Handbook of Clinical Neurology, Vol.

156 (3rd series)

Thermoregulation: From Basic Neuroscience to Clinical Neurology, Part I
A.A. Romanovsky, Editor
https://doi.org/10.1016/B978-0-444-63912-7.00025-4
Copyright © 2018 Elsevier B.V. All rights reserved

Chapter 25

Interactions between body fluid homeostasis

and thermoregulation in humans

HIROSHI NOSE*, YOSHI-ICHIRO KAMIJO, AND SHIZUE MASUKI

Department of Sports Medical Sciences, Shinshu University Graduate School of Medicine, Institute for Biomedical Sciences,
Shinshu University, Matsumoto, Japan

Abstract
Humans are unique in their ability to control body temperature with a large amount of skin blood flow and
sweat rate while exercising in an upright position. However, cutaneous vasodilation in the body reduces
total peripheral resistance and blood pooling in cutaneous veins decreases venous return to the heart and
cardiac filling pressure. In addition, hypovolemia by sweating accelerates the reduction in cardiac filling
pressure. These may threaten the maintenance of blood pressure if they are not compensated for. To prevent
this, cutaneous vasodilation and sweat rate are suppressed by baroreflexes or hyperosmolality with dehy-
dration. These mechanisms suppress heat dissipation, accelerate the increase in body temperature, and
sometimes cause heat stroke. As a countermeasure to prevent this, we have recommended glucose elec-
trolyte solutions but recently found that aerobic training with carbohydrate + whey protein supplementa-
tion markedly improves heat dissipation mechanisms by plasma volume expansion. In this article, we will
discuss the importance of improving body fluid homeostasis for thermoregulation under heat stress in
humans and the strategy to attain this.

1981a, b; Mack et al., 1987, 1988, 1995) and/or

INTRODUCTION
The interactions between body fluid and body temper-
ature regulations were classically reported by Adolph
and his colleagues (1947) in a model utilizing soldiers
after they had marched in the desert. These authors
suggested that rectal temperature at rest in a thermoneu-
tral condition increased with body weight loss due to
sweating. The results clearly showed that body temper-
ature regulation in a hot environment is influenced
by body fluid loss with sweating. Since the osmolality
of sweat is lower than that of the body, a large amount
of sweat loss causes hyperosmolality as well as
hypovolemia (Nose et al., 1988b), which in turn sup-
press heat dissipation by skin blood flow and sweating
through baroreceptors (Nadel et al., 1980; Fortney et al.,
central osmoreceptors (Fortney et al.,1984; Takamata
et al., 1995a, b, 1997). This suppression may accelerate
the increase in body temperature and, sometimes,
cause heat-related illness (Nakai, 2015). In this
review, we will describe how hypovolemia and hyper-
osmolality after thermal dehydration suppress heat
dissipation. In addition, we propose a strategy to
improve thermoregulation by using glucose and elec-
trolyte supplementation (Nose et al., 1988b, c;
Kamijo et al., 2012) and increasing baseline plasma vol-
ume (Okazaki et al., 2009a, b; Goto et al., 2010), which
might be helpful not only for young people participating
in sport, but also for older people who experience a
higher incidence of heat illness than young people
(Nakai, 2015).

