THERMAL BIOLOGY OF THE LABORATORY RAT
CHRISTOPHER J. GORDON
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THERMAL BIOLOGY OF THE LABORATORY RAT
CHRISTOPHER J. GORDON
Neurotoxicology Divison
Health Effects Research Laboratory
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina 27711
Address Correspondence to:
Dr. C.J. Gordon
MD-74 B
NTD/HERL
US EPA
Research Triangle Park, NC 27711
919-541-1509
This paper has been reviewed by the Health Effects Research
Laboratory, U.S. Environmental Protection Agency, and approved for
publication. Mention of trade names or commercial products does not
constitute endorsement or recommendation for use.
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ABSTRACT
In view of the array of thermal interactions commonly reported in
physiological, pharmacological and behavioral studies of the rat, it
would be timely to thoroughly review and develop a data base of the
basic thermoregulatory parameters of the laboratory rat. This review
contains the pertinent papers dealing with the thermal biology of the
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laboratory rat, including; metabolism, thermoneutrality, core and
brain temperature, thermal tolerance, thermal conductance-and
insulation, thermoregulatory effectors (i.e., thermogenesis,
peripheral vasomotor tone, evaporation, and behavior), thermal
acclimation, growth and reproduction, ontogeny, aging, motor activity
and exercise, circadian rhythm and sleep, gender differences, and
other parameters. It is shown that the laboratory rat exhibits unique
thermoregulatory responses compared to other rodents.
Key words: temperature regulation, metabolism, core temperature, body
temperature, skin temperature, thermoneutral zone, thermal tolerance,
growth, development, shivering, nonshivering thermogenesis, behavioral
thermoregulation, thermal acclimation, gender differences, pregnancy,
circadian rhythm, sleep.
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INTRODUCTION
The laboratory rat is undoubtedly one of the most commonly used
species in biological research including specific fields such as
physiology, psychology, pharmacology, toxicology, and others. In many
of these studies one or more components of the rat thermoregulatory
system may be directly or indirectly pertinent to the overall goal of
a study. Indeed, in a survey of papers published during the last 23
years which used the laboratory rat as the experimental subject
(Medline literature search), more than 5400 publications have dealt
with some aspect of body temperature and/or temperature regulation.
In view of the propensity for thermal interactions in
experimental studies of the rat, it is obvious that researchers not
trained in the field of temperature regulation should nonetheless have
a general source providing basic details of rat thermal biology. To
the best of my knowledge there has been no recent attempt to address
these issues. Perhaps the best and most frequently cited review on rat
thermal biology is that written by J.S. Hart almost 30 years ago which
reviewed most of the literature on the thermoregulatory patterns of
all rodents (Hart, 1971). Obviously, there has been an abundance of
new data published on the rat thermoregulatory system that can be
synthesized into an up-to-date review.
It should be noted that numerous reviews have been published on
specific areas of thermal biology and these are usually replete with
data on the laboratory rat. In this review, these areas are either not
covered or discussed only briefly. Hence, areas of rat thermal biology
not covered in the present review include: (i) the neuropharmacology
of temperature regulation, excellently reviewed by W.G. Clark and
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others (Clark and Lipton, 1985, 1986, Clark, 1981, Clark, 1979; Lomax
and Schonbaum, 1979; Lipton and Clark, 1986; Cox and Lomax, 1977);
(ii) neurophysiology and neurological mechanisms of temperature
regulation, of which a majority of the data are from the laboratory
rat (Hensel, 1973; Cabanac, 1975; Gilbert and Blatteis, 1977;
Blatteis, 1981; Boulant, 1986; Gordon and Heath, 1986; Kobayashi,
1989); and (iii) the role of fever in thermoregulation which has been
covered elsewhere in detail (Lipton, 1980; Dascombe, 1985; Kluger,
1979). The level of detail in this review will depend primarily upon
the availability of past publications. For example, nonshivering
thermogenesis, a well studied phenomenon in rat thermal biology, is
not given as much detail as other, less reviewed areas of study.
Hence, the major goal of this review is to present the basic
thermoregulatory responses of the laboratory rat. An index of
principal areas of research reviewed is given below:
I. BODY HEAT BALANCE EQUATION
II. METABOLISM AND ENVIRONMENTAL TEMPERATURE
1. Thermoneutral Zone Characteristics
III. THERMAL CONDUCTANCE
IV. INSULATION
V. CORE BODY TEMPERATURE
1. Effect of Ta on Core Body Temperature
2. Brain-Body Temperature Relationships
VI. THERMAL TOLERANCE
1. Upper Limits
2. Lower Limits
VII. THERMOREGULATORY EFFECTORS
1. Metabolic Thermogenesis
a. Shivering Thermogenesis
b. Nonshivering Thermogenesis
2. Peripheral Vasomotor Tone
3. Evaporative Water Loss
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4. Behavioral Thermoregulation
a. Temperture Gradients
b. Operant Systems
c. Other Forms of Behavior
VIII. ACCLIMATION TO THERMAL STRESS
1. Cold Acclimation
2. Heat Acclimation
IX. GROWTH, REPRODUCTION, AND DEVELOPMENT
1. Optimal Environmental Conditions for Growth
2. Reproduction and Thermal Stress
3. Thermoregulation during Pregnancy and Lactation
4. Ontogeny of Thermoregulation
a. Hyperthermic-Induced Seizures
5. Aging and Thermoregulation
X. MOTOR ACTIVITY AND THERMOREGULATION
1. Spontaneous Activity and Ta
2. Exercise
a. Maximum Metabolic Thermogenesis
XI. CIRCADIAN THERMOREGULATORY RHYTHM
1. Sleep and Thermoregulation
XII. GENDER DIFFERENCES
XIII. GENETIC DIFFERENCES
XIV. EFFECT OF RESTRAINT
XV. COMPUTER SIMULATION OF THERMOREGULATION
XVI. MISCELLANEOUS STIMULI AND THERMOREGULATION
XVII. CONCLUSION
I. BODY HEAT BALANCE EQUATION
The heat balance equation, derived from the principles of the First
Law of Thermodynamics, describes the net exchange of heat between a
body and the environment. It is a most useful means of understanding
the fundamentals of thermal biology of the rat and other species and
has been explained in several excellent articles (e.g., Bligh and
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Johnson, 1973; Hardy and Bard, 1974; Cossins and Bowler, 1987). In the
absence of performing work, heat balance can be described as:
S=M±E±R±C±K 1.1
Where: S = rate of heat storage (+ for net gain of heat); M =
metabolic heat production (always +); E = evaporative heat transfer (-
for heat loss); R = radiant heat exchange (- for heat loss); C =
convective heat transfer ( for heat heat loss); and K = conductive
heat transfer (- for heat loss)
It should be noted that evaporative heat transfer is almost
always negative, but evaporative heat gain may occur if water vapor
condenses on the body. Under steady state conditions, the rate of heat
production equals the rate of heat loss and S = 0. If total heat loss
exceeds heat production then S is negative and the animal becomes
hypothermic. If heat production exceeds total heat loss then S is
positive and the animal becomes hyperthermic. A thermal equilibrium is
achieved when heat loss and heat production are equal.
II. METABOLISM AND ENVIRONMENTAL TEMPERATURE
The effect of Ta on metabolic rate of homeothermic animals is one
of the most well studied mechanisms in thermal physiology. Typically,
metabolism as a function of Ta exhibits three phases in the homeotherm
(Figure 1) . There is a range of Ta's where metabolic rate is minimal
and body temperature is regulated primarily through the modulation of
peripheral vasomotor tone (i.e., skin blood flow) and the concomitant
control of dry or sensible heat loss (i.e., C + R + K); this range of
Ta's is termed the thermoneutral zone (TNZ). As Ta increases above the
TNZ, metabolic rate increases as a result of several physiological and
behavioral processes: (i) the elevation in tissue temperature directly
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accelerates cellular respiration, (ii) rodents, such as the rat,
display an increase in locomotor activity in the heat because of both
increases in escape behavior and as well as grooming behavior which
augments evaporative water loss; and (iii) increased breathing rate
elevates energy expenditure. The Ta at which metabolic rate increases
above the TNZ is termed the upper critical temperature (UCT). The UCT
is also defined as the Ta above which a resting animal recruits
evaporative mechanisms for thermoregulation (Bligh and Johnson, 1973).
As Ta drops below the TNZ dry heat loss is minimal as a result of
peripheral vasoconstriction. Thus, metabolic heat production via
shivering and/or nonshivering thermogenesis must be increased in order
to maintain a balance between heat loss and heat production. The Ta
below which metabolism is elevated above minimal levels is defined as
the lower critical temperature (LCT).
The pivotal work of Scholander et al., (1950) demonstrated that,
for many mammals, the metabolic rate at Ta's below the TNZ can be
described using an equation derived from Newton's Law of Cooling
(Bradley and Deavers, 1980; Folk, 1974):
M = C(Tb-Ta) 1.2
where: M = metabolic rate; C = thermal conductance; T& = body (core)
temperature; and Ta = ambient tmperature.
Thus, if metabolic rate is extrapolated to zero (cf. dashed line,
Figure 1) then T^ would equal Ta. Although many mammalian species
follow this general idealistic pattern (Scholander et al., 1950),
other species' metabolic responses are not so easily predictable. As
will be shown below, the laboratory rat often displays metabolic
responses which deviate considerably from the idealistic relationship.
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A controversy in the metabolic profile of the rat is the
definition of the minimal metabolic expenditure required for the
maintenance of homeothermy. In clinical studies this value is termed
the BASAL METABOLIC RATE (BMR) which is defined as the metabolic rate
of a individual that is resting, but not sleeping, 14 to 18 hours
after eating. BMR is expressed in terms of heat loss per hour per
square meter of surface area. However, under steady conditions, heat
loss is equal to heat production and many researchers report the
latter parameter as a measure of BMR.
Most would agree that the BMR cannot be determined in a species
such as the rat because it is nearly impossible to achieve a state
where the animal is at absolute rest, but is not sleeping. Over a 24
hour period, spontaneous locomotor activity (i.e., including feeding
and nonfeeding behaviors) accounts for approximately 25% of the rat's
total metabolic expenditure (Morrison, 1968). Bramante (1968) made a
thorough analysis of this issue using albino rats of the Simonson
strain (i.e., Sprague-Dawley derived). Measuring activity and oxygen
consumption simultaneously he found that over a five hour period the
rat exhibited periods of no activity only 4.9% of the time. During
these periods of inactivity the least observable metabolic rate (LOMR)
was calculated which can be defined as the BMR (Table 1; A). However,
in 48% of the experiments the rats exhibited "microactivties" which
corresponded to a minimal observed metabolic rates (MOMR). The MOMR
was 5% greater than the LOMR and it was proposed that the former be
used to define the resting metabolic rate of the rat (Table 1). I've
used Bramante's data to calculate the LOMR's for the rat with a body
mass of 0.1, 0.2, and 0.3 kg (Table 1).
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Metabolic expenditure of the rat measured at thermoneutrality
differs considerably from that under more practical laboratory
conditions. For example, using an environment common to a typical
animal facility (Ta=23.9 °C; RH=50%), Besch and Woods (1977)
determined the metabolic heat ratio (MHR) of the Sprague-Dawley rat
over a 24 hour period. The MHR is a ratio equal to the actual
metabolic rate divided by the BMR. Over a 24 hour period the MHR
averaged 1.95 with a minimum of 1.1 at 1600 hrs and a maximum of 2.5
at 2300 hrs. Thus, metabolic rate of the rat is "basal" at only one
relatively short period of time during a 24 hour cycle under standard
animal facility conditions. Overall, metabolic rate is approximately
double that of the BMR.
