes in HR (Marey, 1863)
suggested a negative feedback control system (Rowell
et al. 1996). Over the course of many years and many
experiments, elegantly reviewed by Sagawa (1983) and
concisely presented by Rowell et al. (1996), the engineering
concepts of the arterial baroreceptor’s sigmoidal stimulus–
response curve were described. This stimulus–response
curve has been shown to conform to a logistic function
model (Kent et al. 1972) from which several baroreflex
parameters can be derived, see Fig. 1.
Operating
Point
Responding Range
Max gain
MAP or HR
(A1)
Slope (A2)
Centring
Point
(A3)
Minimum
Response Operating Range
(A4)
Threshold Saturation
Estimated Carotid Sinus Pressure
Figure 1. A schematic model of the carotid baroreflex (CBR)
function curve and its operational parameters
This model is based upon the logistic model of Kent et al. (1972) and
describes the peak heart rate (HR) and mean arterial pressure (MAP)
responses derived from the application of neck pressure and neck
suction. The responding range (A1) is the maximum to minimum
change in the dependent variable and the operating range is the
difference between the carotid sinus pressures at the threshold and
saturation of the reflex. Threshold is the carotid sinus pressure at
which no further increases in MAP or HR response occur. Saturation is
the carotid sinus pressure at which no further decreases in HR or MAP
occur. At rest the operating point (the prestimulus MAP, or carotid
sinus pressure) and the centring point (A3, the point at which there is
an equal pressor and depressor response to a given change in carotid
sinus pressure) are positioned together. The maximal gain is calculated
as the gain value at the centring point and is applied as an index of
CBR responsiveness. The slope of the CBR function curve represents
the gain coefficient (A2). A4 is the minimum MAP or HR response.
P. B. Raven and others Exp Physiol 91.1 pp 37–49
Initially, questions as to whether the arterial baroreflex
was ‘reset’, ‘switched off’, ‘attenuated’ or ‘overridden’
emanated from the lack of congruence between the
results obtained from the more invasive surgical or
pharmacological techniques used in animal experiments
compared with the non-invasive experimental techniques
employed in human subject experimentation.
Experimental techniques used in animal studies to
evaluate the arterial baroreflexes included: (i) surgical
isolation of the baroreceptors (Melcher & Donald, 1981);
(ii) direct electrical stimulation of the baroreceptor’s
neural afferents (Guo & Thames, 1983); (iii) acute
electrical or chemical blockade of the baroreflex’s
neural afferents (Seagard et al. 1993); (iv) surgical
denervation of the baroreceptors (Walgenbach &
Donald, 1983); and (v) pharmacological manipulation
of the systemic vasculature (DiCarlo & Bishop, 1992).
Alternatively, human experimentation was primarily
limited to the indirect techniques of: (i) stimulating
the arterial (carotid and aortic) baroreceptors by the
pharmacological manipulation of the arterial vasculature
with phenylephrine and nitroprusside to raise and
lower ABP, respectively (i.e. the Oxford technique); and
(ii) manipulating the carotid baroreceptors using the
variable pressure neck collar to provide carotid sinus
hypotension via neck pressure (NP) and carotid sinus
hypertension via neck suction (NS; Eckberg & Sleight,
1992).
The introduction of the variable pressure neck collar
(Ernsting & Perry, 1957) and its subsequent mechanical
modification (Eckberg et al. 1975) and customized
computer-controlled operation (Pawelczyk & Raven,
1989) provided the ability to obtain stimulus–response
logistic function curves of the carotid baroreflex (CBR)
control of HR and mean arterial pressure (MAP) in
humans at rest and during exercise. However, the initial
NP/NS protocol, which used rapid pulses of 500 ms
duration of NP and NS of approximately 40, 40, 40,
40, 25, 10, 0–5, −20, −35, −50 and −65 mmHg
during an end-expiratory breath hold, was technically and
physiologically impractical during exercise when the R–R
interval approached 500 ms (i.e. HR of 120 beats min−1 ).
Additionally, a 12–15 s end-expiratory breath hold during
moderate to high intensity exercise can result in activation
of the autonomic nervous system via chemoreceptor reflex
activation. Therefore, in order to overcome these technical
complications, Potts et al. (1993) developed a protocol
using more sustained pulses of NP and NS (5 s pulses),
which were brief enough to establish reflex responses via
the parasympathetic and the sympathetic arms of the
CBR without resulting in counteractive responses from
the aortic baroreceptors. During the application of these
techniques, recording peak HR and ABP responses and
developing the best-fit linear or logistic regression model
of the response data to assess G max or sensitivity of the