*Correspondence to: Hiroshi Nose, M.D., Ph.D., Department of Sports Medical Sciences, Shinshu University Graduate School of
Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan. Tel: +81-263-37-2681, Fax: +81-263-34-6721, E-mail: nosehir@shinshu-u.ac.jp
418 H. NOSE ET AL.
PLASMA VOLUME AND PLASMA
OSMOLALITY DURING EXERCISE
IN A HOT ENVIRONMENT
First, we describe the degree of change in plasma volume
and plasma osmolality at a given sweat loss after thermal
dehydration. Human subjects can secrete 1.5–2.0 liters of
sweat per hour maximum in active young people, while
in active older people, the volume is decreased to approx-
imately one-third of that in active young people (Okazaki
et al., 2002, 2009b; Ichinose et al., 2005; Goto et al.,
2010). Once sweat water comes from plasma, the loss
is immediately buffered by fluid shifted from the intersti-
tial space according to the Starling force in the capillary
area, and then the interstitial fluid loss is buffered by the
fluid shifted from the intracellular space according to the
crystal osmotic gradient between the spaces.
As a result, Costill et al. (1976) suggested in young
subjects that, when total sweat loss is 2.2% of body
weight, 60% of the loss comes from the interstitial fluid
space, 30% from the intracellular fluid space, and 10%
from plasma, with an 6 mosmol/kgH2O increase in
plasma osmolality. Similarly, they suggested that, when
total sweat loss is 4.1% of body weight, 38% of the loss
comes from the interstitial fluid space, 52% from the
intracellular space, and 10% from plasma volume, with
15 mosmol/kgH2O increase in plasma osmolality.
Finally, when total sweat loss is 5.8% of body weight,
39% of the loss comes from the interstitial space, 50%
from the intracellular space, and 11% from plasma vol-
ume, with 20 mosmol/kgH2O increase in plasma
osmolality. Thus, plasma volume loss is equivalent to
10% body weight loss from sweating regardless of total
sweat volume, whereas plasma osmolality increases by
3 mosmol/kgH2O for every 1% body weight lost with
sweating.
Also, plasma volume decreases and plasma osmolal-
ity increases within a few minutes of the start of exercise
before sweating starts. These changes occur in propor-
tion to exercise intensity relative to individual maximal
aerobic capacity, and at maximal intensity, the decrease
in plasma volume reaches 20% of baseline plasma
volume (Convertino et al., 1983; Nose et al., 1991),
which is equivalent to 500–600 mL of plasma volume,
and then, the increase in plasma osmolality reaches
20 mosmol/kg H2O (Nose et al., 1991; Takamata
et al., 2000).
Regarding the mechanisms, Sjogaard et al. (1985)
suggested that the fluid shift out of plasma during knee
extension exercise was caused by increased capillary
pressure at lower exercise intensity, and at higher exer-
cise intensity, the accumulation of osmoles, i.e., lactic
acid in the contracting muscles, causes osmotic move-
ment from the intra- to extracellular spaces to decrease
plasma volume. Thus, the hypovolemia and hyperosmol-
ality due to sweating override those changes by exercise
alone (Costill and Fink, 1974; Fortney et al., 1981a).
EFFECTS OF VARIED PLASMA VOLUME
ON THERMOREGULATION
Human beings are unique in that they exercise in an
upright position and 70% of blood volume is located
below the heart (Rowell, 1986). Therefore, the reduced
venous return to the heart with hypovolemia or blood
pooling in cutaneous vessels in an upright position
decreases cardiac filling pressure and cardiac stroke
volume and, if not compensated for, may threaten the
maintenance of arterial blood pressure (Gauer and
Thron, 1965; Fortney et al., 1983, Nose et al., 1994).
To prevent this, feedback mechanisms work to control
skin blood flow and sweating.
For example, cutaneous vasodilation is suppressed
during exercise in an upright position (Brengelmann
et al., 1977). Further, suppression is enhanced by
acute hypovolemia with administration of diuretics
(Nadel et al., 1980; Kamijo and Nose, 2006)
(Fig. 25.1A). In contrast, the suppression is attenuated
with acute blood expansion (Fortney et al., 1981b;
Nose et al., 1990). Additionally, Ikegawa et al. (2011)
suggested that, although the cutaneous vasodilation
response was improved after 5 days of aerobic training,
the improvement was eliminated when the plasma vol-
ume expansion after training was reduced to baseline
prior to training. These results suggest that blood volume
is likely involved in controlling skin blood flow via
baroreflexes.
In addition, the exercise intensity-dependent hypovo-
lemia might be involved in the suppression of cutaneous
vasodilation in hyperthermia. Miyagawa et al. (2011)
suggested that enhanced plasma volume loss with
increased relative exercise intensity in a hypoxic
condition enhanced an upward shift of the esophageal
temperature (Tes) threshold for cutaneous vasodilation
but the shift was in accordance with the value by
diuretic-induced hypovolemia in normoxia. Thus, not
only hypohydration-induced hypovolemia but also
exercise-induced hypovolemia suppresses cutaneous
vasodilation.
As for the afferent path of baroreflexes, cardiopulmo-
nary mechanoreceptors have been suggested. Johnson
et al. (1974) examined the effects of graded lower-body
negative pressure on hyperthermic cutaneous vasodila-
tion in resting subjects in a supine position and suggested
that cutaneous vasodilation in hyperthermia was sup-
pressed when venous return to the heart was reduced
by using a lower-body negative-pressure method to the
level prior to arterial pressure decrease. Previously, we
 BODY FLUID HOMEOSTASIS AND THERMOREGULATION IN HUMANS 419
0.30 A 0.30 B
FVCmax
0.25 0.25

0.20 0.20

Forearm skin vascular conductance, units

0.15 Control 0.15

0.10 0.10 NPVHOS

LPVIOS
0.05 0.05
THFVC
0.00 0.00
36.6 37.0 37.4 37.8 38.2 38.6 36.6 37.0 37.4 37.8 38.2 38.6

0.30
C
0.25

0.20

0.15

0.10
LPCHOS
0.05

0.00
36.6 37.0 37.4 37.8 38.2 38.6
Esophageal temperature, °C
Fig. 25.1. The forearm cutaneous vascular conductance at a given increase in esophageal temperature during exercise at 60% of
peak aerobic capacity is shown as the mean and standard error bars for 6 subjects. (A) Control, normovolemia, and iso-osmolality
(open circles); LPVIOS, hypovolemia and iso-osmolality (inverted open triangles); (B) NPVHOS, normovolemia and hyperosmol-
ality (closed circles); (C) LPVHOS, hypovolemia and hyperosmolality (inverted closed triangles); THFVC, the Tes threshold for cuta-
neous vasodilation; FVCmax, maximal skin vascular conductance. (From Kamijo Y, Nose H (2006) Heat illness during working and
preventive considerations from body fluid homeostasisis. Indust Health 44: 345–358, with permission from National Institute of
Occupational Safety and Health, Japan.)

