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Departments of Internal Medicine and Physiology and Biophysics, University of Iowa College of Medicine; and Veterans Administration Medical Center, Iowa City, Iowa 52242
THERMOREGULATION IS
A SUBJECT that clearly reflects the regulatory, integrative, and
comparative portions of the journal's title. Body temperature is
closely regulated via the integration of a number of mechanisms whose
study has been greatly assisted by exploitation of comparative
physiology. Ground squirrels, be they golden mantled (8, 15,
20), thirteen lined (2), or Arctic (4,
18), have all been found to be suitable subjects for the study
of the biochemical, metabolic, and immunological aspects of temperature
regulation during sleep, wakefulness, arousal, and torpor. Studies of
temperature regulation and energy turnover have also been conducted
during hibernation in the gray mouse lemur (14), little
brown bat (7), and Alpine marmot (12).
The complex relationship between body temperature regulation,
febrigenic signaling, and metabolic responses to fasting has been
examined in the fatty Zucker rat, which has a mutation in the leptin
receptor gene and expresses a dysfunctional leptin receptor. Fatty
Zucker rats have a body core temperature (Tb) that is below
that of lean Zucker rats. One study (9) examined whether
this was due to a result of deficits in thermoregulation or a downward
resetting of the set point for Tb. Fatty Zucker rats had
lower Tb and oxygen consumption than lean Zucker rats. In
addition, fatty Zucker rats chose to occupy a cooler ambient temperature (Ta) in a thermal gradient (Ta:
15-35°C) than lean Zucker rats. This indicates a lower set point
for Tb in the fatty Zucker rats as they refused the option
to select a warmer Ta that might allow them to counteract
any thermoregulatory deficiency that leads to a low Tb.
Another study (6) sought to determine if leptin was
involved in febrigenic signaling from the periphery to the brain.
Colonic temperatures (Tc) were measured in fatty and lean
Zucker rats challenged with intravenous Escherichia coli
lipopolysaccharide (infectious fever) or intramuscular saline (stress
fever). When Ta was 20°C, the increases in Tc
in response to both infectious and stress fever were attenuated in
fatty compared with lean Zucker rats. However, no differences
were observed at a thermoneutral Ta of 29°C.
The normal febrile responses of fatty Zucker rats to a pyrogenic
stimulus at thermoneutrality indicate that the fatty mutation in the
leptin receptor gene does not interrupt febrigenic signaling from the
periphery to the brain.
Another study tested the hypothesis that reduced leptin signaling is
necessary to elicit the cardiovascular and metabolic responses to
fasting (13). The cardiovascular and metabolic responses
of both fatty and lean Zucker rats to fasting (Ta = 23°C) and thermoneutrality (Ta = 29°C) were
similar. It appears that intact leptin signaling may not be a requisite
for the cardiovascular and metabolic consequences to reduced energy intake.
Similarly, in mice, food restriction and fasting, as occur in
hibernation, resulted in decreases in arterial pressure, heart rate,
oxygen consumption, and locomotor activity at Tas of either 23 or 30°C (thermoneutral) (21). However, torpor (heart
rate <300 beats/min; oxygen consumption <1.0 ml/min) was only
observed at Ta of 23°C.
Rats have proved suitable for detailed mechanistic analyses of
thermoregulation. Infant rats respond to cold exposure with increased
heat production by brown adipose tissue (BAT) (3). BAT
thermogenesis increases steadily with increasing cold exposure, but a
point occurs at which thermogenesis cannot increase further, resulting
in cold-induced bradycardia. However, arterial pressure is maintained
when heart rate decreases as much as 50% from baseline values,
indicating a major role for compensatory increases in total peripheral
resistance. It was found that combined blockade (triple blockade) of
Removal of the midbrain tonic inhibitory mechanism on nonshivering
thermogenesis results in increased temperatures in BAT and rectum via
an enhanced central sympathetic output (19). As it is
unlikely that primary neurons of the midbrain inhibitory mechanism
tonically inhibit BAT monosynaptically, there must be secondary or
tertiary neurons caudal to the midbrain that increase their activity
after removal of the midbrain tonic inhibition. After removal of
midbrain tonic inhibition by procaine microinjection, increases in BAT
and rectal temperatures were associated with appearance of
c-Fos-positive neurons in both the inferior olive (IO) and the
intermediolateral (IML) cell column of the thoracic spinal cord.
Electrical stimulation of and L-glutamate microinjections into IO increased BAT and rectum temperatures. Midbrain
procaine-induced increases in BAT and rectum temperatures were blocked
by electrolytic IO lesions. Thus thermal-induced central neural signals
produced in the midbrain are transmitted to BAT through the IO and IML, and the IO has a role in central sympathetic function.
The effect of central ANG II type 1 receptor blockade (AT1)
on thermoregulation and water intake after heat exposure was studied in
rats (10). In response to external heating (chamber
temperature 39°C), Tc increased greater in rats that
received intracerebroventricular losartan than in control rats that
received intracerebroventricular artificial cerebrospinal fluid.
Despite similar body weight (i.e., water) loss, the losartan-treated
rats drank less water than the control rats. Losartan did not impair
the drinking response to intracerebroventricular carbachol, suggesting
that losartan did not nonspecifically depress drinking behavior. Thus
central angiotensinergic mechanisms are involved in both
thermoregulatory adjustments to heat stress and the ensuing
compensatory water intake.