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Exp Physiol 91.1 pp 37–49 Baroreflex resetting during exercise
reflex was the method of choice (Potts et al. 1993; Papelier
et al. 1994).
The development of two dynamic measurement
techniques: (i) the sequence technique (Iellamo et al.
1997); and (ii) the estimate of a transfer function gain
using linear dynamic analysis of HR and ABP variability
(Zhang et al. 2001), have added to the complexity of
interpretation of data with regards to baroreflex function
during exercise. A point to consider is that these dynamic
techniques only determine the gain around the operating
point of the reflex, which is very different from the
maximal gain obtained from logistic modelling of the full
stimulus–response curve. This is an important distinction,
considering that the operating point of the reflex moves
during exercise. As such, the reduced gain reported during
exercise in studies using dynamic analyses probably reflects
the movement of the operating point away from the
centring point and closer to the threshold of the reflex,
and so to a locus of lesser gain. Therefore, it is the gain
around the operating point that is reduced during exercise,
while the maximal gain of the stimulus–response curve is
well preserved. Another complexity involved in assessing
baroreflex function is the physiological interpretation
of representing changes in heart period as the R–R
interval (RRI) or as changes in HR because of the
inverse exponential relationship between HR and RRI.
This is of particular importance when baseline heart
rates are different, such as between rest and exercise as
described in detail previously (O’Leary, 1996; Raven et al.
1997).
Mechanisms by which the carotid baroreflex responds
to changes in pressure
In order to establish that HR and MAP changes in response
to NP and NS are indeed representative of the carotid–
cardiac (CBR–HR) and carotid–vasomotor (CBR–MAP)
reflexes, respectively, measurements of stroke volume (SV)
and muscle sympathetic nerve activity (MSNA) and the
calculation of changes in systemic vascular conductance at
rest and during exercise have been obtained (Fadel et al.
2001; Ogoh et al. 2002a, 2003; Wray et al. 2004). At rest,
measures of SV, using Doppler ultrasound technology,
were found to be unchanged during both the rapid pulse
train protocol and the 5 s pulses of NP and NS (Levine et al.
1990; Ogoh et al. 2002a). More importantly, during cycling
exercise up to heart rates of 150 beats min−1 estimations
of changes in SV from the impedance changes of the
arterial blood flow velocity curve obtained from beat-
to-beat measurements of arterial pressure (Modelflow
method) were not different during the 5 s NP/NS protocol
(Ogoh et al. 2003). Identification of an unchanged SV
during the NP/NS stimuli of the carotid baroreceptors
demonstrated that the reflex changes in HR (CBR–HR)


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39
represent the carotid baroreflex control of cardiac output
(i.e. the carotid–cardiac arm of the CBR).
The determination of SV during the application of
NP and NS permitted the calculation of percentage
contributions of cardiac output ( Q̇) and systemic vascular
conductance (SVC) to the CBR-mediated change in MAP
at rest and during exercise (Ogoh et al. 2002a, 2003).
Considering that peak changes in HR occur early in
response to neck pressure and suction (i.e. 3–4 s, when
MAP only changes (2–3 mmHg) and return to baseline at
the time of the peak MAP response (Raven et al. 1997;
Fadel et al. 2003), the percentage contributions of CO
and SVC have been calculated not only at the time of
the peak MAP response, but also at the time of the peak
HR response. These data calculations have indicated that
the rapid changes in HR cause subsequent changes in Q̇
that are solely responsible for the initial reflex-mediated
change in MAP (i.e. at the time of the peak HR response).
At the same time, SVC changed minimally during these
first few seconds, but changed dramatically at the time of
the peak MAP response (i.e. 6–8 s from initiation of the
stimulus), when the change in MAP evoked by NP and NS
was primarily the consequence of alterations in SVC (see
Fig. 2). These data demonstrated that alterations in SVC
predominate over Q̇ in mediating CBR changes in MAP.
A further demonstration of the importance of
peripheral vascular changes for CBR function was the
profound effect that NP and NS had on MSNA (Rea
& Eckberg, 1987; Fadel et al. 2001). In fact, percentage
changes in MSNA measured during NP/NS at rest
Q SVC
Percentage contribution at time of
100
peak CBR-MAP response
50
0
Rest Ex 90 Ex 120 Ex 150
Figure 2. The percentage contribution of cardiac output ( Q̇) and
systemic vascular conductance (SVC) to the CBR-mediated
changes in MAP at rest and during cycling exercise at heart
rates of 90 (Ex 90), 120 (Ex 120) and 150 beats min−1 (Ex 150)
These responses were derived at the time of the peak CBR–MAP
response and clearly demonstrate the dominant contribution of
reflex-induced alterations in systemic vascular conductance to the
CBR-mediated change in MAP both at rest and during exercise.
(Adapted from Ogoh et al. 2003).
40 P. B. Raven and others Exp Physiol 91.1 pp 37–49