measured right atrial pressure and forearm skin blood In contrast, Kamijo et al. (2005) suggested that acute
flow during exercise in a hot environment and suggested diuretic-induced hypovolemia did not reduce sweat rate
that right atrial pressure decreased as skin vascular con- on the chest during exercise in a hot environment.
ductance increased, while arterial pressure remained Furthermore, exercise intensity-induced hypovolemia
unchanged (Nose et al., 1994). did not cause an upward shift in the Tes threshold for
More recently, Nagashima et al. (1998) suggested sweating (Miyagawa et al., 2011). In contrast, Ikegawa
that, when the reduction in venous return to the heart with et al. (2011) suggested that the Tes threshold for sweating
increased skin blood flow was prevented by negative- increased after 5 days of endurance training in a hot envi-
pressure breathing, the reduction in skin vascular ronment, but the increase was partially attenuated when
conductance above a Tes of 37.5°C was prevented, the training-induced plasma volume expansion was
and more importantly, during this period, arterial pres- reduced to the baseline prior to training. Thus, whether
sure decreased by 10 mmHg. These results suggest that acute isotonic hypovolemia reduces the sweat rate
the attenuation of skin vascular conductance in hypovo- remains controversial.
lemia is caused by unloading of cardiopulmonary
baroreceptors rather than of arterial baroreceptors.
There have been several studies suggesting that
EFFECTS OF HYPEROSMOLALITY
hypovolemia suppresses sweat rate. Fortney et al.
ON THERMOREGULATION
(1981a) examined the effects of acute diuretic-induced
hypovolemia on local sweat rate during exercise in a Hyperosmolality due to hypotonic sweat loss is
hot environment and suggested that, although the Tes suggested to reduce skin blood flow (Fig. 25.1B) and
threshold for sweating remained unchanged, the slopes sweat rate (Senay, 1968; Nielsen et al., 1974). Fortney
of the sweat rate response to increased Tes on the chest et al. (1984) examined the effects of hypertonic saline-
and the forearm were reduced. More recently, Mack induced hyperosmolality on skin blood flow and
et al. (1995) suggested that sweat rate was reduced by sweat rate during exercise in a hot environment and sug-
lower-body negative pressure during exercise. gested that an 10-mosmol/kg H2O increase in plasma
420 H. NOSE ET AL.
osmolality increased the Tes thresholds for both cutane-
ous vasodilation and sweating by 0.22°C.
Takamata et al. (1997) quantified the effect of plasma
osmolality on the Tes threshold for cutaneous vasodilation
and sweating in passively heated subjects by immersing
their lower legs in 42°C water. They suggested that, when
plasma osmolality was increased by 3, 9, and 15 mosmol/
kgH2O by intravenous infusion of hypertonic saline solu-
tions, the Tes thresholds for cutaneous vasodilation and
sweating increased linearly by 0.044°C and 0.034°C per
1 mosmol/kgH2O increase, respectively. In contrast, there
were no effects of hyperosmolality on the slopes of the
cutaneous vasodilation and sweat rate in response to a
given increase in Tes.
Accordingly, Takamata et al. (1998) examined
whether exercise intensity-dependent hyperosmolality
contributes to the exercise intensity-dependent increase
in the Tes threshold for cutaneous vasodilation (Mack
et al., 1994), and suggested that the upward shift in the
Tes threshold at a given increase in plasma osmolality
during graded exercise was identical to that in subjects
passively heated by hypertonic saline infusion. These
results suggest that the exercise intensity-dependent
increase in the Tes threshold for cutaneous vasodilation
was explained by an exercise intensity-dependent
increase in plasma osmolality.
Notably, because plasma volume decreases as exer-
cise intensity increases (Nose et al., 1991), and also
because the decrease was enhanced when relative exer-
cise intensity increased in hypoxia (Miyagawa et al.,
2011), the exercise intensity-dependent increase in Tes
threshold would be caused by baroreceptor unloading
rather than by hyperosmolality. Moreover, the accumu-
lation of lactic acid in contracting muscles suppresses
cutaneous vasodilation via metaboreceptors in the mus-
cles (Crandall et al., 1998). To elucidate the effects of
hyperosmolality on the exercise intensity-dependent
upward shift of the Tes threshold for cutaneous vasodi-
lation, we needed to exclude effects of exercise
intensity-dependent hypovolemia.
Mitono et al. (2005) examined whether the exercise
intensity-dependent upward shift of the Tes threshold
for cutaneous vasodilation was eliminated when the
hyperosmolality was prevented by hypotonic saline infu-
sion before exercise. They determined the Tes threshold
during three exercise trials in young subjects: 30% peak
aerobic capacity with no saline infusion, 65% peak aer-
obic capacity with isotonic infusion to adjust the plasma
volume profile during exercise similar to that in the
hypotonic infusion trial, and 65% peak aerobic capacity
with hypotonic infusion. Then, they determined the rela-
tionship between plasma osmolality and the Tes thresh-
old. They found that the point determined by plasma
osmolality and the Tes threshold at 65% peak aerobic
capacity with hypotonic infusion was located on the line
of the relationship between plasma osmolality and the Tes
thresholds determined from the trials at 30% peak
aerobic capacity and 65% peak aerobic capacity with
isotonic infusion. They confirmed that there were no sig-
nificant differences in the plasma volume profile and
lactate concentration in plasma during exercise between
the isotonic and hypotonic infusion trials at 65% peak
aerobic capacity. These results suggest that exercise
intensity-dependent hyperosmolality significantly con-
tributes to the increase of the Tes threshold for cutaneous
vasodilation.
Regarding the significance of the hyperosmotic sup-
pression of cutaneous vasodilation, a few studies have
suggested that the suppression works to maintain arterial
pressure during exercise. Nakajima et al. (1998) exam-
ined the effects of hypovolemia and/or hyperosmolality
on skin blood flow and arterial pressure regulation in
awake and resting rats exposed to heat and suggested that
the arterial pressure decreased as the tail vascular con-
ductance increased in hyperthermic, hypovolemic, and
iso-osmotic rats; however, it remained unchanged when
tail vasodilation was suppressed in hyperthermic, hypo-
volemic, and hyperosmotic rats. Since intravascular dose
of a vasopressin V1 antagonist evoked no change in the
responses, they concluded that the hyperosmotic sup-
pression of tail vasodilation was caused by activated
sympathetic nervous activity outflow to tail vessels to
maintain arterial pressure in a hypovolemic condition.
Kamijo et al. (2005) assessed this issue in human sub-
jects. They measured forearm skin vascular conductance
and arterial blood pressure during exercise for 60 minutes
in a hot environment in four conditions: normovolemia +
iso-osmolality, normovolemia + hyperosmolality, hypo-
volemia + iso-osmolality, and hypovolemia + hyperos-
molality. In addition, at 40 minutes of exercise, when
the Tes reached steady state, they had subjects drink a
glass of water warmed to the current Tes and continued
the measurements for the following 20 minutes in each
trial. They suggested that, immediately after the water
intake, mean arterial pressure fell by 5 mmHg with
an increase in forearm skin vascular conductance by
10–20% of the level prior to drinking in the hyperosmol-
ality conditions but not in the iso-osmolality conditions.
The mechanisms for the release of the hyperosmotic
suppression of cutaneous vasodilation by drinking even
a small amount of water in the hyperosmotic conditions
are discussed in subsequent sections (Takamata et al.,
1995a; Kamijo et al., 2005). These results suggest that
hyperosmolality significantly contributes to the mainte-
nance of arterial pressure by suppressing cutaneous vaso-
dilation in dehydration. In addition, this mechanism may
work to supply more blood flow to the active muscles by
reducing skin blood flow at the onset of exercise when an
 BODY FLUID HOMEOSTASIS AND THERMOREGULATION IN HUMANS
increase in cardiac output is too limited to provide the
amount of oxygen demanded by contracting muscles
(Takamata et al., 1998; Mitono et al., 2005).
On the other hand, there have been few studies on the
significance of hyperosmotic suppression of the sweat
rate; however, from a teleologic consideration, the sup-
pression may occur to prevent hypotension due to exces-
sive hypovolemia with dehydration, although at the
sacrifice of body temperature regulation.
INTERACTIVE EFFECTS OF VARIED
PLASMA VOLUME AND
HYPEROSMOLALITY ON
THERMOREGULATION
As mentioned above, since hypotonic sweat loss induces
not only hypovolemia but also hyperosmolality, they
might have interactive effects on cutaneous vasodilation.
Nakajima et al. (1998) assessed this issue in awake and
resting rats exposed to heat and suggested that hypovo-
lemia alone decreased maximal tail vascular conduc-
tance, whereas it did not alter the rectal temperature
threshold for tail cutaneous vasodilation. On the other
hand, hypovolemia + hyperosmolality increased the rec-
tal temperature threshold for tail vasodilation, whereas it
did not decrease maximal tail vascular conductance more
than that observed in hypovolemia alone. These results
suggest that the suppression of tail cutaneous vasodila-
tion by hypovolemia and hyperosmolality is independent
of each other, and the effects are additive in rats.
More recently, Kamijo et al. (2001) assessed this issue