The central heme oxygenase (HO) pathway has an important role in the
genesis of lipopolysaccharide fever, but the HO product involved
[biliverdine, free iron, carbon monoxide (CO)] is not known
(16). Intracerebroventricular administration of
heme-lysinate, an inducer of the HO pathway, increased body
Tb in conscious rats; this was prevented by an HO
inhibitor. Other components of the HO pathway (biliverdine and iron
salts) had no effect on Tc and the iron chelator
deferoxamine did not affect heme-induced fever. Heme-induced fever was
completely prevented by a soluble guanylate cyclase inhibitor. As CO
produces most of its actions via soluble guanylate cyclase, these data
imply that CO is the only HO product with a pyretic action in the
central nervous system.
Studies in human subjects allow detailed analysis of the responses to
heat and cold stress in clinically relevant settings. As with body
temperature, which is lower in the early morning and higher in the
evening, there is a similar diurnal variation in the cutaneous
circulatory response to heat stress. A study (1) examined
the roles of the noradrenergic vasoconstrictor and nonadrenergic active
vasodilator systems in the diurnal (0630, 1630) cutaneous circulatory
response to whole body heating in human subjects. The oral temperature
(Tor) threshold for cutaneous vasodilation was
significantly higher in the PM for both control and bretylium (blockade
of noradrenergic vasoconstriction)-treated skin sites, suggesting that
the diurnal shift in threshold depends on the nonadrenergic active
vasodilator system. The slope of cutaneous vascular conductance with
respect to Tor was lower in the AM at control sites only
and bretylium increased it. This suggests that the sensitivity of
cutaneous vasodilation depends on vasoconstrictor system function. Thus
the diurnal variation in the reflex control of cutaneous blood flow
during heat stress involves both vasoconstrictor and active vasodilator systems.
Heat acclimatization improves thermoregulatory responses (sweating,
cutaneous vasodilation) to heat stress and decreases sweat sodium
concentration (sweat [Na+]) (17). The
decreased sweat [Na+] results in a larger increase in
plasma osmolality (Posm) at a given amount of sweat output.
The increase in Posm inhibits thermoregulatory responses to
increased body core (esophagus) temperature (Tes). It was
hypothesized that the inhibitory effect of increased Posm
on the thermoregulatory responses to heat stress would be attenuated
with the decrease of sweat [Na+] due to heat
acclimatization. Human subjects had their legs immersed in 42°C water
and received isotonic or hypertonic saline infusion. The
Tes thresholds for sweating and cutaneous vasodilation were lower in subjects with normal compared with increased plasma
osmolality, confirming osmotic inhibition of thermoregulatory responses
to heat stress. Subjects with lower sweat [Na+] had a
smaller elevation in the osmotic Tes threshold (change in
Tes threshold per unit change in Posm) for
sweating and cutaneous vasodilation. The results suggest that heat
acclimatization limits osmotic inhibition of thermoregulatory responses
to heat stress as well as reducing sweat [Na+].
The thermoregulatory responses to core cooling (intravenous cold
infusion) were examined in young (age 18-23 yr) and older (age
55-71 yr) individuals (5). Compared with the younger
subjects, the older subjects had lower Tc thresholds for
vasoconstriction, heat production, and plasma norepinephrine responses.
Despite a lower Tc in the older subjects, their maximum
intensity of both vasoconstriction and heat production was less than in
the younger subjects. The vasoconstrictor response for a given change
in plasma norepinephrine concentration was also less in older than
younger subjects. Thus aging is associated with a decreased
Tc threshold and maximum response intensity for
vasoconstriction, heat production, and norepinephrine release and a
decreased vasoconstrictor response to norepinephrine.
Lower abdominal surgery under general anesthesia is accompanied by mild
hypothermia. A study (11) tested the hypothesis that
cardiac baroreceptor loading/unloading modifies thermoregulatory peripheral vasoconstriction and, thus, body temperature in this situation.
Subjects undergoing lower abdominal surgery under anesthesia were
divided into four groups: control (C), applied positive end-expiratory
pressure (PEEP), leg elevation (L), and leg-elevated subjects with PEEP
starting 90 min later. Compared with C, PEEP decreased right atrial
pressure, reversed the decrease in body temperature, and increased the
threshold for thermal peripheral vasoconstriction, whereas L increased
right atrial pressure, magnified the decrease in body temperature, and
decreased the threshold for thermal peripheral vasoconstriction. The
adverse effects of L were attenuated by subsequent application of PEEP.
Thus cardiac baroreceptor loading augments and unloading prevents
perioperative hypothermia in anesthetized and paralyzed subjects by
decreasing and increasing the body temperature threshold for thermal
peripheral vasoconstriction, respectively.
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1-adrenoceptors (prazosin), ANG II type 1 receptors
(losartan), and vasopressin receptors (Manning compound) was required
to achieve a decrease in arterial pressure with cold exposure.
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ACKNOWLEDGEMENTS |
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This work was supported by National Institutes of Health Grants DK-15843, DK-52617, and HL-55006 and by a Department of Veterans Affairs Merit Review Award.
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FOOTNOTES |
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Address for reprint requests and other correspondence: G. F. DiBona, Dept. Internal Medicine, Univ. of Iowa College of Medicine, 200 Hawkins Dr., Iowa City, IA 52242 (E-mail: gerald-dibona{at}uiowa.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/ajpregu.00571.2002
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