were similar to those obtained during 50% V̇O2 peak arm
cycling exercise (Fadel et al. 2001). More recent work
directly measuring blood flow using Doppler ultrasound
technology has identified the dominant effect that the
CBR has on leg vascular conductance (LVC). Using one
legged knee extension exercise, Keller et al. (2003, 2004)
measured CBR-mediated changes in LVC in both a non-
exercising and an exercising leg. Although LVC responses
were attenuated in the exercising leg compared to the
non-exercising leg, it was clear from these data that the
capacity of the CBR to regulate blood pressure depends
critically on its ability to alter vascular tone both at rest
and during exercise. Subsequent work using dynamic
linear analysis of the HR, MAP, MSNA, femoral blood
velocity and tissue oxygenation responses to 0.1 Hz NP
stimuli of the CBR over a 5 min period confirmed the
importance of vascular changes in CBR function (Wray
et al. 2004). Perhaps more importantly, these data also
demonstrated simultaneous entrainment of all CBR end-
organ measurements, clearly linking the CBR-mediated
alterations in MSNA to changes in the upstream (femoral
blood velocity) and downstream (tissue oxygenation)
vasculature. Collectively, these findings indicate that peak
changes in MAP in response to NP and NS are a measure
of vasomotor reflexes and confirm the basis of the carotid–
vasomotor (CBR–MAP) arm of the CBR.
Arterial baroreflex resetting during exercise
Several investigations have demonstrated resetting of
the baroreflex stimulus–response curve during exercise,
indicating a vertical upward shift on the response arm
and a lateral rightward shift to higher operating pressures.
Functionally this allows the baroreflex to operate at the
prevailing ABP evoked by the exercise (Fig. 3).
In two investigations using slightly different NP/NS
protocols at rest and during bicycle exercise at work
intensities ranging from 25 to 75% V̇O2 peak exercise,
it was clearly demonstrated that both the carotid–
cardiac (CBR–HR) and the carotid–vasomotor (CBR–
MAP) reflex function curves had been ‘reset’ (Potts et al.
1993; Papelier et al. 1994). An additional investigation,
using a combination of leg and arm exercise, identified
that this resetting of the CBR–HR and CBR–MAP function
curves was maintained up to 100% V̇O2 peak (Norton et al.
1999a). Collectively, these investigations identified that the
upward and rightward resetting of the CBR function curves
occurred in direct relation to the intensity of dynamic

A B
OP
OP
CP
Mean Arterial Pressure

CP
Ex (heavy)
Heart Rate

Ex (heavy)
Ex (moderate)
Ex (moderate)

Ex (light) Ex (light)

Rest Rest

ECSP ECSP

Operating Range Operating Range

Figure 3. A schematic summary of the carotid–cardiac (CBR–HR) and carotid–vasomotor (CBR–MAP)

resetting that occurs from rest to heavy exercise
The reader is referred to Potts et al. (1993), Norton et al. (1999a), Fadel et al. (2001), and Ogoh et al. (2003,
2005). A, the CBR–HR function curve is progressively reset from rest to heavy exercise. As workload increases the
operating point (OP) moves to a lower arterial pressure than that associated with the centring point (CP) and
therefore operates with a reduced gain. The CP gain or maximal gain of the CBR–HR reflex remains unchanged
from rest to heavy exercise. The operating range and responding range are progressively reduced as the exercise
workload increases. Both the relocation of the OP and reductions in operating and responding ranges have been
found to be linked to the progressive vagal withdrawal associated with the increases in exercise intensity. B, the
CBR–MAP function curve is also progressively reset from rest to heavy exercise. Although some studies have
identified a relocation of the OP away from the CP to a point of reduced gain on the CBR–MAP function curve as
the workload increases, other studies were unable to confirm this finding. Possible reasons for these inconsistencies
are described in the text. The operating range, responding range and maximal gain of the CBR–MAP function curve
are unchanged with increasing exercise workloads.