Expressing the dimensions of metabolism in thermal physiology is
often complex and deserves some attention in this review. As outlined
by Kleiber and Cole (1950), metabolic rate per unit body mass provides
a total measure of the intensity of tissue metabolism, metabolic rate
per unit surface area is useful when studying processes of heat
exchange, and metabolic rate per unit of the 0.75 power of body mass
(defined as metabolic level, see Bligh and Johnson, 1973) eliminates
the effect of size in interspecies comparisons. Interestingly, it
appears that the metabolic rate (LOMR) of the rat is best scaled to
the 0.62 power of body mass (Bramante, 1968).
In studies of rodents and other species, metabolism is usually
measured as the rate of uptake of oxygen. This value is often
converted to heat production by assuming a respiratory quotient (RQ)
of 0.81 and thus, 1.0 ml consumed oxygen equals 20.1 J; for an RQ of
0.71, 1.0 ml of oxygen equals 19.6 J; and for an RQ of 1.0, 1.0 ml of
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oxygen is equal to 21.1 J (Harper, 1975). Others have measured the
metabolic heat production directly using calorimetric methods (Table
1). Ideally, metabolic rate should be expressed in dimensions of W
(watts), W/kg, W/m2, or W/kg°-75 (Bligh and Johnson, 1973); however,
it is not appropriate to always assume an RQ of 0.81 in converting
from oxygen consumption to metabolic heat production (Table 1; D).
Hence, in this paper only the dimensions of metabolism as actually
measured in a given study are reported.
1. Thermoneutral Zone Characteristics
Several studies have determined values of the LCT, UCT and, TNZ
of the laboratory rat (Table 1; B). Not surprisingly, there is some
variation among the reports of these important thermoregulatory
characteristics. The majority of studies report the LCT in the range
of 26 to 30 °C and the UCT in the range of 27 to 33 "C. For a given
study, the rat exhibits a relatively narrow thermoneutral zone ranging
from 0 to 6 "C (Pace and Rahlmann, 1983; Herrington, 1940; Gordon,
1988). In many cases, the metabolic response of the rat deviates
considerably from the response predicted using Newton's law of cooling
(cf. Figure 1). That is, extrapolation of the metabolism versus Ta
regression line to a metabolic rate of zero results in temperatures
that far exceed the normal body temperature of the rat. Hence, it
would appear that metabolic response of the rat to Ta's below the LCT
does not follow the classic pattern predicted by Newton's Law of
Cooling.
III. THERMAL CONDUCTANCE
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Thermal conductance is essentially a measure of the facility or
ease with which heat is lost to the environment via convection,
conduction, radiation, and evaporation depending upon whether or not
dry or wet thermal conductance is calculated (Table 1; E and F).
Thermal conductance is a very useful parameter in comparative
thermoregulatory studies of rodents (Hart, 1971; McNab, 1980; Bradley
and Deavers, 1980). Thermal conductance is derived from equation 1.2
by the formula (Hart, 1971; Bradley and Deavers, 1980; Aschoff, 1981):
C = M/(Tb-Ta) 1.3
Because metabolic rate is commonly measured with indirect
calorimetry, thermal conductance is often reported in dimensions of
rol 02/(g-min-°C). However, because thermal conductance is a measure of
heat transfer, it is desirable to use approriate conversion factors to
express it in dimensions appropriate to that of heat rather than
oxygen consumption (e.g., W/(kg-°C).
The reciprocal of thermal conductance is a measure of whole-body
insulation. The magnitude of thermal conductance is dependent on
several factors such as the insulative quality of the fur, the degree
of vascularization of the peripheral tissues, tissue chemical
composition, and especially body mass. Since heat is lost primarily
from the surface, and, the surface arearbody mass ratio is inversely
related to body mass, thermal conductance is inversely proportional to
body mass (Schmidt-Nielsen, 1975). On a double logarithmic plot,
thermal conductance of most species of rodents decreases in a linear
fashion with increasing mass (Aschoff, 1981). That thermal conductance
decreases with increasing mass is also clear in an intraspecies
comparsion such as the laboratory rat (Table 1; E).
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Ideally, thermal conductance is minimal and constant at Ta's
below the LCT. As Ta increases above the LCT, thermal conductance
increases because the animal vasodilates the peripheral vasculature.
In many studies the calculation of thermal conductance ignores the
heat loss by evaporation. At Ta's below the TNZ, where thermal
conductance is minimal, evaporative heat loss accounts for only 5-15%
of the total heat loss. Thus, the term "wet thermal conductance"
applies to calculations where evaporation is not taken into account
and can be justified as a reasonable estimate of thermal conductance
(McNab, 1980). Minimal wet thermal conductance (Cw) is a useful
parameter for comparing standard thermoregulatory responses between
species at relatively cool Ta's (McNab, 1980). On the other hand, "wet
thermal conductance" is meaningless at relatively high environmental
temperatures where evaporation becomes a significant route of heat
dissipation. In this case "dry" thermal conductance (Cj) is determined
using the formula:
Cd = (M-E)/(Tb-Ta) 1.4
Where: E = evaporative heat loss.
Thermal conductance, also referred to as whole-body thermal
conductance should not be confused with tissue thermal conductance:
k = M-Eres/Tr-Tsk 1-5
Where: k = tissue thermal conductance, W/(m2-°C); Eres = respiratory
evaporative water loss, W/m2; Tr = rectal temperture, °C; and Tsk =
skin temperature, "C.
Tissue thermal conductance is a measure of the rate of heat
transfer down a temperature gradient from a tissue to its immediate
environment (IUPS, 1987) is commonly applied in human and other
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primate studies where Ts|< and Eres can be determined. However, these
variables are quite difficult to determine in unstressed rats and
other rodents. There are some measurements of tissue thermal
conductance in the restrained rat (Table 1; G); under these conditions
tissue thermal conductance will more than double in magnitude when Ta
is increased from standard room temperature to that above the TNZ.
IV. INSULATION
The quality of insulation of fur of the rat and other rodents is
not as well studied as that of larger, domesticated species. The
insulation of the pelt has been estimated at 0.27 "C/W-m^ (Table 2).
The fur comprises approximately 1.6% of the body mass of the adult rat
(Roussel .and Bittel, 1979). Metabolic rate and sensible heat loss
increase by 30 to 50% following depilation in the rat (Roussel and
Bittel, 1979). Depilation results in a 7 "C increase in the threshold
for initiation of shivering in the rat (Stoner, 1971).
V. CORE BODY TEMPERATURE
The internal or core body temperature of the rat is probably the
most commonly measured thermal parameter. The thermal core consists of
"...those inner tissues of the body whose temperatures are not changed
in their relationship to each other by circulatory adjustments and
changes in heat dissipation to the environment..." (IUPS, 1987). The
core body temperature has generally been determined by inserting a
thermocouple or thermistor probe into the rectum or colon. Acceptable
distances for probe insertion to achieve accurate measurements of deep
body temperature range from 6 to 8 cm for a 0.2 to 0.3 kg rat (Lomax,
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1966). The measured temperature falls dramatically at distances less
than 5 cm from the anal opening. By using a probe with low thermal
inertia and, thus, a fast response time, a single point determination
of deep body temperature can be made in approximately 5 sec. Using
this method its been shown that diurnal measurements of the colonic
temperature of the unrestrained rat at a normal room temperature of 20
to 24 °C ranges from approximately 37 to 38 °C (Table 1; H). Securing
a colonic probe to the rat for an extended period of time or repeated
determination of the colonic temperature results in stress-induced
elevations in body temperature (Briese and Quijada, 1970; Poole and
Stephenson, 1977). For example, Gallaher et al., (1985) demonstrated
that the measurement colonic temperature using a temperature probe
resulted in a nearly 1.0 8C rise in deep body temperature which did
not fully recover for over 3 hrs. Simple handling of laboratory rats
has been shown to lead to a prolonged elevation in body temperature
(Lotz and Michael son, 1978). Moreover, core temperature of the rat may
increase during normal laboratory procedures such as the simple
presence of personnel in the animal quarters (Georgiev, 1978). Basal
colonic temperature of the unstressed rat varies little about a mean
of 37.2 °C when measured at 0900 to 1500 hrs; however, at 1700 hrs
colonic temperature has increased by 0.6 °C, which reflects the
characteristic elevation in core temperature of the rat during the
nocturnal phase of the circadian cycle (Briese and Quijada, 1970).
Hence, based on these and other data (cf. Table 1 and Circadian
Thermoregulatory Rhythm section), it can be concluded that core
temperature of the unstressed rat is quite stable throughout the
normal working hours of a typical laboratory setting.
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Surgical implantation of telemetry devices provides accurate and
presumably, artifact-free measurements of the internal body
temperature (Table 1). Telemetry devices implanted in the abdominal
cavity yield values of deep body temperature which are generally
similar to that of single-time determination of colonic temperature
(Table 1). The core temperature determined with a probe inserted 6 cm
beyond the anal sphincter is practically indistinguishable from that
measured with a telemetry device implanted in the abdominal cavity
(Thornhill et al., 1978). Although not well studied, some evidence
suggests the presence of isotherms within the core of the rat. For
example, at a Ta of 28 "C the temperature of the liver, mesentery, and
lower abdomen of the conscious rat is reported to be 39.3, 39.1, and
38.5 "C, respectively (Grayson and Menden, 1956). These unusually high
temperatures may result from undue stress during the experimental
procedure, but the data indicate some nonuniformity of rat core
temperature (excluding the head, see below).
1. Effect of Ta on the Core Body Temperature
Homeothermy is defined as "the pattern of temperature regulation
in a tachymetabolic species in which the cyclic variation in core
temperature, either nychethemerally or seasonally, is maintained...
despite much larger variations in ambient temperature" (Bligh and
Johnson, 1973; also see lups, 1987). Numerous studies have shown that
the laboratory rat is an excellent thermoregulator and will activate
an array of autonomic and behavioral mechanisms to maintain core
temperature at a constant level (Table 1; I).
One would expect that the determination of the limits of
homeothermic capacity in a species such as the rat would be a
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relatively simple test. However, exposure time is a key variable
important in assessing overall homeothermic capacity. For example,
maintenance of a constant internal temperature was demonstrated over a
Ta range of 0 to 32 8C, but in this particular study Ta was changed at
regular levels with exposure to a given Ta lasting not more than 10 to
20 min (Poole and Stephenson, 1977). Over a 60 min exposure period
rats remain normothermic over a Ta range of 5 to 30 °C (Gordon and
Watkinson, 1988). Likewise, for 90 min exposures, normothermia is
maintained in rats of the Fischer, Long-Evans, and Sprague-Dawley
strains over Ta ranges of 14 to 30 "C (Gordon, 1987). With six hour
exposures, normothermia in the rat was maintained over a Ta range of
approximately 12 to 25 °C (Herrington, 1940). Interestingly, it has
been noted in several rat strains that over a moderate range of Ta's
of approximately 15 to 35 °C, core temperature exhibits a U-shaped
function with the lowest body temperature occurring at Ta's of 25 to
32 °C (Herrington, 1940; Hamilton, 1963; Gordon, 1987).
Clearly, the limits of normothermia would be most easily detected
at critical Ta's when exposure time is extended. The demarcation
between normothermia and failure to thermoregulate is probably most
easily detected as Ta is increased. Most studies indicate that a Ta
of 30 to 31 °C is the critical upper Ta above which core temperature
is not regulated at normal levels with a minimal exposure time of 90
min (Herrington, 1940; Poole and Stephenson, 1977; Gordon, 1987).
Raising Ta above 30 °C results in a notable increase in core
temperature in the Sprague-Dawley, Long-Evans, and Wistar strains;
however, the Fischer 344 strain remains normothermic up to a Ta of 34
°C (Table 1).