in human subjects exercising in a hot environment. As
shown in Figure 25.1, they suggested that hypovolemia
alone decreased maximal forearm vascular conductance
and caused an upward shift of the Tes threshold for
cutaneous vasodilation. On the other hand, hyperosmol-
ality alone increased the Tes threshold for cutaneous
vasodilation, whereas the maximal forearm skin vascular
conductance was not suppressed within the range of Tes
observed. Finally, although hypovolemia + hyperosmol-
ality decreased the maximal skin vascular conductance
by the same degree as was seen in hypovolemia alone,
the increase in the Tes threshold for cutaneous vasodila-
tion remained almost at the same level as that of both
the hypovolemia alone and hyperosmolality alone
conditions. These results suggest that the effects of hypo-
volemia and hyperosmolality on maximal skin vascular
conductance are independent, as was observed in rats,
whereas the effects on the Tes threshold for cutaneous
vasodilation are interactive. Although the precise reasons
for the discrepancy between rat and human studies
remain unknown, it might be caused by higher contribu-
tion of baroreflexes to control of skin blood flow in
humans than in other animal species.
421
The significance of the interactive effects of hypovo-
lemia and hyperosmolality on cutaneous vasodilation has
been suggested in human subjects who are acclimatized
to a hot environment and secrete diluted sweat (Sawka
et al., 1996). Experimentally, Nose et al. (1988a) exam-
ined the hypothesis that plasma water loss due to sweat-
ing might depend on the sodium (Na+) concentration in
sweat and suggested that hypotonic sweat loss is advan-
tageous for the maintenance of plasma volume because
the larger amount of free-water loss in sweat causes a
greater increase in osmolality in body fluid, which, in
turn, moves more fluid volume from the intracellular
space to the vascular space. For example, 75% of sweat
loss comes from the extracellular space in a subject
secreting 110 mM NaCl in sweat compared with only
45% in a subject secreting 30 mM NaCl in sweat. In other
words, when sweat loss is 1400 mL in both subjects, the
subject secreting 110 mM NaCl in sweat loses 315 mL of
plasma volume, whereas the subject secreting 30 mM
NaCl in sweat loses only 105 mL. Thus, although the
attenuated plasma volume loss at a given sweat loss by
secreting diluted sweat may be advantageous to maintain
cutaneous blood flow according to the baroreflex mech-
anisms stated above, the enhanced hyperosmolality
might suppress cutaneous vasodilation.
In response to these conflicting stories, Takamata
et al. (2001) examined the hypothesis that the suppres-
sion effects of plasma hyperosmolality on thermoregula-
tory responses to increased Tes would be inhibited in
heat-acclimatized individuals and that this attenuation
is one of the mechanisms that allows heat-acclimatized
individuals to maintain higher cutaneous blood flow
and sweating during progressive dehydration induced
by extensive sweating. They determined the Tes thresh-
olds for cutaneous vasodilation and sweating during
passive warming by immersing their lower legs into
water at 42°C in isotonic and hyperosmotic conditions
that were attained by isotonic and hypertonic saline
infusion, respectively. The isotonic infusion was done
to adjust the plasma volume to be similar between the
conditions prior to warming. The results suggested that
the hyperosmolality-induced upward shifts in the Tes
thresholds for cutaneous vasodilation and sweating were
both reduced in subjects secreting diluted sweat, who
were assumed to be acclimatized to a hot environment
(Sawka et al., 1996).
Ichinose et al. (2005) examined the effects of aerobic
training-induced hypervolemia on the sensitivity of the
upward shift in Tes thresholds for cutaneous vasodilation
and sweating by assessing hyperosmolality during
exercise. They suggested that 10 days of endurance train-
ing in a warm environment (30°C) increased blood
volume by 4% on average, followed by a reduction in
the Tes threshold for cutaneous vasodilation by 0.26°C
422 H. NOSE ET AL.
and an increase in the maximal cutaneous vascular con-
ductance by 20% but not in the Tes threshold for sweat-
ing and the maximal sweat rate. Although there was no
significant change in the baseline plasma osmolality after
training, the sensitivity of the upward shift of the Tes
threshold for cutaneous vasodilation in response to hyper-
tonic saline infusion was reduced by 50% compared with
that before training. Moreover, the individual reductions
in the upward shift of the Tes threshold for cutaneous vaso-
dilation by hypertonic saline infusion were highly and
inversely correlated with the increase in blood volume
after training. In contrast, there was no alteration in the
sensitivity of the increase in the Tes threshold for sweating
after training. These results suggest that the downward
shift in the Tes threshold for cutaneous vasodilation after
aerobic training was partially explained by the blunted
sensitivity to hyperosmolality, which occurred in propor-
tion to the increase in blood volume.
Taken together, the hyperosmotic suppression of
cutaneous vasodilation works to maintain arterial pres-
sure; however, the sensitivity varies with plasma volume,
and the significance of the hyperosmotic suppression of
sweat rate remains unknown.
SYMPATHETIC NERVE ACTIVITY FOR
CONTROLLING CUTANEOUS BLOOD
FLOW AND SWEAT RATE
Although cutaneous vasodilation in hyperthermia is sup-
pressed during hypovolemia, the efferent neural pathway
mediating this suppression has not been identified. To
determine this, Kamijo et al. (2011) measured skin sym-
pathetic nerve activity (SSNA) with microneurography
from the peroneal nerve, skin blood flow on the ipsilat-
eral dorsal foot with a laser Doppler flowmeter, mean
arterial pressure, and Tes before and during 45 minutes
of passive warming in healthy young subjects in normo-
volemic and hypovolemic conditions, respectively. Hypo-
volemia was achieved by diuretic administration. The
authors suggested that cutaneous vascular conductance,
SSNA burst frequency, and total SSNA obtained from
the rectified and filtered SSNA signal increased as Tes
increased during warming in both groups. In contrast,
although the increase in cutaneous vascular conductance
was suppressed in hypovolemia compared with normovo-
lemia, there was no significant difference in the increase in
burst frequency and total SSNA between groups.
However, as shown in Figure 25.2, using an alterna-
tive analysis that constructed spike incidence histograms
from the original signal using 0.05-second bins during
the 5 seconds following a given R wave, they found an
SSNA component that was synchronized with the car-
diac cycle. This component increased with an increase
in Tes, and the increase was significantly suppressed by
hypovolemia. The researchers found that the incidence
of the component synchronized with the cardiac cycle
was highly correlated with the cutaneous vascular con-
ductance (Fig. 25.3A), whereas that of the component
that was not synchronized with cardiac cycle was highly
correlated with sweat rate (Fig. 25.3B) when they were
pooled in normovolemia and hypovolemia. They con-
cluded that the hypovolemic suppression of cutaneous
vasodilation during hyperthermia was caused by a reduc-
tion in the SSNA component synchronized with cardiac
cycle. These results suggest that the SSNA component
synchronized with the cardiac cycle is an active cutane-
ous vasodilator signal in response to hyperthermia that is
modified by baroreflexes.
Recently, Ogawa et al. (2017) examined whether the
SSNA component synchronized with the cardiac cycle
was involved in the maintenance of arterial pressure in
hyperthermia by the suppression of cutaneous vasodila-
tion when the posture changes from a supine to upright
position. They continuously measured the SSNA in
young men before and after passive warming with a per-
fusion suit, during which periods the posture was chan-
ged from supine to 30° head-up tilt positions. During
these periods, they also simultaneously measured muscle
sympathetic nerve activity (MSNA), to distinguish the
SSNA from the MSNA, and the right atrial volume with
echocardiography because the baroreceptors for the
reflexes are reportedly located in the right atrium
(Nagashima et al., 1998).
The results suggested that the SSNA component syn-
chronized with the cardiac cycle increased in hyperther-
mia but decreased with postural change and that the
peak incidence of the SSNA component was observed
0.7–0.8 seconds after the peak right atrial volume,
which can be explained by the conduction velocity of
the SSNA reported previously (Fagius and Wallin,
1980). Furthermore, the SSNA component during the
postural change before and after warming was highly
and positively correlated with the cutaneous vascular
conductance, but the MSNA component was not
(Fig. 25.4). These results suggest that the SSNA com-
ponent synchronized with the cardiac cycle appeared
to be involved in suppressing cutaneous vasodilation
during postural change.
Regarding the possible mechanisms for generating
the SSNA component synchronized with the cardiac
cycle (Kamijo et al., 2011; Ogawa et al., 2017), the affer-
ent signals from atrial baroreceptors may control the
SSNA component outflow in the “cardiovascular center”
in the medulla like a gate, passing the efferent signals
when baroreceptors are loaded, while blocking them
when they are unloaded, as suggested in the control
MSNA outflow which synchronizes with arterial pres-
sure waves (Kienbaum et al., 2001).
 BODY FLUID HOMEOSTASIS AND THERMOREGULATION IN HUMANS 423