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Exp Physiol 91.1 pp 37–49 Baroreflex resetting during exercise
exercise without a change in G max or sensitivity (see Fig. 3)
(Potts et al. 1993; Papelier et al. 1994; Norton et al. 1999a).
This resetting of the CBR without a change in sensitivity
has also been reported during isometric (static) exercise
(Ebert, 1986). The importance of this resetting of the
arterial baroreflex during exercise has been demonstrated
using the instrumented exercising rabbit model. In these
experiments ABP was maintained at resting values using
nitroprusside infusions during the first 60 s of treadmill
exercise. Both HR and renal sympathetic nerve activity
were immediately increased above that of control exercise
conditions, indicating that the ABR normally buffers
these responses to adequately control ABP during exercise
(DiCarlo & Bishop, 1992). Similar findings have been
reported in humans, in that HR and MSNA responses
to static handgrip exercise were greatly elevated when
nitroprusside was infused to prevent the exercise-induced
increase in ABP (Scherrer et al. 1990).
Another fundamental alteration associated with
baroreflex resetting during exercise is the movement of the
operating point away from the centring point and closer to
the threshold of the reflex (see Fig. 3). This is an important
change with regard to baroreflex control because it places
the baroreflex in a more optimal position to counteract
hypertensive stimuli. However, once the operating point
moves away from the centring point (i.e. its point of
maximal sensitivity, or G max ) the reflex operates at a
lower MAP and a reduced gain. Most studies employing
the NP/NS protocol have reported this movement of the
operating point away from the centring point, with the
exception of one investigation that was only able to fit
response data to a linear regression model (Papelier et al.
1994) instead of the typical logistic function model (Potts
et al. 1993; Norton et al. 1999a). It is important to note
that this relocation of the operating point to a position
of reduced gain occurs in direct relation to the exercise
intensity. We believe this movement of the operating point
provides both a physiological and a mathematical basis
for the differences in interpretation of data from those
studies which suggest that the arterial baroreceptors are
‘switched off’ or are working with a reduced gain compared
to those that suggest they are ‘reset’ and functioning with
a similar gain as at rest. In this regard, if a study only
examines the gain at the operating point, for example
when using dynamic analyses, then the results will indicate
a reduced baroreflex gain during exercise. However, if a
study incorporates full stimulus–response curves than the
ability to identify the maximal gain at the centring point
will indicate a preserved baroreflex gain.
Dynamic analysis techniques such as the sequence
technique have been used to gain an understanding of
the vagal withdrawal associated with the transition from
rest to progressive increases in exercise workload (Ogoh
et al. 2005). Interpretation of data from these studies has
indicated that vagal control of the heart was virtually


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absent at heart rates > 120 beats min−1 and therefore the
cardiac arterial baroreflex appeared to be ‘switched off’.
In contrast, linear transfer function analysis between HR
variability and SBP variability in the low frequency domain
identified a gradual reduction in baroreflex sensitivity to
heart rates > 150 beats min−1 , reflective of the progressive
reduction in vagally mediated reflex control of the heart
as workload increased (Ogoh et al. 2005). An elegant
animal experiment verified the presence of a decreasing
vagal influence on the heart up to maximal exercise
(O’Leary & Seamans, 1993). Recently, CBR resetting from
rest to bicycle exercise at heart rates of 90, 120 and
150 beats min−1 , along with the documented relocation of
the CBR–HR operating point and reduced HR responding
range with increasing exercise intensity, was found to result
from vagal withdrawal. Furthermore, the sensitivity at the
operating point obtained from the logistic modelling of the
HR responses to NP and NS was similar to the sensitivity
of the cardiac baroreflex assessed by the two methods
of dynamic analysis (Ogoh et al. 2005). Importantly, the
sensitivity at the centreing point (G max ) of the CBR–
HR curve was not different from rest. Nevertheless, of
physiological importance is that the relocation of the
operating point to a position of reduced gain on the
modelled CBR–HR function curve reflects the intensity-
related decreases in vagal tone, which leads to a progressive
operational reduction in the baroreflex control of the heart
from rest to maximal exercise.
With regard to the baroreflex control of the vasculature
(CBR–MAP (vasomotor) curve), a consistent relocation
of the operating point of the CBR–MAP function curve