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The rat is clearly better adapted to defend its temperature
against cold rather than heat exposure. With a six hour exposure
period, Herrington (1940) noted a fall in colonic temperature at Ta's
of approximately 14-15 °C. Rats of the Fischer 344, Long-Evans and
Sprague-Dawley strains exposed to 14 "C for 90 min had colonic
temperatures equal to or above that measured at a Ta of 25 "C (Gordon,
1987). Sprague-Dawley rats acclimated to 30 °C were normothermic at a
Ta of -5.7 °C after exposure times of 30 to 135 min (Depocas et al.,
1950). Exposure to a Ta of -15 °C led to a precipitous fall in core
temperature (Depocas et al., 1957).
2. Brain-Body Temperature Relationships
Because of the temperature dependency of neurological processes,
it is important to understand the relationship between brain and body
temperature in the rat. The temperature of the brain has
conventionally been considered part of the "core temperature";
however, as will be shown below, selective cooling may cause the
temperature of the brain to deviate from the that of the core (lups,
1987). Among the few studies in this important area of research the
data are quite contradictory. It is clear that the brain temperature
may be quite labile and can fluctuate by at least 1.0 °C during the
nocturnal cycle (Abrams and Hammel, 1965). An inactive rat that
begins to feed will undergo over a 1.0 °C elevation in brain
temperature (Abrams and Hammel, 1964; Grossman and Rechtschaffen,
1967). A fasted rat given food undergoes a simultaneous increase in
intracranial temperature and decrease in rectal temperature, an effect
that may be mediated by shifts in vasomotor tone (Rampone and Shirasu,
1964). Preoptic temperature is reported to be 0.4 °C below colonic
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temperature in the Fischer rat maintained at a Ta of 20 °C (Mohler and
Gordon, 1989).
It seems clear that the major factor involved in regulating
brain temperature is the temperature of blood in the body core (Abrams
et al., 1965). Variations in brain temperature in the rat during
feeding and sleeping are well correlated with shifts in arterial blood
temperature (Abrams et al., 1965). There is some evidence that the
rat brain can increase metabolism during ambient cooling and thereby
assist in controlling brain temperature (Donhoffer et al., 1959;
Szelenyi and Donhoffer, 1978). Using a novel telemetric system,
Blumberg et al., (1987) found that hypothalamic temperature decreased
below abdominal temperature during ejaculation and suggested that
venous blood draining the nasal mucosa and facial surfaces may be
involved in cooling the brain.
VI. THERMAL TOLERANCE
The above discussion examined the accuracy of the rat
thermoregulatory system as a function of Ta. There are Ta limits above
or below which the core temperature will increase or decrease,
respectively. However, these Ta's should not be considered as lethal
or near-lethal exposures. Again, the maximum or minimum tolerated Ta's
will depend, to a large extent, on the time of exposure (Table 1; J).
1. Upper limits
Key variables in the study of thermal tolerance in mammals are
(i) lethal core temperature, (ii) critical thermal maximum or minimum,
(iii) elevated defended core temperature, and (iv) time to reach total
thermoregulatory collapse. The critical thermal maximum (CTMax) is a
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core temperature that was originally defined in the study of ectotherm
thermal biology and is: "...the thermal point at which locomotor
activity becomes disorganized and the animal loses its ability to
escape from conditions that will promptly lead to its death" (Cowles
and Bogert, 1944). The CTMax is a relatively quick method to determine
thermal tolerance. It is measured in mammals exposed to relatively
high Ta's and the values for the CTMax are usually lower than that of
lethal body temperature (Erskine and Hutchison, 1982). White rats
exposed to a Ta of 40 °C initially undergo a rapid elevation in
colonic temperature from 37 to approximately 40 "C in less than 25
min. This temperature, referred to as the elevated defended
temperature (EOT), is maintained for an average of 153 min upon which
time the rat's thermal dissipating mechanisms break down and there is
a concomitant rapid rise in temperature which reaches the CTMax within
10-20 min (Erskine and Hutchison, 1982). Interestingly, the rat always
exhibits the EOT response during acute heat exposure and appears,
compared to other rodents, to display good thermal tolerance. The
CTMax of the white rat, characterized as the core temperature at which
the animal exhibits uncoordinated spasmodic twitching of the limbs and
loss of righting reflex, was estimated to be 44.2 °C (Table 1). On the
other hand, rats with decreased thermal resistance tend to undergo a
type of linear elevation in core temperature and fail to establish an
EOT during acute heat exposure (Wright et al., 1977).
The upper limit of thermal survival is governed by several key
environmental factors including (i) air temperature, (ii) relative
humidity (RH), (iii) water availability, (iv) time of exposure, (v)
degree of restraint, (vi) level of activity, (vii) previous thermal
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history (e.g., acclimation), and circadian cycle (Hart, 1971). Adolph
(1947) demonstrated the deleterious effects of increased relative
humidity on survival of rodents in the heat. Wistar rats exposed to a
Ta of 42.5 °C have survival times of approximately 95 min; however,
the lethal body temperature varied as a function of the circadian
cycle with heat resistance increasing during the light phase (Table 1;
Isobe et al., 1980). Another study reported that survival in the heat
was maximal during the late afternoon-early evening (Wright et al.,
1977). The maximum survivable body temperature for a variety of
strains of rats exposed to a Ta of 42.5 °C and 48% RH has been
reported to be 43.1 °C for males and 43.3 °C for females (Furuyama,
1982). Moreover, the degree of saliva spreading appeared to be a good
index of survival in acute heat with rats of Fischer 344/MK and
Sprague-Dawley strains displaying significantly better heat tolerance
than other strains. Furuyama (1982) also noted that rats exposed to
colonic temperatures as high has 42.5 °C survived and displayed normal
thermoregulatory responses for several months. On the other hand,
Adolph (1947) estimated the LDso rectal temperature for the rat to be
42.5 8C. Because surface area/volume decreases with increasing body
mass, one would expect an inverse relationship between rate of body
warming and body mass (e.g., Adolph, 1947). Thus, it is not suprising
to find that body mass correlates directly with survival time in the
heat in some strains of rats (Furuyama , 1982). Restrained rats have
significantly shorted survival times during heat exposure (Frankel,
1959). The lethal upper body temperature of the rat is also affected
by the rate of heating (Robinson et al., 1968). The lethal core
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temperature can be increased by 2 °C when the exposure Ta is elevated
from 45 to 60 °C.
2. Lower Limits
The principle of determining the core temperature at which
coordination is lost has also been applied in assessing the lower
limits of thermoregulatory capacity in the rat (Ferguson and Folk,
1970). White rats weighing 160-190 g and exposed to a Ta of -40 °C
reached their critical thermal minimum (CTMin) within 40 to 60 min
(Table 1). The core (i.e., liver) temperature at which loss of
righting reflex occurred was 16 to 20 °C which, curiously, is similar
for a variety of rodent species (Ferguson and Folk, 1970). Spontaneous
motor activity in the Long-Evans rat is suppressed at core
temperatures below 20.7 °C (Panuska et al., 1969). The colonic
temperature of rats exposed to -40 °C displays a sigmoid curve with an
inflection point occurring at a colonic temperature of approximately
32.9 °C (Heroux et al., 1975). Normal rats reach the inflection point
in approximately 21 min. As exposure time continues beyond the
inflection point, colonic temperature decreases rapidly. In spite of
the loss of motor function at core temperatures below 20 °C, it should
be noted that the severely hypothermic rat (Tco] = 13.5 to 17.0 °C)
can spontaneously rewarm itself when maintatined at a Ta of 16 °C
(Musacchia and Jacobs, 1973).
There are several estimates on the lower lethal body temperature
of the laboratory rat. As with heat exposure, determining the lower
limits of survival is influenced by rate of cooling, exposure time and
other factors (Hart, 1971). Rapid cooling in water results in a lethal
temperature of approximately 15 °C (Table 1). Lethality at this body
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temperture is due to the cessation of breathing, but with artificial
respiration the heart will continue to beat below tempertures of 10 °C
(Adolph, 1959).
Lower lethal core temperature is not affected by age (above one
month), temperature acclimation, body mass, or gender (Adolph, 1948).
The LDso core temperture below which the rat could not spontaneously
recover was estimated to be 23 8C at a Ta of 5 °C (Adolph and
Richmond, 1955), whereas for the golden hamster and ground squirrel,
the core temperature for spontaneous recovery was 15 and 11 °C,
respectively. On the other hand, using hypercapnic hypoxia as a means
of body cooling, rats can be cooled to temperatures of 0 to 1 °C and
successfully rewarmed using microwave radiation (Andjus and Lovelock,
1955). The adult rat can survive a body temperature of 15 °C for
approximately 9 hours, but ca'n be revived from this body temperature
for durations of up to 5.5 hours (Popovic, 1960).
VII. THERMOREGULATORY EFFECTORS
1. Metabolic Thermogenesis
a. Shivering
Since the LCT for elevating metabolism above resting levels is
estimated to be approximately 28 °C, it can be argued that this is the
approximate threshold temperature for the initiation of shivering
and/or nonshivering thermogenesis (ST and NST, respectively). However,
significant ST in the rat is not observed until Ta decreases below -20
°C (Table 1; K). ST is thought to be the primary mode of heat
production in the rat acclimated to temperatures near
thermoneutrality; however, this does not mean that the normal rat
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cannot employ both ST and NST during cold exposure. Fuller et al.,
(1975) showed that in the cold exposed rat, artificial warming of the
hypothalamus resulted in an inhibition in NST along with a concomitant
elevation in ST. Propranolol, a beta-blocking agent which inhibits
NST, but not ST, impairs thermogenesis in warm-acclimated rats exposed
to a cold Ta (Griggio, 1982).
During cold acclimation the development of NST through
activation of the brown adipose tissue (BAT) becomes prounounced and
replaces ST as the primary mode of heat production (Himms-Hagen,
1984). Cold acclimated rats given mephenesin, a muscle relaxant and
blocker of ST, are able to thermoregulate in the cold nearly as well
as controls, whereas warm-acclimated rats given mephenesin become
significantly hypothermic during cold exposure (Griggio, 1982). The
replacement of ST with NST following prolonged cold exposure
represents a beneficial adaptation because: (i) since the heat
generated from ST is produced in peripheral tissues, this mode of
thermogenesis is a relatively inefficient means of heat production;
(ii) body movements associated with ST may acutally enhance convective
heat loss; and (iii) in man and probably rodents as well, ST is an
uncomfortable state and skeletal muscles that must be dedicated to
shivering cannot be used as well for other motor functions (Jansky,
1979).
Dawson and Malcolm (1981) calculated a threshold Ta for
initiation of ST of 23.5 "C when the chamber was cooled at a moderate
rate. However, it was not possible to discern a clear threshold Ta for
the initiation of shivering when the cooling rate of Ta was
excessively high or low. It was concluded that the change in skin
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temperature was very important in the onset and offset of ST. Using
spectral analysis the frequency of shivering in the tibia!is anterior
and gastrocnemius muscles of the rat has been determined to be 31.3 +/
4.9 Hz (Gunther et al., 1983). It appears that shivering frequency
increases with decreasing body mass in rodents (Gunther et al., 1983).
Restraint suppresses ST in naive, cold-exposed rats; however,
adaptation to the restraining device alleviated most of the inhibitory
effects of restraint on ST (Shimada and Stitt, 1983).
b. Nonshivering Thermogenesis
This is an area of rat thermal biology that is well studied and
has been presented in many excellent reviews (Jansky, 1971, 1973;
Himms-Hagen, 1984; Chaffee and Roberts, 1971; Girardier and Stock,
1983; Astrup, 1988; Landsberg et al., 1984; Horowitz, 1979; Nicholls
and Locke, 1984). By strict definition, NST can refer to all forms of
heat production other than shivering. Indeed, the heat produced at
thermoneutrality could be called NST. Hayward (in Jansky, 1971)
proposed that the resting or basal metabolic rate could be defined as
"obligatory" NST. At Ta's below the LCT, the increase in metabolic
rate above resting levels could be partitioned into "thermoregulatory"
NST and shivering thermogenesis.