Fig. 25.2. (A) Electrocardiogram (ECG: upper) and original recording of skin sympathetic nerve activity (SSNA: bottom). (B)
R-wave and spike incidence histograms from the time of a given R-wave of the ECG in the 5-second window in 0.05-second bins.
The numbers 1, 2, and 3 above the histograms correspond to the numbers of the 5-second windows in (A). (C) The averaged histo-
grams for every minute (left) and the autocorrelation functions (right) of the R-wave incidence (upper) and SSNA spike incidence
(bottom). TR and TS, the peak-to-peak intervals of the R-wave and the SSNA spike incidences, respectively, determined from the
averaged histograms of each minute in individual subjects by auto-correlation analysis; TRS, the time between a given peak of
R-wave incidence and the following peak of SSNA spike incidence by cross-correlation analysis. (D) The upper (UA) and lower
(LA) areas, the components that are synchronized and not synchronized with the cardiac cycle, respectively, are shown in one
subject from the normovolemia (Nor, left) and hypovolemia (Hypo, right) group at 1 minute of the thermoneutral condition (upper)
and the 545th minute in the warming condition (bottom). TR is identical to TS. The UA is suppressed by hypovolemia; TRS is in
accordance with the value estimated from the electric conduction velocity of SSNA (Fagius and Wallin, 1980), assuming that the
incidence of the SSNA component synchronized with the cardiac cycle is triggered by inflation of the right atrial wall. (Reproduced
from Kamijo Y, Okada Y, Ikegawa S et al. (2011) Skin sympathetic nerave activity component synchronizing with cardiac cycle is
involved in hypovolemic suppression of cutaneous vasodilatation in hyperthermia. J Physiol 589: 6231–6242, with permission
from the Physiological Society.)