away from the centring point and closer to the threshold
to a point of lesser gain is not present for all of
the NP/NS modelling investigations (Potts et al. 1993;
Norton et al. 1999a; Gallagher et al. 2001b; Ogoh
et al. 2003, 2005). Furthermore, there is no evidence
of a reduction in the response range of the CBR–MAP
function curve from rest to maximal exercise (Norton et al.
1999a; Ogoh et al. 2003, 2005). However, in subsequent
investigations, in which arm exercise was added to leg
exercise, the operating point of regulated ABP was either
increased above or was maintained at the ABP of the
leg exercise (Secher et al. 1977; Norton et al. 1999a). In
contrast, when leg exercise was added to arm exercise
the operating point of ABP was reduced below that of
the arm exercise alone (Volianitis et al. 2003). These data
suggest that the amount of central blood volume and its
consequent cardiopulmonary baroreceptor load provides
modulatory neural information to the establishment of the
operating carotid ABP. This concept has been preliminarily
confirmed by assessing CBR function during rest, arm
exercise only, leg exercise only and the combination
of arm and leg exercise (Volianitis et al. 2004). The
importance of a modulatory role of central blood volume
in establishing the ABP to be regulated during exercise
42 P. B. Raven and others
in healthy humans remains unknown. However, this
interaction may provide an explanation for the lack of
consistency in observing a relocation of the operating
point of the CBR–MAP function curve. In these studies,
exercise protocols consisted of cycling exercise in the
70 deg-back supported semirecumbent position (Potts
et al. 1993), upright and supine cycling (Volianitis et al.
Central Command
Overall Resetting
OP
CP
HR or MAP
Ex
Con
ECSP
Exercise Pressor Reflex
Figure 4. A schematic representation of the neural mechanisms
mediating carotid arterial baroreflex resetting in the transition
from rest (Con) to exercise (Ex)
As discussed in the text, this schematic identifies that independent
activation of central command and the exercise pressor reflex, or a
combination of both, results in an upward and rightward resetting of
the CBR–HR and CBR–MAP function curves. ECSP, estimated carotid
sinus pressure.
Exp Physiol 91.1 pp 37–49
2004) or seated leg kicking (Keller et al. 2004; Wray
et al. 2004). Therefore, the differences in the movement
of the operating point on the CBR–MAP curve may be
due to the substantial differences in subject positioning
and its subsequent effect on central blood volume and
cardiopulmonary baroreceptor loading.
Neural mechanisms involved in baroreflex resetting
during exercise
Having established that the CBR is reset during dynamic
exercise to functionally operate around the prevailing
ABP elicited by the exercise workload, investigation of the
integrated neural mechanisms involved in accomplishing
this resetting required the a priori establishment of a
hypothetical model. Based upon the extensive background
of investigation of muscle chemoreflex activation of the
sympathetic nervous system in animal and human models,
Rowell & O’Leary (1990) formulated a working hypothesis
of arterial baroreflex resetting during exercise and its
regulation of sympathetic nerve activity. They proposed
that central command and the muscle metaboreflex
(i.e. the chemical component of the exercise pressor reflex)
mediate the resetting of the arterial baroreflex during
exercise. Using hypothetical baroreflex function curves,
they suggested that central command was responsible
for relocating the initial operating point of the CBR
(i.e. the prevailing blood pressure) to higher arterial blood
pressures, the consequence being a resetting of the entire
stimulus–response curve around the newly established
operating pressure. In addition, vertical shifts in the
stimulus–response curves could be produced via activation
of the muscle metaboreflex to raise the dependent
variable (e.g. MAP or MSNA), without changing the initial
operating point of the reflex. Together, the concerted
actions of both central command and the muscle
metaboreflex would produce a rightward and upward
relocation of the baroreflex curve during exercise, thereby
preserving the functionality of the reflex during exercise.
As illustrated in Fig. 3, both the CBR–HR and the CBR–
MAP function curves were reset in a similar fashion,
suggesting to us that both central command and the
exercise pressor reflex independently or in combination
were involved in resetting the carotid–cardiac and carotid–
vasomotor reflex function curves during exercise; see
Fig. 4.
In testing the proposed hypothetical model of resetting,
animal and human experiments require an integrative
experimental design which directly activates central
command or the exercise pressor reflex (EPR), while
holding the neural information arising from the other
neural input constant. The following sections summarize
recent experiments that have tested this hypothetical
model.