It has been clearly established that BAT is the primary organ
responsible for NST (Himms-Hagen, 1984). BAT is located in numerous
anatomical sites including; interscapular, cervical, pericardial,
intercostal and perirenal areas. BAT can be identified in the 18-day-
old rat fetus and approaches its full development in the warm-
acclimated rat at an age of approximately 4 weeks (Suter, 1969). The
interscapular BAT is by far the most well studied fat deposit (Himms-
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Hagen, 1984). BAT is one of the most thermogenic tissues and is under
control of the sympathetic nervous system. The anatomical nature of
the neural innervation of BAT and criteria for differentiation between
white and brown adipose tissue have been studied in detail (Daniel and
Derry, 1969; Flaim et al., 1976). In vitro studies of isolated BAT
cells suggest that BAT is capable of generating heat at an incredible
rate of approximately 400 W/kg under proper catecholamine stimulation
(Girardier, 1983). Stimulation of nerves innvervating BAT will lead
to a localized increase in its temperature (Flaim et al., 1976). It is
of interest to compare the contribution of NST to other forms of heat
production in the rat. The normal (i.e., non cold-acclimated) rat will
undergo, at best, a 1.25-fold elevation in metabolic rate above
baseline following parenteral administration of NE; the same type of
rat maintained at an extremely cold Ta of -5 "C will maintain a 2.06-
fold elevation in metabolic rate; a cold-acclimated rat infused with
NE will undergo a 2.7-fold elevation in metabolism (Jansky, 1973;
Jansky, 1979; Depocas et al., 1957). On the other hand, during
strenuous exercise in a cold environment, the rat can maintain a
transient 5- to 6-fold elevation in metabolic rate (cf. Table 5).
It is well known that cold exposure will bring about stimulation
of NST. In the cold acclimated rat, blood flow to BAT increases 25-
fold when Ta is reduced from 25 to -19 °C (Foster and Frydman, 1979).
In comparison, blood flow to other anatomical locations such as heart,
skeletal muscle, and diaphragm increase by only 2-3 fold during cold
exposure. Continued exposure to cold accentuates development of BAT
(Table 2). In the past decade it has been established that diet-
induced thermogenesis is another principal means of stimulating NST in
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BAT (Rothwell and Stock, 1979; Girardier and Stock, 1983). That is,
ingestion of food, especially palatable "cafeteria" types of diets,
stimulates BAT thermogenesis in a similar manner as that of cold
exposure. And, in a related issue, the role of BAT in the regulation
obesity as become a critical research issue using the rat as a key
experimental model (e.g., SeydouxT 1983; Himms-Hagen, 1989).
2. Peripheral Vasomotor Mechanisms
The tail of the rat has been commonly used in the study of
peripheral vasomotor control (Table 1; L). Several physiological and
physical properties make the tail of the rat crucial in the
dissipation of body heat: (i) it lacks fur which accentuates heat
loss; (ii) it is highly vascularized, permiting a high rate of blood
flow during heat stress; and (iii) it has a relatively high surface
area:volume ratio which further aids in heat exchange. The specialized
adapations of the tail can be illustrated by the fact that it
comprises approximately 7% of the rat's total surface area (Lin et
al., 1979); nevertheless, under steady-state conditions, approximately
20% of the total heat production is dissipated from the tail (Rand et
al., 1965; Young and Dawson, 1982). Surgical amputation of the rat
tail severely impairs thermoregulation in the heat (Strieker and
Hainsworth, 1971; Spiers et al., 1981). The length of the tail in the
growing rat is directly proportional to the environmental temperature
at which it is raised (Chevillard et al., 1963).
The foregoing studies illustrate the important role of the tail
in thermoregulation. Unfortunately, for a variety of reasons, most of
the physiological studies have been performed using either restrained
or anesthetized preparations. Hence, data such as threshold for
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vasodilation, etc. are difficult to interpret in relation to other
thermoregulatory parameters that are commonly measured in
unrestrained, awake preparations (e.g., metabolism). Thus, one should
be cautious in the interpretation of these data.
Blood flow to the tail is minimal at Ta's equal to or less than
approximately 25 °C (Rand et al., 1965). Generally, an abrupt increase
in tail blood flow occurs at a Ta range of 27 to 30 "C (Table 1). At a
Ta range of 29 to 33 °C there is an on-off sequence of tail
vasodilation and vasconstriction with an approximate time period of 20
min (Young and Dawson, 1982). Hence, it would appear that there is a
mechanism of on-off control in tail heat loss as compared to
proportional control in other thermoregulatory motor outputs.
The control of tail blood flow is mediated through both internal
and peripheral thermal sensors. Raman et al., (1983) found a linear
relationship between core temperature and tail blood flow. Moreover,
it was shown that at a core temperature of 39 °C tail blood flow was
maximal at a tail skin temperature of 30 °C and decreased as tail
temperature rose or fell from this nadir. It would appear that as Ta
approaches tail skin temperture, blood flow to the tail is reduced in
an attempt to restrict heat gain from the environment (Raman et al.,
1983). Minimal and maximal blood flow in the rat tail range from
approximately 1.6 to 70 ml/100 cc-min (Table 1).
Several minutes of immersion of the rat tail in an ice bath
results in a cold-induced vasodilation, a response reminiscent of a
Lewis-wave hunting reflex, but is conventionally referred to as cold-
induced vasodilation (CIVD) (Hellstrom, 1975). The increase in tail
temperature during ice water immersion is correlated with a large
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increase in metabolic heat production (Eide, 1976). Moreover, CIVD
can be demonstrated in vitro using isolated rat tail arteries (Gardner
and Webb, 1986). Raman et al., (1987) developed a mathematical model
of the blood flow-heat loss relationships in the rat tail and
predicted, among other observations, that counter-current heat
transfer represents a minor 10% savings in heat loss from the tail.
The tail is not the only site for the regulation of dry heat
loss. Other areas of the rat which lack fur and thus could be
important in heat loss are the ears and feet. Interestingly, the ears
lack arterial-venous anastomoses (Gemmell and Hales, 1977) and do not
vasodilate in response to whole-body heating (Grant, 1963) or exercise
(Thompson and Stevenson, 1965). On the other hand, the feet and distal
portions of the limbs are well vascularized and appear to be quite
sensitive to thermal stimuli. Indeed, these areas make up
approximately 10% of the total surface area of the Sprague-Dawley rat
which is somewhat more area than that of the tail (Lin et al., 1979).
Unfortunately, it is difficult to obtain recordings of foot skin
temperature, especially in free-moving rats. Thus, little is known of
the importance of the foot in heat dissipation in rodents. The foot
and tail have been shown to simultaneously vasodilate in response to
hypothermic-inducing chemical agents in the anesthetized (Gordon and
Watkinson, 1988) and restrained rat (Lin et al., 1978). The foot and
tail also vasodilate simultaneously when colonic temperature reaches
39.3 °C during treadmill exercise (Thompson and Stevenson, 1965). In
the restrained rat, temperature of the tail and feet increases
abruptly at Ta's above 22 °C (Lin et al., 1979).
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Exposing the foot of the anesthetized rat to 0 °C results in
cold-induced vasoconstriction and a resultant -9 "C fall in limb
temperature; however, after 21 to 28 days of acclimation to 5 "C,
there is a significant attenuation of the heterothermic response and
limb temperature decreases only 2 to 4 "C (Brown and Baust, 1980). The
cold-exposed foot also shows CIVD hunting reflexes as has been noted
in the tail (Brown and Baust, 1980). In the anesthetized rat, tail
blood flow decreases sharply as Ta is lowered from 40 to 10 °C;
however, a further decrease of Ta to 5 °C results in a slight but
significant elevation in tail blood flow (Berry et al., 1984).
3. Evaporative Water Loss
As Ta increases, sensible heat loss via radiation, convection,
and conduction diminishes because of the reduced gradient between skin
and ambient temperature. Thus, evaporative water loss becomes a
significant avenue of heat dissipation at warm Ta's (i.e., > 30 °C).
The two avenues of evaporative water loss in mammals is: (i) the
insensible loss of water by diffusion through the skin and that lost
through normal respiration and (ii) the active loss of water via
sweating, panting, and application of saliva or urine to the skin and
fur. Although the rat and other rodents have been reported to have
eccrine sweat glands (Sivadjian, 1975), they are apparently
nonfunctional in thermoregulation. Hence, active dissipation of heat
by evaporation is restricted to respiratory mechanisms and, most
importantly, the application of body fluids to the integument.
The dimensions of evaporative water loss are usually normalized
with respect to the body mass when water loss from the whole animal is
determined (i.e., mg H20/(kg-min)). However, because of the production
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of water from metabolism, it is often desirable to normalize the rate
of water loss to the rate of oxygen consumption yielding dimensions of
mg water loss per ml consumed oxygen (Schmidt-Nielsen and Schmidt-
Nielsen, 1950). In this way the water evaporated for thermoregulatory
requirements can be distinguished from that produced through
metabolism (e.g., Gordon, 1987).
There is a considerable rate of insensible water loss in the rat
(Tennent, 1946; Wang et al., 1980). At a Ta of 23-25 8C and relative
humidity of 46-50%, 54% of the total insensible water loss occurs by
diffusion through the skin with the remaining water lost through
respiration. Assuming a metabolic rate of 6.0 W/kg and a latent heat
of vaporization of 2.51 J per mg h^O evaporated, then the insensible
water loss accounts for 13% of the total heat loss (Table 1; M).
Under dry air conditions the rate of insensible water loss has been
estimated to be equivalent to approximately 11% of the total heat loss
(Schmidt-Nielsen and Schmidt-Nielsen, 1950). In the restrained rat,
respiratory evaporative water loss increases 5-fold when Ta is raised
from 8 to 31 °C (Lin et al., 1979). At a Ta of 31 °C, respiratory
evaporation accounts for approximately 21% of the total heat loss.
The rate of evaporation will be inversely dependent upon the water
vapor pressure of the ambient air. Welch (1980) has developed an
extremely useful model for predicting whole-body evaporation in
rodents as a function of Ta and ambient water vapor pressure.
The spreading of saliva on the fur and other body surfaces is of
paramount importance for evaporative water loss in the rat. The
increase in evaporative water loss above insensible levels represents
a unique integration of behavioral and autonomic processes.
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Autonomically, an increase in saliva secretion from the salivary
glands via parasympathetic activation must occur in conjunction with
the animal's behavioral grooming with the saliva. As mentioned earlier
(Metabolism and Environmental Temperature section), one of the reasons
metabolic rate increases as Ta is elevated above the LCT is the
increased activity associated with applying saliva to the integument
(Hainsworth, 1967).
Normal grooming at a Ta of 25 "C constitutes 7-8% of the total
daily evaporative water loss in the Sprague-Dawley rat (MacFarlane and
Epstein, 1981). The time spent spreading saliva increases dramatically
as Ta is increased from 28 to 32 *C in male rats and from 32 to 36 °C
in female rats (Hainsworth, 1967). Saliva is often applied to bare,
vascularized surfaces such as the paws, scrotum, and base of tail as
well as to the fur (Hainsworth, 1967; Strieker and Hainsworth, 1971;
Hubbard et al., 1982).
In assessing the time to reach ataxia during severe heat stress,
Clark (1971) found that time spent grooming was not as strong a factor
in affecting thermal resistance as was time spent in locomotion. Rats
with the greatest resistance times were those able to lower locomotion
and thereby lessen the metabolic heat load during heat stress. Rats
exposed to a Ta of 40 "C and given access to a pool of water will
readily immerse themselves in the pool and/or apply the water to their
fur to enhance evaporation and thus maintain a stable core temperature
(Strieker et al., 1968).