As shown in Figure 25.5, the efferent signals for cuta-
neous vasodilation and sweating likely originate from the
“thermoregulatory center” in the hypothalamus where
thermosensitive neurons are reportedly observed (Silva
and Boulant, 1984; Nakashima et al., 1985). Kamijo
et al. (2009) examined the effects of hyperosmolality
on the SSNA components that were synchronized and
not synchronized with the cardiac cycle in passively
warmed young men in the supine position. They sug-
gested that both components increased as Tes increased,
but the increases in both SSNA components were
reduced by hyperosmolality with the suppression of cuta-
neous vasodilation and sweat rate.
Takamata et al. (1995a) examined the effects of drink-
ing a glass of water on the suppression of sweating in pas-
sively warmed and hyperosmotic subjects and suggested
that the stimulation of the oropharyngeal mechanorecep-
tors by the drinking released the suppression of the sweat
rate, accompanied by a rapid fall in plasma vasopressin
concentration.
Again, Kamijo et al. (2005) suggested that the stimu-
lation of oropharyngeal mechanoreceptors by drinking
424
30.0
ΔCVC, %max
15.0
0.0
0 5 10
A ΔUAmin, counts min-1
0.4
ΔSR, mg min-1 cm-2
0.2
0.0
0 20 40 60
B ΔLAmin, counts min-1
Fig. 25.3. Relationship between the changes in cutaneous vas-
cular conductance (DCVC) from thermoneutral values and those
in the upper area per minute (DUAmin), the skin sympathetic
nerve activity (SSNA) component synchronized with the cardiac
cycle (A) and between the changes in the sweat rate (DSR) and
those in the lower area per minute (DLAmin), the SSNA compo-
nent not synchronized with the cardiac cycle (B) from thermo-
neutral values during warming in normovolemia (open circles)
and hypovolemia (closed circles) conditions. Values are means
and standard error bars for 10 subjects determined every minute.
Standard error bars are shown at 0, 15, 30, and 40 minutes of
warming. (Reproduced from Kamijo Y, Okada Y, Ikegawa
S et al. (2011) Skin sympathetic nerave activity component
synchronizing with cardiac cycle is involved in hypovolemic
suppression of cutaneous vasodilatation in hyperthermia.
J Physiol 589: 6231–6242, with permission from the Physiolog-
ical Society).
released the suppression of cutaneous vasodilation and
sweating in hyperosmotic subjects exercising in a hot
environment. These results suggest that hyperosmolality
suppressed the efferent signals for cutaneous vasodila-
tion and sweating originating from the thermosensitive
neurons in the hypothalamus by stimulating the neurons
directly (Nakashima et al., 1985) or indirectly through
oropharyngeal mechanoreceptors or central osmorecep-
tors (Takamata et al., 1995a).
The efferent signals for cutaneous vasodilation and
sweating might be enhanced by thermal stress lasting
H. NOSE ET AL.
for a given period. Takeno et al. (2001) compared the
effects of exercise training on the cutaneous vasodilation
response at 60% peak aerobic capacity for 1 hour/day for
10 days in a hot environment (30°C) and in a cool envi-
ronment (20°C) and suggested that the Tes threshold for
cutaneous vasodilation and the slope of the cutaneous
vasodilation response to increased Tes during exercise
increased more after training in a hot environment than
in a cool environment, although the plasma volume
increased similarly in both thermal conditions. These
results suggest that thermal stress is the primary factor
15
that enhances the efferent signals for cutaneous vasodi-
lation, and plasma volume expansion is the secondary
factor that modulates the signals. Although they did
not report the sweat rate response to the increased Tes
in the study, the sensitivity was likely more enhanced
after training in a hot environment than in a cool
environment.
Taken together, as shown in Figure 25.5, the efferent
signals for cutaneous vasodilation originate from the
thermoregulatory center in the hypothalamus, are passed
along to the cardiovascular center in the medulla, being
modified by the afferent signals from the cardiopulmo-
nary baroreceptors, and reach skin vessels as the SSNA
80 component that is synchronized with the cardiac cycle.
The sudomotor signals originate from the thermoregula-
tory center in the hypothalamus, are less modified by the
baroreflexes than the signals for cutaneous vasodilation
at the cardiovascular center in the medulla, and reach the
sweat glands as the SSNA component that is not synchro-
nized with the cardiac cycle. Hyperosmolality may
suppress the thermosensitive neuronal activity in the
thermoregulatory center of the hypothalamus directly
or indirectly to decrease the SSNA outflow for cutaneous
vasodilation and sweating.
COUNTERMEASURES AGAINST
HEAT-RELATED ILLNESS
The incidence of heat illness has rapidly increased to
50,000 per year during the midsummer for the last
decade in Japan as the atmospheric temperature (Ta)
has increased. Notably, 50% of incidences occurred
in people aged 65 and older (Nakai, 2015) due to reduced
cardiovascular performance and body temperature regu-
lation under heat stress with aging (Okazaki et al., 2002;
Goto et al., 2010).
One of the countermeasures against heat-related
illness is to ingest glucose and electrolyte solutions to
prevent hypovolemia and hyperosmolality to counteract
large-volume sweat loss. Nose et al. (1988b, c) examined
the effects of diluted salt solutions on the restoration of
body fluids from thermal dehydration in young subjects,
 BODY FLUID HOMEOSTASIS AND THERMOREGULATION IN HUMANS 425
SSNA MSNA
100 100