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Exp Physiol 91.1 pp 37–49 Baroreflex resetting during exercise 43

Central command activation augmented. However, a limitation of this protocol was

that, in addition to increasing central command activation,
The experiments that have demonstrated CBR resetting
the 2% lignocaine may also have interrupted afferent
using NP and NS were generally performed during 20 min
neural information emanating from the exercising muscle
steady-state dynamic exercise in attempts to establish
(i.e. EPR input). Unfortunately, this compromised the
a constant central command and EPR input into the
interpretation of these data.
cardiovascular control centres (Potts et al. 1993; Norton
To address this issue, Gallagher et al. (2001a)
et al. 1999a; Ogoh et al. 2002b). However, during
used a curare derivative (Norcuron) to induce partial
prolonged (60 min) cycling exercise cardiovascular drift
neuromuscular blockade and muscle weakness. The
occurs and results in progressive increases in HR, oxygen
systemic administration of Norcuron to reduce muscle
uptake and ratings of perceived exertion (RPE), indicating
strength by ∼50% caused a further resetting of the
progressive increases in central command activation
CBR–HR and CBR–MAP function curves upward on
(Norton et al. 1999b). The importance of this progressive
the response arm and rightward to higher arterial
increase in central command was the finding that the CBR
pressures in comparison to exercise without blockade
was progressively reset in direct relation to the increased
(Fig. 5A). This augmentation in CBR resetting occurred
activation of central command (as mainly determined
without any change in the maximal gain of the reflex.
from increases in RPE and HR). The elevation in central
In such experiments that produce muscle weakness,
command input was presumably related to increases in
issues related to subject anxiety and possible activation
muscle fibre recruitment in order to maintain the same
of central neural pathways contributing to the elicited
power output throughout 60 min of exercise. However,
physiological responses remains a caveat of interpretation
as an increasing number of single muscle fibres became
(see Williamson et al.’s review regarding this issue).
fatigued, skeletal muscle afferents were probably activated,
Furthermore, because the muscle weakening experiments
and so increases in the EPR input to the cardiovascular
require volitional increases in central command, it is
centres may also have contributed to this progressive
unclear whether the act of CBR resetting is a culmination
resetting of the CBR during prolonged exercise.
of active physiological mechanisms or whether it results
To address the question of the influence of central
primarily from the active increase in arterial blood
command on baroreflex resetting during exercise more
pressure.
specifically, several studies have attempted to manipulate
Involuntary manipulation of central command was
central command input directly by either reducing or
achieved previously in a classical experimental protocol
increasing central command activation during exercise. In
using agonist tendon vibration to assist in producing a
order to minimize central command input, Iellamo et al.
given muscle tension and antagonist tendon vibration
(1997) assessed baroreflex function during involuntary
to inhibit the development of a given muscle tension
muscle contraction. During electrically induced exercise
(Goodwin et al. 1972). In this experimental protocol
the sensitivity of the relationship between systolic arterial
agonist tendon vibration reduces central command
pressure and R–R interval was decreased, suggesting that
input and antagonist tendon vibration increases central
central command was necessary to preserve baroreflex
command input, while the same static workload is
sensitivity. However, it should be noted that these findings
performed. Recently, by reducing central command input
were unable to be reproduced by Carrington & White
with agonist tendon vibration during knee extension
(2002). A plausible explanation for these contradictory
exercise, Ogoh et al. (2002b) reported a shifting of the
findings may be the use of dynamic analyses techniques to
CBR–HR and CBR–MAP function curves downward
assess baroreflex sensitivity. Moreover, these procedures
on the response arm and leftward to lower arterial
do not allow the full baroreflex function curve to be
pressures in comparison to the location of the curves
determined.
during exercise without vibration (Fig. 5A). Conversely,
In an attempt to address this concern, Querry et al.
increasing central command input with antagonist tendon
(2001) constructed full baroreflex function curves during
vibration further reset the CBR function curves upward
static and dynamic handgrip exercise performed before
and rightward compared to exercise without vibration.
and after partial axillary blockade (2% lignocaine) to block
Additional experiments in which the actual muscle
motor fibres and increase central command input. Under
contration was performed at the same rating of perceived
blockade conditions, dynamic and static exercise relocated
exertion (i.e. equal central command input) observed
the CBR–HR and CBR–MAP function curves upward
during the agonist and antagonist protocols identified
on the response arm and rightward to higher arterial
that the CBR–HR resetting was a result of 100% central
pressures to a greater magnitude than during exercise
command activation while CBR–MAP resetting resulted
without blockade (Fig. 5A). In addition, the operating
from a 50%:50% activation of central command and the
point of the carotid–cardiac curve was shifted closer to
exercise pressor reflex (Ogoh et al. 2002b).
the threshold of the reflex when central command was

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44 P. B. Raven and others Exp Physiol 91.1 pp 37–49

In summary, these human investigations support the
concept that CBR resetting occurs during exercise as
a result of central command activation and are in
agreement with the elegant animal work in which
stimulation of the mesencephalic locomotor region (a
brain anatomical site potentially involved in central
command) was reported to reset the arterial baroreflex
(Waldrop et al. 1996; McIlveen et al. 2001). The
involvement of central command in resetting the CBR–
HR reflex is not surprising and is consistent with previous

A
OP
OP

Mean arterial pressure

+CC
+CC
Heart rate

Con-Ex Con-Ex

-CC -CC

ECSP ECSP

OP
Mean arterial pressure

-EPR Con-Ex +EPR

Heart rate

+EPR

OP

Con-Ex

-EPR
-

ECSP ECSP

Figure 5. A schematic representation of the alterations in carotid–cardiac (HR) and carotid–vasomotor

(MAP) stimulus–response curves caused by changes in central command (CC) and the exercise pressor
reflex (EPR)
A, resetting of the CBR–HR and CBR–MAP function curves during exercise is further reset upward and rightward
with increased activation of central command (+CC) and downward and leftward with decreased central command
input (−CC). Reflex gain is not altered with changes in CC. The OP is reset upward closer to threshold with increased
CC and away from threshold downward with decreases in CC. B, CBR–MAP resetting during exercise is further
reset upward and rightward during augmentation of the EPR (+EPR) and downward and leftward with inhibition
of the EPR (−EPR). Carotid–cardiac baroreflex resetting during exercise is only further reset rightward with +EPR
and leftward with −EPR. Reflex gain and OP are not altered with either +EPR or −EPR. Con-Ex, control exercise;
ECSP, estimated carotid sinus pressure. (Reproduced with permission from Fadel et al. 2004.)