Whole-body evaporative water loss in the rat tends to increase
sharply at a Ta range of 32 to 36 °C (Table 1). Although it is not
clear whether the increase in evaporation is due to insensible water
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loss or increased salivary secretions. Early studies suggested that
increased breathing rate does not appear to play a significant role
during heat stress (Adolph, 1947; Hart, 1971); however, in my opinion,
the literature seems lacking in this area of study. There are
substantial elevations in respiratory water loss and breathing rate in
the rat exposed to elevated Ta's (Table 1). The anesthetized rat at a
Ta of 33-34 °C has a 73% greater rate of insensible water loss from
the skin and respiratory tract compared to that at a Ta of 22-24 °C
(Tennent, 1946). This would suggest that both insensible and salivary
water loss are important in heat dissipation at Ta's > 30 °C. The
partitioning of the major avenues of evaporative water loss in the rat
has been estimated (Rodland and Hainsworth, 1974). At a Ta a of 30 °C
the proportions are: respiratory, 23%; cutaneous, 77%; and salivary,
0%; At a Ta of 40 8C the partitioning changes dramatically with
respiratory, 27%; cutaneous, 13%; and salivary, 60%. When exposed to a
Ta of 40 °C, a 0.3 kg rat will lose water at a rate of 3 to 4 ml/hr
until it becomes dehydrated (Hainsworth et al., 1968).
The submaxillary gland appears to be the important salivary gland
for evaporative water loss during heat stress (Elmer and Ohlin, 1970;
Hainsworth and Strieker, 1971; Horowitz et al., 1983). It has been
estimated that the evaporation from the submaxillary gland accounts
for 60% of the heat loss at a Ta of 36 °C (Horowitz et al., 1983). The
threshold core temperature for the initiation of saliva secretion from
the submaxillary gland has been estimated at 39.7 °C; however, two
days of acclimation to 34 °C reduced this threshold to only 37.7 °C
(Horowitz et al. 1983). Control of saliva secretion during heat stress
appears to be mediated through parasympathetic cholinergic nerves
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(Elmer and Ohlin, 1971; Rodland and Hainsworth, 1973; Hubbard et al.,
1982). Surgical ligation of the salivary ducts leads to significant
impairment of thermoregulation under heat stress (Hainsworth, 1967;
Strieker and Hainsworth, 1971; Horowitz et al., 1983). In the
anesthetized rat vasodilation of the tail occurs at a rectal
temperture approximately 3 °C below the threshold temperature for an
increase in salivary secretion (Nakayama et al., 1986). Interestingly,
surgically desalivated rats will apply urine to their fur in an
attempt to increase evaporative water loss (Hubbard et al., 1982;
Mathew et al., 1986).
4. Behavioral Thermoregulation
Behavioral modification of the thermal environment is perhaps the
most common of all thermoregulatory effectors found throughout the
animal kingdom. Behavioral thermoregulation requires relatively little
metabolic energy compared to autonomic effectors. Generally, it is
found that various species will employ behavioral thermoregulatory
reponses before activating autonomic effectors of thermoregulation
(Adair, 1976; Schmidt, 1978; Gordon, 1983). Behavioral
thermoregulation in the laboratory rat has been well studied using two
principal methods: the temperature gradient (or thermocline) and
operant selection of thermal reinforcements. There are several
justifications for using a given methodology, many of which have been
summarized by Laughter and Blatteis (1985): (i) temperature gradients
utilize unrestrained animals under conditions that would most likely
be representative of inherent thermoregulatory behavior in the natural
environment; (ii) temperature gradients are usually mechanically
simple with relatively little equipment required for operation; (iii)
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operant systems, on the other hand, are usually more complex and
require extensive training which may or may not be achieved by all
experimental animals; (iv) operant systems do provide a precise
quantitative measure of thermoregulatory behavior whereas gradient
systems represent continuums of temperature providing more of a gross
measure of thermal selection; (v) operant systems generally provide a
measure of number of thermal reinforcements per unit time and do not
estimate acutal selected Ta as in a gradient system; (vi) with operant
systems the animal must continually perform a motor task in order to
regulate the thermal environment, whereas in a temperature gradient,
the selected Ta can be achieved quickly with no additional muscular
effort. This can be important in behavioral thermoregulatory studies
where experimental manipulation (e.g., drugs, surgery, etc.) impairs
motor activity and thereby indirectly affects behavioral
thermoregulatory responses in an operant system.
a. Temperature Gradients
Reports on the selected Ta (i.e., thermopreferendum) of the
laboratory rat are quite variable (Table 1; M). While the majority of
studies suggest that the selected Ta is in the range of 19 to 25 "C, a
few studies report the selected Ta in the rat to be as high as 30 to
31 °C. It is not clear why there is such a discrepancy in the data
from these studies.
Generally, one expects rodents to select Ta's associated with
minimal energy expenditure (Hart, 1971). Indeed, this has been shown
to be true for the mouse, hamster, and guinea pig (Gordon, 1985; 1986;
Gordon et al., 1986). However, the laboratory rat appears to be quite
distinct from other rodents. Poole and Stephenson (1977) first
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suggested that the metabolic thermoneutral zone was notably higher
than the Ta zone of normal behavioral activity. In a recent study from
this laboratory, it was found that the selected Ta for several strains
of the rat was 3 to 8 °C below the LCT for elevating metabolic rate
(Gordon, 1987). In a related study, it was found that rats permitted
free range in a temperature gradient selected relatively cool Ta's and
had higher metabolic rates compared to animals confined in the
gradient to Ta's no lower than that of the LCT (Gordon, 1988). Thus,
the gradient studies suggest that the rat's zone of thermal preference
is significantly lower than the zone of metabolic thermoneutrality.
b. Operant Systems
The work of Weiss and Laties (e.g., 1961) was pivotal in the
advancement of operant systems for studying behavioral thermo-
regulation in rodents. Their basic system utilized an escape-
avoidance schedule where a rat placed in an adversely warm or cold
environment performed an operant task in order to receive a thermal
reinforcement. In a hot environment rats can be trained to operate a
fan of cool air or water shower to enhance heat dissipation (Epstein
and Milestone, 1968; Szymusiak et al., 1985). In a cold environment
the rat's fur is often clipped to accentuate heat loss and the animals
receive reinforcements from an infrared lamp or warm air source to
minimize heat loss (Weiss and Laties, 1961; Satinoff and Rutstein,
1970; Refinetti and Carlisle, 1986; Szymusiak et al., 1985). Under an
operant thermal reinforcement scenario, the rat will attempt to
regulate tail skin temperture as well as body temperature within
narrow limits (Lipton et al., 1970). In a summary of several operant
studies Corbit (1970) concluded that the neutral zone of Ta's was 21
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to 24 8C; hence, as Ta decreases below this zone there is a near
linear increase in operant reinforcements for radiant heat, whereas
Ta increases above this zone there is an increased rate of
reinforcements for cool air.
Refinetti and Carlisle (1987a) have developed some useful
equations for quantitating the heat intake of a rat while performing a
thermal avoidance task. These measurements have advanced the
understanding of the interaction between metabolic heat production and
behavioral heat intake as a function of reward duration effort
expended during operant thermoregulation (Refinetti and Carlisle,
1986, 19875). Refinetti and Horvath (1989) recently developed an
operant system which permitted the rat to control its selected Ta. The
animal could choose between 10 or 40 °C airstreams by moving from one
side of the cage to the other. In this situation rats of the Long-
Evans strain selected Ta's of 19 "C which is remarkably close to that
of rats of the same strain placed in a temperature gradient (Gordon,
1987; Table 1). In a related system Briese (1986) secured
thermocouples above the head to measure selected Ta of the rat while
it shuttled between hot and cold compartments. It was found that
selected Ta varied with the circadian cycle with cooler Ta's selected
during the nocturnal phase.
c. Other Forms of Behavior
Alteration in body posture represents a fundamental type of
thermoregulatory behavior inherent in rodents; however, such behavior
is difficult to quantitate and has not been studied in as much detail
as the preferred Ta and operant thermoregulatory behaviors discussed
above.
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When exposed to cold environments, rats assume a ball-like shape
to conceal appendages from direct exposure and thereby impede heat
loss (i.e., the surface area/body mass is minimized). Group huddling
in adult as well as neonatal animals provides distinct advantages for
conserving metabolic expenditure in the cold (Hart, 1971).
In the heat rats exhibit three principal behaviors: increased
grooming, increased locomotion (i.e., escape behavior), and assumption
of an extended posture (Roberts et al. 1974; Roberts, 1988). Increased
grooming of saliva to augment evaporative heat loss (see Evaporative
Water Loss section) and increased locomotion occur early in the
exposure to heat. On the other hand, assumption of an extended
posture, which lowers internal heat production and enhances heat loss
through an increase in the surface area/body mass ratio, is elicited
in the latter stages of heat exposure (Roberts, 1988). Simple
behaviors such as time required to escape an intense heat source have
also been applied to study behavioral thermoregulation in the rat (Cox
et al., 1975).
Thermal stress can modify the regulation of other behaviors. For
example, hoarding of food which normally is not displayed in the
laboratory rat in ad lib feeding situations, will occur when exposed
to cold Ta's of 5 and 17.5 °C (Fantino and Cabanac, 1984). Johnson and
Cabanac (1982) developed an interesting experimental paradigm showing
that rats forced to leave a thermoneutral environment to feed in an
extremly cold environment (-15 °C) increased their feeding duration in
order to avoid prolonged exposure to cold but were nonetheless able to
maintain caloric balance.
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VIII. ACCLIMATION TO THERMAL STRESS
In the study of the physiological responses during relatively
long term exposure to thermal stress, the terms acclimation,
acclimatization, and adaptation are used loosely and are often
interchanged. This author prefers the usage defined by Bligh and
Johnson (1973) and reiterated in a recent update of the glossary for
thermal physiology (IUPS, 1987): ACCLIMATION describes the adaptive
changes which occur within the lifetime of an organism in response to
experimentally induced changes in certain climatic factors (e.g., Ta):
ACCLIMATIZATION is used to describe those changes occuring as a result
of changes in the natural climate. ADAPTATION has often been used
interchangeably with acclimation. However, one commonly finds that
adaptation or, more precisely, genotypic adaptation, refers to
genetically fixed conditions which favor survival under particular
environmental conditions (Bligh and Johnson, 1973; IUPS, 1987).
1. Cold Acclimation
Physiological responses during cold acclimation have been well
studied in the laboratory rat and thus will be covered briefly because
of the excellent reviews available (Sellers, 1957; Chaffee and
Roberts, 1971; Hart, 1971; Folk, 1974; Jansky, 1979). The principal
physiological changes observed in the laboratory rat following cold
acclimation have been summarized (Table 2).
One of the primary effects of cold acclimation is the increased
sensitivity and capacity of physiological systems involved in
metabolic heat production. The function of the sympathetic nervous
system is crucial to the maintenance of thermal homeostasis during the
initial period of cold exposure (Maickel et al., 1967) as well as
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during prolonged acclimation to cold (see below). The development of
nonshivering thermogenesis (NST) is perhaps the most commonly studied
phenomenon in the cold-acclimated laboratory rat. NST capacity is
generally demonstrated by observing the rat's metabolic response
following systemic administration of norepinephrine (NE) (e.g., Jansky
, 1973). The nonacclimated rat increases its metabolic rate by
approximately 25% following a subcutaneous administration of NE
whereas the cold acclimated rat increases metabolism by approximately
100% (Jansky, 1971). The increased sensitivity to NE is brought about
by the enhanced development of brown adipose tissue during cold
acclimation (Smith and Roberts, 1964). It requires approximately 40
days of cold acclimation for the thermogenic response to NE to reach
full capacity (Bartunkova et al., 1971). On the other hand, when cold
acclimated rats are transferred back to near thermoneutral conditions,
the metabolic response to NE decreases rapidly with complete recovery
occuring in 20 to 25 days (Bartunkova et al., 1971).