CVCchest, %max 50 50

0 0
0 20 40 0 40 80
A B
UAmin, counts min−1
Fig. 25.4. Relationship between the upper area per minute (UAmin) for the skin sympathetic nerve activity (SSNA) (A) or muscle
sympathetic nerve activity (MSNA) (B) components synchronized with the cardiac cycle and cutaneous vascular conductance on
the chest (CVCchest) in supine and head-up tilt positions in normothermia and hyperthermia conditions, respectively. The data
points for individual subjects are connected with dotted-line arrows from the supine (open circles) to the head-up tilt position
(closed circles) in the normothermia condition and then from the supine (open triangles) to the head-up tilt position (closed tri-
angles) in hyperthermia condition. DUAmin, upper area per minute. (Reproduced from Ogawa Y, Kmaijo Y, Ikegawa S et al. (2017)
Effects of postural change from supine to head-up tilt on the skin sympathetic nerve activity synchronized with the cardiac cycle in
warmed men. J Physiol 569: 1185–1200, with permission from the Physiological Society.)

central osmoreceptorsin thermosensitive neurons at the
hypothalamus thermoregulatory center in
hypothalamus
oropharyngeal mechanoreceptors
the gate for the signals at
cardiopulmonary baroreceptors the cardiovascular center
in medulla
active cutaneous vasodilator sudomotor
Cutaneous vasodilation Sweating
Fig. 25.5. Interactions between body fluid homeostasis and
thermoregulation in humans. Thermosensitive neurons in the
hypothalamus generate efferent signals for cutaneous vasodi-
lation and sweating in hyperthermia. Signals for active cutane-
ous vasodilation pass through the gate in the cardiovascular
center at the medulla, which is open when cardiopulmonary
mechanoreceptors are loaded and closed when they are
unloaded. In contrast, the sudomotor is likely not modified
in the cardiovascular center. The activation of thermosensitive
neurons is suppressed by hyperosmolality sensed by the central
osmoreceptors in hypothalamus; however, the suppression is
released by activated oropharyngeal mechanoreceptors such
as by drinking.
and the results suggested that these solutions accelerated
restoration by maintaining thirst and reducing urine flow
to recover plasma volume more rapidly than did tap
water. Kamijo et al. (2012) examined the role of glucose
in glucose and electrolyte solutions commercially avail-
able for the restoration of body fluid and suggested that
the presence of glucose not only accelerated the intestinal
absorption rate of ingested fluid but also reduced urine
flow by increasing renal reabsorption rates of body fluids
in the kidney. These results suggest that glucose and elec-
trolyte solution ingestion is advantageous for rapid
recovery of plasma volume from thermal dehydration.
However, body fluid recovery using glucose and electro-
lyte solution ingestion takes some time (Nose et al.,
1988b; Kamijo et al., 2012), so it might increase the risk
of heat-related illness in the field.
To solve this issue, Okazaki et al. (2002) examined the
effects of aerobic exercise – cycling training at 20°C at
50–80% peak aerobic capacity for 60 minutes/day,
3 days/week, for 18 weeks – on thermoregulatory func-
tions in older men aged 64 years. They suggested that
the Tes threshold for cutaneous vasodilation and sweating
increased slightly, but the slopes of the cutaneous vaso-
dilation and sweat rate responses to increased Tes
remained unchanged after training; however, when they
analyzed the relationships between the changes in
plasma volume and the slopes after training in individual
subjects, they found that both slopes increased in sub-
jects in whom the plasma volume increased, while they
decreased in subjects in whom the plasma volume
decreased with significant positive correlations between
them. Accordingly, these results suggested that plasma
volume expansion by exercise training is a key factor
to improve thermoregulation in older men.
426 H. NOSE ET AL.
As a next step, they examined the hypothesis that car-
bohydrate + whey protein supplementation immediately
after exercise would enhance the exercise-induced
plasma volume expansion (Okazaki et al., 2009a)
because the albumin synthesis rate in the liver was report-
edly enhanced after a bout of exercise (Nagashima
et al., 2000). They suggested that carbohydrate (35
grams) + whey protein (10 grams) supplementation
immediately after a bout of aerobic exercise enhanced
the plasma volume and albumin content in plasma start-
ing at the first hour after exercise and maintained the
level until the 23rd hour in young and older men.
Accordingly, they examined the effects of the supple-
mentation during aerobic training at 60–75% of peak
aerobic capacity for 1 hour/day, 3 days/week for 8 weeks
and suggested that, after training, both the plasma
volume and plasma albumin content increased by 6%,
accompanied by increases in the slopes of the cutaneous
vasodilation and sweat rate responses to increased Tes
by 80 and 18%, respectively, with a slight downward
shift in the Tes threshold for cutaneous vasodilation in
the supplementation group, while all of the variables
remained unchanged in the control group (Fig. 25.6).
These results suggest that carbohydrate + whey protein
supplementation during aerobic training accelerates heat
adaptation by increasing plasma volume in older people.
However, the increase in plasma volume to improve
thermoregulation by this regimen would worsen the
symptoms of hypertension, from which more than 60%
of people aged 65 years and older suffer. To assess this
issue, Kataoka et al. (2016) examined the effects of
plasma volume expansion by carbohydrate (15 grams)
+ whey protein (10 grams) supplementation immediately
after daily exercise for 1 hour/day, 3 days/week, and for
8 weeks on the symptoms in hypertensive older people.
They confirmed that after 8 weeks of training both the
plasma volume and albumin content in plasma increased
by 7% with improved thermoregulatory responses in the
supplementation group, while none of these changes
occurred in the control group that received 25 grams
glucose supplementation after daily exercise. In addition,
they suggested that, despite the increase in plasma vol-
ume in the carbohydrate + whey protein supplementation
group, the mean arterial pressure rather decreased at
rest and during exercise with increased sensitivity for
baroreflex control of the heart rate by a similar degree
as that observed in the control group. Moreover, in the
carbohydrate + whey protein supplementation group,
carotid arterial compliance significantly increased, while
there was no change in the control group. These results
suggest that cardiovascular adaptation to aerobic training
is high enough to buffer against the possible increase in
arterial pressure by plasma volume expansion in hyper-
tensive older people.
1.4
DSR/DTes, mg.cm-2·min-1.°C-1
1.2
1.0
0.8
0.6
0.4
0.2
0.0
Pre Post Pre Post
CNT Pro-CHO
14
DFVC/DTes, units·°C-1
12
10
8
6
4
2
0
Pre Post Pre Post
CNT Pro-CHO
Fig. 25.6. The sensitivities of the chest sweat rate and forearm
cutaneous vascular conductance responses to increased esoph-
ageal temperature (Tes) during exercise at 60% VO2peak at 30°C
for 20 minutes in older subjects. DSR, changes in sweat rate;
DFVC, changes in forearm vascular conductance; CNT, aero-
bic training group with placebo supplementation at 60–75%
VO2peak at 19°C, 60 min/day, 3 days/week, for 8 weeks; Pro-
CHO, aerobic training group with carbohydrate (35 grams)
+ whey protein (10 grams) supplementation with the same
training protocol as the CNT group. Values are the means
and standard error bars for 7 subjects. Open and closed col-
umns indicate before and after training, respectively. (Repro-
duced from Okazaki K, Ichinose T, Mitono H, et al. (2009b)
Impact of protein and carbohydrate supplementation on
plasma volume expansion and thermoregulatory adaptation
by aerobic training in older men. J Appl Physiol 107:
725–733, with permission from the American Physiological
Society.)
In addition to older people, Goto et al. (2010) exam-
ined the effects of carbohydrate (70 grams) + whey
protein (20 grams) supplementation, twofold higher than
was given in older people (Okazaki et al., 2002), on
plasma volume and thermoregulatory responses in
young subjects immediately after daily exercise at 70%
peak aerobic capacity for 30 minutes/day for 5 consecu-
tive days. These results suggested that plasma volume
increased in the supplementation group by twofold that
in the placebo group, and the sensitivities of the cutane-
ous vasodilation and sweat rate responses to increased Tes
during exercise increased in the supplementation group
by threefold that in the placebo group (Fig. 25.7).
 BODY FLUID HOMEOSTASIS AND THERMOREGULATION IN HUMANS 427