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Exp Physiol 91.1 pp 37–49 Baroreflex resetting during exercise
work (Mitchell, 1990). Additionally, it is important to note
that many of the human exercise experiments which used
exercise intensities below 30% maximal intensity identified
involvement of central command in the resetting of the
CBR–MAP function curve (Gallagher et al. 2001a; Querry
et al. 2001; Ogoh et al. 2002b). These data strongly suggest
that central command regulates sympathetic nerve activity
from rest to exercise without regard to exercise intensity.
Finally, in contrast to the initial working hypothesis, in
which activation of central command would selectively
shift the CBR function curve to higher arterial blood
pressures (Rowell & O’Leary, 1990), the findings from
these studies indicate that central command produces not
only a rightward relocation to higher pressures but also
an upward relocation of the curve on the response arm.
That is, central command activation results in the classic
upward and rightward resetting of the baroreflex during
exercise.
Exercise pressor reflex
The involvement of the exercise pressor reflex in the
neural control of the circulation during exercise has
been the subject of a number of excellent reviews
(Mitchell et al. 1981; Rowell et al. 1996). Its postulated
involvement in arterial baroreflex resetting was a result
of experiments involving muscle chemoreflex activation
(Rowell & O’Leary, 1990; Kaufman & Forster, 1996; Rowell
et al. 1996; Carrington et al. 2001; Fisher & White,
2004) and sino-aortic baroreceptor denervation (Sheriff
et al. 1990). As noted above (Page 6, Neural mechanisms
involved in baroreflex resetting during exercize), activation
of the muscle metaboreflex was hypothesized to result
in vertical shifts in the baroreflex function curves which
would raise the dependent variable (e.g. MAP), without
changing the initial operating point of the reflex.
Several studies have attempted to examine the
involvement of the exercise pressor reflex in baroreflex
resetting during exercise. Papelier et al. (1997) reported
that the selective activation of the muscle metaboreflex
(metabolic component of the exercise pressor reflex)
with postexercise ischaemia altered the sensitivity of
the carotid–vasomotor arm of CBR without altering
the sensitivity of the carotid–cardiac arm. Others have
reported that activation of the exercise pressor reflex with
lower-body positive pressure resets the cardiac component
of the CBR and increases its sensitivity (Eiken et al.
1992). However, lower body positive pressure has also
been shown to decrease the sensitivity of the CBR (Shi
et al. 1993). Nevertheless, these studies clearly indicate
that the exercise pressor reflex can modulate baroreflex
function.
In a subsequent study, Gallagher et al. (2001b)
used medical antishock trousers to stimulate both the
mechanoreceptors and the metaboreceptors of the exercise


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45
pressor reflex and reported that the CBR–MAP function
curve was reset upward on the response arm and rightward
to higher carotid sinus pressures compared to control
exercise (Fig. 5B). However, the carotid–cardiac reflex
function curve was relocated rightward towards higher
carotid sinus pressures only. These relocations of the CBR
function curves occurred without any changes in maximal
sensitivity or any relocation of the operating point when
compared with control exercise (Gallagher et al. 2001b).
The latter findings are in direct contrast to those when
central command was selectively altered and indicate that
the exercise pressor reflex is not involved in relocation of
the operating point of either arm of the baroreflex.
Further studies using epidural anaesthesia to reduce
EPR activation during static and dynamic exercise resulted
in a relocation of the CBR–MAP function curve downward
on the response arm and leftward to lower carotid sinus
pressure compared to control exercise (Fig. 5B; Smith et al.
2003). During static exercise, the carotid–cardiac reflex
curve was likewise relocated; however, it only exhibited a
leftward shift on the response arm. These changes occurred
without alterations in maximal sensitivity, the response
range of the CBR, or the relocation of the operating point
away from the centring point. Collectively, these studies
indicate that the exercise pressor reflex is capable of actively
resetting the CBR–MAP function curve during exercise,
but it appears only to modulate the carotid–cardiac reflex
function curve. Additionally, the exercise pressor reflex has
little effect on the relocation of the operating point of the
CBR during exercise.
Animal experiments have provided invaluable
information regarding exercise pressor reflex control,
mainly using static muscle contraction protocols as well
as infusions of chemical substances into the vasculature
of locomotor muscles and passive muscle stretch to
activate the metabolic and mechanical components of
the EPR, respectively (Wildenthal et al. 1968; Kaufman
et al. 1982; Tallarida et al. 1982; Rybicki et al. 1984;
Stebbins & Longhurst, 1985; Stebbins et al. 1988; Sinoway
et al. 1994; Hanna et al. 2002; Li & Sinoway, 2002). In
a recent study, McIlveen et al. (2001) provided clear
evidence that the exercise pressor reflex is capable of
resetting the CBR in decerebrate unanaesthetized cats.
Similar results were originally reported by Coote &
Dodds (1976). Furthermore, using techniques of nerve
degeneration and markers of synaptic stimulation, such
as c-fos oncoprotein and antergrade staining (Waldrop
et al. 1996; Potts et al. 1998), both baroreceptor and
skeletal muscle somatosensory afferents have been
demonstrated to colocate within the nucleus tractus
solitarii, an essential cardiovascular regulatory centre
within the central nervous system (Fig. 6). Collectively,
these animal investigations establish the anatomical and
physiological foundation of baroreflex resetting associated
with activation of the exercise pressor reflex.
46 P. B. Raven and others Exp Physiol 91.1 pp 37–49