Concomitant with the development of NST during cold acclimation
is the gradual suppression of shivering thermogenesis which decreases
drastically over the first 4 weeks of cold acclimation (Davis et al.,
1960). Moriya et al., (1985) performed a detailed study on the effect
of cold acclimation for 8 to 11 successive generations in the rat. One
interesting observation was an enhanced ability for NST in rats raised
for 3 generations at a Ta of 25 °C after being raised for many
generations at a Ta of 5 "C. Lifespan is severely reduced in rats
maintained continuously at a Ta of 9 °C compared to animals maintained
at 28 "C (Kibler and Johnson, 1961).
2. Heat Acclimation
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In comparison to the data base on response of the rat to cold
acclimation, there is relatively little information on the
physiological and behavioral responses which occur during heat
acclimation. Some of the principal physiological effects from heat
acclimation in the laboratory rat are summarized in Table 3.
Distinct physiological changes occur in the rat when the
environmental temperature is maintained at 30 to 35 "C for at least
several days. It appears that -the strategy of the laboratory rat
during heat acclimation is the rapid development of enhanced
capability to dissipate heat evaporatively, followed by biochemical
modifications leading to a depression in the resting metabolic rate.
There is an intensification of mitotic activity and concomitant
hypertrophy in the submaxillary gland of the rat within 2 days after
continued exposure to a temperature of 34.5 °C (Horowitz and Soskolne,
1978). However, the enhanced mitotic activity in the salivary gland
returns to basal levels within 5 days of heat exposure. Hypertrophy of
the submaxiallary gland during heat stress can be nearly abolished
with parasympathectomy, but not sympathectomy (Elmer and Ohlin, 1970).
A reduction in resting metabolic rate has been demonstrated by day 4-5
of exposure to 34 °C (Yousef and Johnson, 1967) and day 30 of exposure
to 35 °C (Sod-Moriah, 1971. Food intake and voluntary activity are
reduced while water consumption is significantly increased during heat
acclimation in the rat (Hamilton, 1963; Kerr et al ., 1975). Weight
of most organs such as the liver, kidney, and spleen decreases, while
that of the submaxillary gland increases over a 28-day exposure to a
temperature of 34.5 °C (Horowitz and Soskolne, 1978). Moreover, renal
function is severly compromised (Chayoth et al., 1984) while cardiac
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capacity is accentuated (Horowitz et al., 1985) in the heat-acclimated
rat. On the other hand, prolonged exposure to high environmental
temperature is reported to have no effect on the weight of the brain
and principal reproductive organs of the rat (Ray et al., 1968).
Plasma corticosterone levels peak after 24 hours of continuous
exposure to 34 °C and then quickly subside (Kotby and Johnson, 1967).
Some data indicate that there may be an upward resetting of the
set-point for body temperature during heat acclimation (Sod-Moriah and
Yagil, 1973; Gwosdow et al., 1985). Indeed, the sensitivity of the
preoptic area and anterior hypothalamus to neuromodulating substances
is significantly altered in the warm-acclimated rat (Ferguson et al.,
1984). However, there is an apparent paradox in this finding because
of the reported reduction in threshold core temperatures for
activating tail vasodilation and salivation following heat acclimation
(Horowitz and Meiri, 1985). An elevation in the set-point during heat
acclimation would lower water requirements for evaporation during
heat stress. Interestingly, there is no evidence for a lowering of
set-point during cold-acclimation which, if it occurred, would lower
the demand for energy expenditure. The potential for environmental
modification of the body temperature set-point needs further study.
IX. GROWTH, REPRODUCTION, DEVELOPMENT, AND AGING
1. Optimal Environmental Conditions for Growth
It is well known that extreme changes in environmental
temperature will exert profound effects on the growth and development
of the rat (cf. Thermal Acclimation). However, it would be useful to
know how subtle changes in Ta can affect growth and development,
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because such information would help standardize experimental data
collected from different animal colonies. To this end, several studies
have attempted to determine the optimal environmental conditions for
growth, reproduction, and development of the laboratory rat, and how
much can Ta deviate from optimum conditions without affecting growth
and development of the rat. Optimum or recommended environmental
temperatures for the laboratory rat are reported to range from 17 to
29 "C (see Yamauchi et al ., 1981). This seems to be an incredibly
large variation that needs more precise refinement.
Yamauchi et al., (1981) performed a thorough study of the effect
of Ta's of 12 to 32 °C (50% relative humidity) on an array of growth
and developmental parameters in the laboratory rat (Jcl:(WI) strain).
To briefly summarize their data, the Ta range at which various
parameters were unaffected were; body weight gain, 18 to 0 °C; food
intake, 20 to 26 °C; water intake, 12 to 26 "C; blood chemistry, 20 to
26 °C; organ weights, 18 to 28 °C; and reproductive function, 12 to 30
or 32 °C. It was concluded that the optimal Ta range for the
laboratory rat was 20 to 26 °C. It is interesting to note that the
upper value of the optimum temperature is below the lower critical Ta
for elevating metabolic rate and coincides with the preferred Ta
reported in many studies (cf. Table 1; M).
The interaction between relative humidity and Ta on growth and
development of the rat can be significant (Weihe, 1965). Ta's of 21 to
26 °C are optimal for growth at relative humidities of 45 to 55%.
Humdities below 30% at cool Ta's result in increased water and mineral
requirements and may lead to an increased incidence of ringtail
disease (Weihe, 1965).
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2. Reproduction and Thermal Stress
Acclimation to temperatures above 30 "C generally results in
adverse effects on reproduction in the male and female rat. At a Ta of
35 °C the scrotal and deep body temperature of the male rat is
elevated which may be a contributing factor in heat-induced
degerneration of seminiferous tubules (Sod-Moriah et al., 1974). The
body-scrotal temperature gradient appears to be crucial in affecting
spermatogenesis in the rat (Sod-Moriah et al., 1974). Heat acclimation
appears to directly affect the pituitary-testicular axis in the rat.
Acclimation to a temperature of 35 °C results in reduced serum
prolactin and testosterone levels as well as a reduced capacity of the
testes to synthesize testosterone (Chap and Bedrak, 1983; Bedrak and
Chap, 1984). Rearing rats at a Ta of 30 °C results in a slight but
significantly heavier testes; however, acclimation temperatures as low
as 12 °C have no effect on the weight of the testes or ovaries
(Yamauchi et al., 1981). Blumberg and Horowitz (1988) have recently
reported on a rapid cooling of the hypothalamus of the male rat
following ejaculation which appears to be mediated through modulations
in nasal vasomotor tone. It is not known how this brain cooling
process might be influenced following warm acclimation.
Heat acclimation exerts a variety of deleterious effects on the
reproductive tract of the female rat. The duration and irregularity of
the estrus cycle are increased following acclimation to 35 °C (Sod-
Moriah, 1971). Although the number of corpora lutea produced is not
affected by heat acclimation, the percentage of fertilized and
implanted ova, and number of young born are all decreased in the heat
acclimated rat when these variable are expressed as a percentage of
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total corpora lutea produced (Sod-Moriah, 1971). Heat acclimation also
increases the variability of the length of gestation (Sod-Moriah,
1971). Cell proliferation of fertilized ova is also reduced in the
heat-acclimated rat (Banai and Sod-Moriah, 1976). This may be
attributed to increased serum progesterone level that occurs during
heat acclimation (Bedrak and Sod-Moriah, 1974). Rats raised from birth
at Ta's of 30 and 32 °C have significantly smaller litters and weaning
rates compared to animals raised at cooler Ta's (Yamauchi et al.,
1981). Interestingly, most male and female rats that survived exposure
to heat that resulted in colonic temperatures of 42.5 °C were able to
reproduce normally at a later time although there was a possibility of
increased sterility in the male rats (Furuyama et al., 1984).
3. ThermoreguTation during Pregnancy and Lactation
The pregnant and lactating rat displays changes in
thermoregulatory function when exposed to heat and cold stress. It
appears that the suppression of thermogenesis is important for energy
economization in the pregnant rat. For example, diet induced
thermogenesis is suppressed during pregnancy in spite of hyperphagia
(Abelenda and Puerta, 1987). Sympathetic activity in brown adipose
tissue (BAT) is suppressed during pregnancy (Villarroya et al., 1987)
and lactation but appears to recover after weaning (Trayhurn, 1985).
Exposure of pregnant rats to 4 °C for the duration of pregnancy also
results in decreased birth weight as well as deficiencies in
respiratory function (Saetta et al., 1988).
The Ta-metabolic rate and Ta-body temperature profiles of the
lactating rat differ tremendously from that of the virgin animal
(Roberts and Coward, 1985). Resting metabolic rate is similar for both
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conditions at thermoneutrality, however; at Ta's below
thermoneutrality the metabolic rate of the lactating animal is much
greater than that of the virgin rat (Roberts and Coward, 1985). Core
temperature of the lactating dam at 4 and 10 days postpartum is
substantially higher than that of the nonlactating rat at Ta's of 4,
22, and 28 °C (Jans and Leon, 1983). During nesting episodes,
temperature of the ventral subcutaneous area and body core of the dam
rise steadily and then drop sharply once she leaves the nest
(Croskerry et al., 1978). Hence, these thermal stimuli may play a
crucial role in governing nesting and nursing behavior in the
lactating rat.
Heat tolerance, as estimated by survival when exposed to a Ta of
39.5 °C, is greatly reduced in the rat during late gestation and
lactation. Impaired heat tolerance in lactating dams may be attributed
to the reduced ability to dissipate heat by evaporation (Knecht et
al., 1980). At day 18-20 of gestation rats maintained continuously at
a Ta of 33 °C sustained more than 50% mortality (Fujita and Yamauchi,
1984). Just prior to death under these conditions blood pressure was
nearly undectable and body temperatures were extremely high (42.0-
43.7 °C). On the other hand, Wilson and Strieker (1979) found that the
pregnant rat attempted to regulate its temperature at a level lower
that virgin rats when exposed to heat stress. Normally, rats exposed
to high Ta's undergo a regulated hyperthermia which is important in
conservation of body fluids during heat stress (see Evaporative Water
Loss section). The pregnant rat applys saliva to its fur at a lower Ta
range (30-36 °C) than the virgin rat (Ta>36 °C). Moreover, the
threshold temperature for salivary secretion during heat stress is
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notably lower in the pregant (37.8 °C) compared to the virgin rat
(39.5 °C) (Wilson and Sticker, 1979). The amplitude of the diurnal
temperature rhythm of the female rat has been reported to decrease
during gestation and then increase during lactation (Kittrell and
Satinoff, 1988).
a. Hyperthermia as a Teratogen
The ability of the pregnant rat to maintain its core temperature
below that of the nonpregnant female during heat stress is indicative
of crucial adaptations to protect the fetus from the potential
deleterious effects of hyperthermia. Hyperthermia of sufficient
magnitude and duration will evoke an array of defects to the fetus of
the rat as well as other species (Germain et al., 1985; Edwards, 1974,
1982; Lary et al., 1986). Edwards (1982) estimated the threshold
embryonic temperture which retards brain development to be 1.5 to 1.7
°C above baseline. The threshold core temperature resulting in
prenatal death and/or birth defects is 41.5 °C for pregnant rats
exposed to 27.12 MHz radiofrequency radiation (Lary et al., 1986). At
9.5 days of gestation, a stage where the rat embryo is most sensitive
to heat, an increase in temperature of 2.5 °C for 60 min was the
threshold for inducing teratogenesis (Germain et al., 1985; Brown-
Woodman et al., 1988). Microcephalia can be detected in 9.5 day-old
fetal rats exposed to 40 "C in vitro (Cockroft and New, 1978).