1.8
CNT Pro-CHO
1.6
1.4

SR, mg.cm-2·min-1
1.2
1.0
0.8
0.6
0.4
0.2
0.0

A B
30

25

20
FVC, units

15

10

0
36.5 37.0 37.5 38.0 38.5 36.5 37.0 37.5 38.0 38.5
C Tes, ˚C D Tes, ˚C

Fig. 25.7. Chest sweat rate (SR) (A and B) and forearm cutaneous vascular conductance (FVC) (C and D) responses to increased
esophageal temperature (Tes) during aerobic exercise at 60% VO2peak at 30°C for 30 minutes before and after 5-day aerobic training
in young subjects. CNT, aerobic training group with placebo supplementation at 65% VO2peak at 30°C, 60 min/day, for 5 consec-
utive days; Pro-CHO, aerobic training group with carbohydrate (70 grams) + whey protein (20 grams) supplementation with the
same training protocol as the CNT group. (Reproduced from Goto M, Okazaki K, Kamijo Y, et al. (2010) Protein and carbohydrate
supplementation during 5-day aerobic training enhanced plasma volume expansion and thermosregulatory adaptation in young
men. J Appl Physiol 109: 1247–1255, with permission from the American Physiological Society.)

Again, Ikegawa et al. (2011) suggested that the
enhanced cutaneous vasodilation sensitivity to increased
Tes by aerobic training with the carbohydrate + whey pro-
tein supplementation was reversed to baseline before
training when the increased plasma volume was reduced
to baseline levels by diuretic administration, while the
enhanced sweat rate response was only partially reversed.
These results suggest that carbohydrate + whey protein
supplementation during aerobic training is an effective
regimen to accelerate heat adaptation by plasma volume
expansion in the short term in older and young people.
Finally, aerobic training itself might be a countermea-
sure against heat-related illness in heart failure patients.
Cui et al. (2013) examined the total SSNA, cutaneous
vasodilation, and sweat rate responses to passive warm-
ing in older patients with chronic heart failure and found
that, although the sweat rate and total SSNA responses
were not significantly different from those of the age-
matched control group, the cutaneous vasodilation
response was markedly attenuated. Accordingly, they
suggested that the attenuated cutaneous vasodilator
response in heart failure patients was not attributable to
a reduction in SSNA outflow to the skin but was rather
due to a reduced responsiveness of the skin vessels to
total SSNA.
However, the successful identification of an active
skin vasodilator system (Kamijo et al., 2011; Ogawa
et al., 2017) suggests another hypothesis, i.e., that the
attenuated cutaneous vasodilation is at least in part
caused by an attenuated increase in the SSNA component
that is synchronized with the cardiac cycle due to reduced
sensitivity of the atrial baroreceptors with increased stiff-
ness of the cardiac wall. In other words, if cardiac
compliance increases, such as with aerobic training
(Arbab-Zadeh et al., 2004), the cutaneous vasodilation
response to hyperthermia and the baroreflex control of
the cutaneous vasodilation response will improve to
prevent heat illness.
428 H. NOSE ET AL.
CONCLUSIONS
The maintenance of body fluid homeostasis is a key fac-
tor in maintaining thermoregulatory capacity in humans.
Aerobic exercise training with carbohydrate + whey pro-
tein supplementation will improve the capacity to pre-
vent heat illness in young and older people.
ACKNOWLEDGMENTS
This work was supported in part by grants from the
Japan Society for the Promotion of Science and the Shin-
shu University Partnership Project between Shinshu
University; Jukunen Taiikudaigaku Research Center;
The Ministry of Education, Culture, Sports, Science,
and Technology of Japan; and Matsumoto City.
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