Summary physiological responses to exercise. For example, in

experiments in which simulated exercise was performed
Over the past 25 years both animal and human
using electrical stimulation (no central command) with
experimentation have verified that the arterial baroreflex
the afferent sensing pathways from the exercise pressor
is reset from rest to exercise in direct relation to the
reflex blocked pharmacologically or absent due to spinal
work intensity. In addition, more recent studies have
injury, blood pressure did not increase (Strange et al.
indicated that activation of central command or the
1993; Winchester et al. 2000). This occurred even though
exercise pressor reflex, independently or in combination, is
a functioning arterial baroreflex was present.
required for the arterial baroreflex to be reset with exercise.
Selective activation of central command has been
Perhaps more importantly, input from all three neural
shown to relocate CBR–HR and CBR–MAP function
mechanisms (central command, the exercise pressor reflex
curves upward on the response arm and rightward
and the arterial baroreflex) are requisite for the normal
to higher arterial pressures without any change in

EXERCISE PRESSOR REFLEX

Mechano- and Metabo-receptors CENTRAL COMMAND

Cardiopulmonary
Baroreceptors

MAP
SNA
SNA SNA
SNA
NTS
NTS

PSNA
PSNA PSNA
PSNA

MAP
Operating Range
Exercise

Rest Exercise

Afferent Nerve Firing

MAP

MAP
Operating Range

Rest Aortic and Carotid

Baroreceptors

Figure 6. A hypothetical model of the neural integration associated with the resetting of the vasomotor
arm of the arterial baroreflex that occurs from rest to exercise
The inset boxes labelled Rest and Exercise identify the outcome of the central resetting that occurs within the
nucleus tractus solitarii (NTS). The primary determinant of this resetting is the feedforward control arising from an
activated central command, with modulatory feedback control arising from the exercise pressor reflex as well as
input from the cardiopulmonary baroreceptors reflecting central blood volume status. The central resetting appears
to re-establish the operating range of the reflex at the exercise intensity-related increase in arterial baroreceptor
afferent neural traffic, which is reflective of the increase in arterial blood pressure. This resetting and relocation of
the operating point ( e) away from the centring point (•) to a position of reduced gain results from the integration
within the NTS and subsequent modulation of efferent sympathetic and parasympathetic neural control to the
vasculature and the heart, respectively. Importantly, the relocation of the operating point places the baroreflex in
a more optimal position to counteract hypertensive stimuli during exercise, as indicated by the arrows within the
inset boxes. MAP, mean arterial pressure; SNA, sympathetic nerve activity; PSNA, parasympathetic nerve activity.

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Exp Physiol 91.1 pp 37–49 Baroreflex resetting during exercise
maximal sensitivity. Furthermore, reductions in central
command relocated both arms of the CBR downward
on the response arm and leftward to lower arterial
pressures without any change in maximal sensitivity.
Several studies have indicated that the progressive vagal
withdrawal accompanying increases in exercise intensity
was the primary mechanism responsible for this central
command-induced CBR–HR resetting, as well as the
relocation of the operating point away from the centring
point and the reduction in the response range of the
carotid–cardiac baroreflex. With regard to exercise pressor
reflex involvement in baroreflex resetting, the EPR has
been shown to reset the CBR–MAP function curve upward
on the response arm and rightward to higher arterial
pressures, whereas it resets the CBR–HR curve only
rightward to higher arterial pressures. The use of epidural
anaesthesia to reduce exercise pressor reflex activation
during exercise resulted in a relocation of the CBR–
MAP function curve downward on the response arm and
leftward to lower carotid sinus pressures compared to
control exercise. Finally, differences in exercise posture,
and so differences in central blood volume and its
consequent load on the cardiopulmonary baroreceptors,
appear to modulate sympathetic nerve activity during
exercise. These postural alterations in cardiopulmonary
baroreceptor load may also be responsible for the
inconsistency of reports concerning the relocation of the
operating point of the CBR–MAP function curve.
Overall, our current understanding of the mechanisms
for baroreflex resetting during exercise is that the
feedforward mechanism of central command is probably
the primary regulator of baroreflex resetting, while the
negative feedback mechanism of the exercise pressor reflex
is more of a modulator of resetting. In summarizing the
findings reported in this review, we present a hypothetical
model in Fig. 6, depicting the neural integration associated
with the resetting of the arterial baroreflex that occurs from
rest to exercise.
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Acknowledgements
The majority of the work by the authors in this review was
supported by NIH grant no. HL-045547 to Dr Raven and by the
Danish National Research Foundation (grant no. 504-14).
Author’s present address
P. J. Fadel: Department of Medical Pharmacology and Physiology,
University of Missouri, One Hospital Drive, MA 516, Columbia,
MO 65212, USA.