4. Ontogeny of Thermoregulation
The newborn rat is essentially poikilothermic and must rely
upon the maternally maintained microenvironment in order to achieve
thermal homeostasis. Thermoregulation in the newborn is a complex
process involving interactions between the individual rat pup, the
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huddle of pups, and the mother. Alberts (1978) reported on the
dynamics of huddling of neonatal rats in a litter. Surface area of
the huddle of rat pups is reduced at cooler Ta's in an attempt to
reduce heat loss. Leon et al., (1978) provided a detailed monograph on
the interaction between temperature and mother-young bouts in the rat.
It can be shown that time spent by the mother with the young is
affected by the heat balance of the pup huddle as well as that of the
mother.
There is some question over whether or not newborn rats can
behaviorally maintain body temperature. It is difficult to develop an
experimental paradigm to quantitate behavioral thermoregulation in the
newborn rat because of their relatively poor locomotive ability. For
example, Fowler and Kellog (1975) concluded that rats less than 5 days
of age exhibited no choice for selecting a warm environment. On the
other hand, Kleitman and Satinoff (1982) demonstrated that given
sufficient time, 1-day-old rats exhibited thermotaxis in a gradient
provided that the initial temperature of placement in the gradient was
not too cold. Johanson (1979) determined that the responsiveness of
young rat pups in a thermal gradient can be influenced by factors such
as maternal deprivation and repeated handling.
As rat pups age the response in a temperature gradient is to
select areas which result in higher core temperatures (Table 4). It is
interesting to note that the core temperature of rat pups in a typical
nest increases with age with values of 35.5 °C for the 5-day-old pup
to 37.1 °C for the 21 days old pup (Conklin and Heggeness, 1971; Table
4). When maintained at Ta's within their TNZ, core temperature of
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Wistar rat pups is maintained within 36 to 37 °C regardless of age
(Takano et al., 1979).
Rat pups have relatively high metabolic rates when normalized to
body mass; however, because of underdeveloped insulation and small
size, these high metabolic rates can only be maintained at relatively
warm Ta's (Table 4). The devlopment of NST in the BAT of the growing
rat pup is crucial to the normal development of the thermoregulatory
system (Skala, 1984; Benito, 1985). Single rat pups maintain higher
metabolic rates compared to groups of rat pups permitted to huddle
(Alberts, 1978). One-day-old rat pups are capable of doubling
metabolic rate with subtle ambient cooling (Thompson and Moore, 1968).
The ability to increase heat production during ambient cooling is
similar in 1- and 6-day-old rats and then increases dramatically from
6 to 20 days of age (Thompson and Moore, 1968). Resting metabolic
rate, normalized to surface area, increases from 25.5 in the 5 to 7
day-old to 32.4 W/m2 in the 17-19 day-old pup when determined at
thermoneutral Ta's (Table 4). Furthermore, the lower critical Ta
decreases from 34.5 °C in the 5 to 7 day-old pup to 32.0 8C in the 17-
19 day-old pup (Spiers and Adair, 1986). In a very thorough study on
the development of cold resistance in the rat, Hill (1947) defined
five general periods in the life span of the rat: (i) birth to 18
days, where there is relatively little resistance to cold; (ii) 18 to
30 days, a period of radid development of cold resistance; (iii) 31 to
60 days, a period with slight improvement; (iv) 61 to 300 days, the
period of maximum cold resistance; and (v) 300 days to death, a period
associated with slow deterioration in cold resistance. There are
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several excellent reviews on thermoregulation in newborn mammals
(Hull, 1973; Alexander, 1975; Leon, 1986).
An endogenous circadian core temperature rhythm appears to
develop during the first postnatal week (Schmidt et al., 1987). Using
implanted telemetry probes, Kittrell and Satinoff (1986) concluded
that the circadian temperature rhythm occurs around day 24 and
continues to develop up through day 50.
A. Hyperthermic-Induced Seizures
The rat pup has been shown to be a useful experimental model for
the study of febrile convulsions. In the two-day-old rat, raising body
and brain temperature above a threshold of approximately 37 °C will
result in convulsions (Holtzman et al., 1981). As the rat pup ages the
threshold core temperature for convulsive activity increases, reaching
its nadir of 44 to 45 °C at 10 to 12 days of age; however,
hyperthermic-induced convulsions were reversible only in animals less
that 10 days of age. In a study of the 15 day-old rat pup, the
threshold seizure temperature was 40.8 to 41.5 °C which also resulted
in well over 50% mortality (Puig et al., 1986). With increasing age
the brain temperature for seizure activity and irreversible cell death
are approximately equal; hence, reversible, hyperthermia-induced
seizures can only be elicited in the relatively young rat pup. The
threshold colonic temperature for the induction of convulsions in the
adult rat exposed to a Ta of 50 °C is 43.19 °C (Kasting et al., 1981).
This core temperture is slightly below the reported lethal body
temperature of most rat strains (cf. Table 1; J).
5. Aging and Thermoregulation
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When one considers the increased mortality of elderly human
populations during temperature extremes, it is clear that animal
models of thermoregulatory deficits with aging should be developed.
The aged rat shows deficits in thermoregulation in both hot and cold
environments and in the ability to dissipate heat during forced
exercise (Cox et al., 1981; Balmagiya and Rozovski, 1983; Kiang-
Ulrich and Horvath, 1985; Durkot et al., 1986). At an age of two
months the rat displays thermoregulatory responses identical to that
of a 12 month-old animal (Cox et al., 1981). Thus, it is likely that
by the age of 2 months the thermoregulatory system is fully developed
in the rat. In the Sprague-Dawley rat maintained at thermoneutrality,
resting metabolic rate decreased 47% and core temperature was reduced
by 0.8 °C with increasing age from 3 to 24 months (Balmagiya and
Rozovski, 1983). Contrarily, Kiang-Ulrich and Horvath (1984a) reported
a significant 0.8 °C elevation in core temperature in the 20-24 month-
old Fischer rat compared to the 3-4 month-old rat.
As aging progresses the ability for NST diminishes and the rat
apparently relies more on ST to maintain heat production in the cold
(Balmagiya and Rozovski, 1983; Lee and Wang, 1985). The significant
attenuation of NE-stimulated thermogenesis, BAT mass, and BAT binding
of GTP in the two-year-old rat is indicative of loss of sympathetic
mediation of NST with aging (McDonald et al., 1988a). Deficiencies in
thermogenesis and thermolysis are observed in the aged rat following
the administration of endotoxin (Tocco-Bradley et al., 1985) and key
neuromodulating substances such as norepinephrine, carbachol,
dopamine, and prostaglandin £2 (Ferguson et al., 1985).
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Deficiencies in thermoregulatory ability during exposure to heat
and cold stress are most pronounced at two years of age but have also
been detected as early as one year. Age-dependent thermoregulatory
deficiences appear to be associated with dysfunction of the autonomic
but not behavioral systems. For example, operant behavioral
thermoregulatory responses are indistinguishable in Sprague-Dawley
rats ranging in age from 7 to 28 months (Jakubczak, 1966). On the
other hand, in tests monitoring response to acute cold exposure, it
was found that 3 month-old rats responded better metabolically that 1
year-old animals (Kiang-Ulrich and Horvath, 1985). Furthermore, the
ability to maintain a normal body temperature during exposure to -10
°C was severely impaired in the two year-old rat. Cox et al., (1981)
reported a deficit in vasodilatory mechansims in the heat stressed rat
at an age of 1.5 and 2 years of age. These same age groups were also
less capable of maintaining normal body temperature in the cold,
whereas vasoconstrictive responses were similar for all age groups
during cold exposure. Ability to acclimate to a cold Ta of 5 °C is
significantly reduced in the 25-month-old Fischer rat (Kiang-Ulrich
and Horvath, 1985a); however, it should be noted that there is some
controversy concerning the ability of aged rats to survive prolonged
cold stress (Gamber and Barboriak, 1982; Kiang-Ulrich and Horvath,
1985). Adaptation to restraint-induced hypothermia is signficantly
attenuated in two-year-old rats compared to 3- and 11-month-old
animals (Pare, 1989).
Exercise training enhances the thermogenic capacity of aged rats
exposed to cold (McDonald et al., 1988). The protective effect of
exercise was attributable to increased shivering capacity in the cold.
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Notable differences in heat dissipation during forced exercise are
seen in rats of 8 versus 30 weeks of age (Durkot et al., 1986).
Younger rats have much better endurance and a reduced rate of heat
gain during exercise compared to older animals. Much of this
difference can be attributed to the difference in body mass between
young and old rats (Durkot et al., 1986).
X. MOTOR ACTIVITY AND THERMOREGULATION IN THE RAT
1. Spontaneous Activity and Ta.
The interaction between spontaneous motor activity, body
temperature and Ta can be quite complex. It was thought at one time
that the rat became more active as a means of thermoregulating during
cold exposure and/or starvation. Indeed, the spontaneous activity of
the rat, such as running in a activity wheel, increases as Ta is
decreased below thermoneutrality (Browman, 1943; Poole and Stephenson,
1977; Finger, 1976; Stevenson and Rixon, 1957) and when the animal is
deprived of food (Stevenson and Rixon, 1957; Campbell and Lynch, 1967,
1968). There is a marked elevation in running wheel activity of the
rat when Ta is lowered from 25 to 20 °C (Fregly, 1956).
Because body temperature of the rat may decrease during food
deprivation and cold exposure, it was reasoned that the observed
increase in motor activity during these conditions was a
thermoregulatory response to increase thermogenesis from skeletal
muscle (for discussion see Bolles et al., 1968; Campbell and Lynch,
1967; Hart, 1971). However, it now seems clear that increased motor
activity is not a thermoregulatory response to produce heat under
conditions of increased heat loss and/or an energy deficit. For
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example, Campbell and Lynch (1967) found that food-deprived rats
maintained at a warm Ta of 31 °C to prevent the development of
hypothermia were more active than ad lib fed rats. Moreover, rats
normally run more during the time of day when their body temperature
is high (Bolles and Duncan, 1969). On the other hand, the rise in body
temperature during running, especially at warm Ta's, is most likely a
critical cue for the cessation of running and thus a measure to
prevent overheating (Campbell and Lynch, 1967). The effect of raising
Ta on motor activity in the rat is occasionally unpredictable; escape
behavior may manifest an elevation in running activity in the heat
(Finger, 1976).
Another controversy involves the issue of whether or not the rat
is active at night because its body temperature is elevated or body
temperature is elevated because of the increased activity, de Castro
(1980) concluded that core temperature varied around bouts of simple
behaviors such as eating, drinking, and running, but core temperature
was not regulating the activation of these behaviors. Clearly,
behaviors such as gross activity, feeding and drinking and autonomic
parameters such as heart rate are all higher during the night in the
rat (de Castro, 1978; Meinrath and D'Amoto, 1979). Bursts of
spontaneous activity can clearly cause transient elevations in core
temperature, however; the core temperature determined at zero level of
activity is notably higher in the dark period of the circadian cycle
(Honma and Hioshige, 1978). Determining the role of activity in the
control of body temperature by comparing day:night differences may be
confounded by the likelihood that the set-point for control of body
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temperature is elevated during the dark phase of the circadian cycle
(see Circadian Rhythm Section).
2. Exercise
The laboratory rat has been commonly used to study the
interaction between exercise and thermoregulation. Most studies have
determined the thermoregulatory effects of forced exercise by
electrically shocking animals to run on a treadmill or running wheel.
Often reported is a direct relationship between work intensity as
based on running velocity and the rise in core temperature during
exercise (Shellock and Rubin, 1984; Wilson et al., 1978; Harri et al.,
1982). The colonic temperature associated with complete exhaustion
from forced running was estimated at 41.8 °C by Gollnick and lanuzzo,
1968; however, others have measured colonic temperatures between 42
and 43 °C in the rat during intense running activity (Shellock and
Rubin, 1984; Fruth and Gisolfi, 1983).
Environmental temperature has a significant effect on the
thermoregulatory response to exercise in the rat. It has generally
been found that the rise in colonic temperature at a given metabolic
rate during running increases with rising Ta (Tanaka et al., 1988;
Harri et al., 1982; Shellock and Rubin, 1984); however, a direct
relationship between work load and elevation in core temperature is
not always evident in the exercising rat (Wilson et al., 1978).
Shellock and Rubin (1984) noted that forced exercise at high Ta's
becomes a problem for the rat because of the inability to increase
evaporative water loss by grooming saliva to the fur as these animals
display normally when exposed to high Ta's (see Evaporative Water Loss
section). However, in spite of the inability to groom during forced
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exercise, rats which were run to exhaustion had a 3.7 to 6.1% loss in
body fluids (Durkot et al., 1986). At extremely cool Ta's forced
exercise generally leads to a reduction in body temperature (Myhre and
Hellstrom, 1973; Tanaka et al., 1988). For example, at a Ta of 4 "C,
the rat's core temperature will remain below its preexercise level
after 30 min of forced exercise until metabolic rate exceeds 70 to 80%
of the V02 max (Tanaka et al., 1988).
Vasomotor control of blood flow to the tail and feet changes
dramatically during exercise in the rat. At normal room temperature
the tail may actually vasoconstrict during the initial phase of
exercise (Wilson et al., 1978; Shellock and Rubin, 1984). As exercise
progresses core temperature increases to a threshold point at which
there is a sudden increase in blood flow to the tail and feet
(Thompson and Stevenson, 1965; Wilson et al., 1978; Shellock and
Rubin, 1984). The tail and foot appear to vasodilate when core
temperature reaches an average of 39.2 8C when running at a Ta of 24
°C (Thompson and Stevenson, 1965). The peripheral vasodilatory
response to exercise is also dependent upon Ta. At cold Ta's of
approximately 5 °C the temperature of the tail will decrease (Myhre
and Hellstrom, 1973; Tanaka et al., 19880). On the other hand, running
at Ta's above the thermoneutral zone results in rapid elevations in
tail temperature with very little latency in response (Shellock and
Rubin, 1984).
The heat produced from exercise imparts interesting interactions
on the function of the thermoregulatory system. Rats subjected to
identical heat loads from passive heating or from exercise encounter
significantly higher rates of mortality when subjected to the exercise
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mode of heating (Hubbard et al., 1977). Rats with a smaller body mass
exhibit lower rates of heat gain and better endurance compared to
heavier, older rats during forced running (Durkot et al., 1986). In
the cold, warm- and cold-acclimated rats will substitute the heat
produced by exercise for heat normally generated by shivering and non-
shivering thermogenesis, respectively (Hart and Jansky, 1963; Arnold
et al., 1986). Exercise training will result in an elevation in the
core temperature of exhaustion (Fruth and Gisolfi, 1983) while heat
acclimation (35 °C) for 4 weeks leads to a reduction in endurance
capacity (Francesconi et al. , 1982).
a. Maximum Metabolic Thermogenesis
The maximum rate of oxygen consumption (V0£ max) of the
laboratory rat has been determined under a variety of exercise and
cold exposure scenarios (Table 5). These type of data are occasionally
controversial because of the difficulty in establishing true steady
state conditions (e.g., see Bedford et al., 1979). In addition, Conley
et al., (1985) have found that V02 max determined with exercise cannot
be used interchangeably with V02 max determined with acute cold
exposure, especially in the study of endurance training.
In general, the V02 max for the rat during exercise and/or cold
exposure reportedly ranges from 85 to 110 ml/(kg-min) which represents
approximately a 5 to 6 fold elevation in metabolic rate above basal
levels. The VC>2 max can be influenced by an array of variables
including gender, training, age, and previous thermal history (Pasquis
et al., 1970; Bedford et al., 1979; Divine and Brooks , 1980). For
example, adaptation to endurance training will lead to a 28% increase
in V02 max (Conley et al., 1985).
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XI. CIRCADIAN THERMOREGULATORY RHYTHM
It is well known that the laboratory rat is a nocturnal animal
and is most active during the dark phase of the circadian cycle.
Moreover, it is commonly known that body temperature, metabolic rate,
heart rate, and activity are all significantly higher during the dark
phase, although, for reasons of convenience, the majority of
thermoregulatory studies in the rat have been performed during the
light phase (see below).
Day to night increments in core temperture are reported to range
from 0.7 to 2.0 °C in the rat (Satinoff et al., 1982; Buttner and
Wollnik, 1982; Scales and Kluger, 1987). When placed on a 12:12 L:D
cycle with lights on at 0600 hrs, core temperature of the rat exhibits
several distinct phases (Scales and Kluger, 1987): (i) a stable
daytime phase with an average core temperature of 37.3 °C; (ii) a
rising phase that begins at 1600 hrs with the sharpest increase at
1730 to 1900 hrs; (iii) a plateau phase between 1900 and 0500 hrs with
an average core temperature of 38.1 °C; and (iv) a phase in which
temperature drops sharply and exhibits a transient undershoot of the
afternoon average temperature.
It was originally thought that the elevation in core temperature
was attributed to the increased activity of the rat during the dark
phase (see Activity section); however, it is now known that while
transient elevations in temperature can be correlated with bursts of
activity, the overall circadian elevation in temperature is
independent of motor activity (Honma and Hiroshige, 1978; Eastman and
Rechtschaffen, 1983). Indeed, placing rats under conditions of
constant light or darkness or blinding the animals will abolish the
57
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circadian body temperature rhythm (Fiorettie et al., 1974) but not
have nearly the same effect on the activity rhythm (Barbely and
Nehaus, 1978). Phase delay in the normal activity cycle of the rat can
be achieved by lowering core temperature below 28 8C (Gibbs, 1981).
The circadian cycle of body temperature has been attributed by
many to represent a cyclic shift in the set-point for control of body
temperature. For example, recent work for the laboratory of M.J.
Kluger indicates that the rise in core temperature during the
nocturnal phase is an elevation in set-point mediated by a central
neural release of prostaglandins of the E series (Dear et al., 1983;
Scales and Kluger, 1987). The correlation between core temperature and
the activation of various thermoregulatory effectors changes from day
to night in the rat which suggests that the nervous system is
modulated to regulate temperature at different levels depending on the
time of day (Shido et al., 1986; Shido, 1987). However, when permitted
to choose among different Ta's, rats select cooler Ta's during the
dark phase of the circadian cycle (Briese, 1985, 1986). The phase
relationship between brain and preferred temperature argues against
the notion of a circadian shift in set-point (Briese, 1986).
a. sleep
The control of body temperature during sleep has been well
studied in a many species (e.g., Heller and Glotzbach, 1977). It is
pertinent to this review since most investigations in the rat are
performed during the light cycle when the rat is most apt to sleep.
The rat, like many species, undergoes a decrease in brain temperature
during the transition period from wakefulness to slow wave sleep (SWS;
Kovalzon, 1973; Glotzbach and Heller, 1977). Interestingly, during
58
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paradoxical sleep there is an elevation in cerebral blood flow and a
transient elevation in brain temperature of the rat while at the same
time there is usually an elevation in dry heat loss (Roussel et al.,
1980; Obal et al., 1985). In a total calorimetric analysis of the rat
during wakefulness and sleep, Schmidek et al., (1983) found that heat
production was maximal during wakefulness, decreased gradually during
synchronized sleep, and was minimal during paradoxical sleep. The
metabolic effect was more pronounced by decreasing Ta and appeared
qualitatively similar in warm (23 °C) and cold acclimated (6 °C)
animals. Also noted was a maximal increase in dry heat loss during
paradoxical sleep at a Ta of 15 "C (Schmidek et al., 1983). Negative
heat storage is always observed in the rat during paradoxical sleep at
Ta's of 15 to 30 °C, whereas at a Ta of 35 "C, heat storage is
positive during this phase of sleep (Schmidek et al., 1983).
The transition between wakefulness and sleep in the rat is very
sensitive to Ta (Schmidek et al., 1972; Szymusiak and Satinoff, 1984).
Szymusiak and Satinoff (1981) found that the thermoneutral zone of the
rat could be defined in more narrow limits when time in REM sleep
rather than metabolic rate was used as a dependent variable. That is,
while metabolic rate was minimal over a Ta range of 25 to 31 °C, time
in REM sleep varied significantly and was maximal at a Ta of 29 °C.
Indeed, the time in REM sleep at 29 °C was more than double that at a
Ta of 23 "C, a common laboratory room temperature. Increasing Ta above
30 °C evokes an even greater inhibition in REM sleep time than that
of lowering Ta. For example, at a Ta of 34 °C the amount of time in
REM sleep is less than 10% of animals maintained at 30 °C (Kent et
al., 1987).
59
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XII. GENDER DIFFERENCES
Although it is a little studied area, it would appear that there
are distinct differences in thermoregulatory response between male and
female rats. During acute cold exposure male rats elicit significantly
greater increases in shivering and metabolic rate compared to females;
however, the control of colonic temperature during cooling is similar
between the two sexes suggesting that female rats are more efficient
at thermoregulation during cold exposure (Doi and Kuroshima, 1981).
Males also elicit greter increases in thermogenesis (Doi and
Kuroshima, 1981) and body temperature (Leblanc et al., 1982)
following administration of norepinephrine. One study suggested that
males were more likely to undergo an increase in body temperature
following administration of endotoxin (Ford and Klugman, 1980).
Under normal room temperature conditions female rats tend to have
slightly higher core temperatures (Fujii and Ohtaki, 1985) and
metabolic rates than males (Perez and Eatwell, 1980). For example, at
70 days of age female rats consume oxygen at a rate that is 23%
greater than males (Castella and Alemany, 1985). Although it should be
noted that a very early, albeit thorough study, showed that male rats
exhibit higher metabolic rates at thermoneutrality (Benedict and
MacLeod, 1929). To further complicate matters, a very recent study
reported no differences in oxygen consumption (mass-independent)
between male and female rats of various ages, but there were higher
colonic temperatures in female rats at thermoneutrality and during
exposure to a Ta of 6 °C (McDonald et al., 1989).
Gender differences is thermoregulation of the rat are often
distinguishable at various times of the reproductive cycle. There is
60
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an approximately 0.5 8C elevation in core temperature of the female
rat at proestrus compared to the second day of diestrus (Marrone et
al., 1976). Ovariectomy leads to a reduction in core temperature
(Yochim and Spencer, 1976). Estrogen replacement to ovariectomized
animals results in significant elevations in metabolic rate
(Laudenslager et al., 1980). Both progesterone and estradiol
replacements raise body temperature in the ovariectomized rat (Marrone
et al., 1976). Estradiol administration increases the behavioral
reinforcement for heat in the ovariectomized female rat, but not in
intact animals (Wilkinson et al., 1980).
Survival to acute cold exposure is improved by castration in
male, but not female rats (Zarrow and Denison, 1956). Thus,
testosterone may antogonize cold resistance in the rat. Overall, the
sexually mature female rat is much better adapted at resisting acute
cold exposure (Zarrow and Denison, 1956). The more efficient
thermoregulatory response of the female rat to acute cold exposure may
be partly attributable to better tissue insulation (Doi and Kuroshima,
1981).
Some studies suggest that male rats may have advantages over
females during acute heat exposure. Males are more active in the heat
and spend a larger percentage of time applying saliva to the fur
(Hainsworth, 1967). During heat exposure the testes decend early and
the scrotum is engorged with blood providing greater surface area for
heat dissipation (Hainsworth, 1967). Male rats in the heat actively
apply saliva to the base of tail and scrotum which enhances
evaporative water loss (Hainsworth, 1967). On the other hand, Furuyama
(1982) found that survival time to acute heat exposure (42.5 °C) was
61
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significantly greater in female Sprague-Dawley rats, but this gender
effect was not found in other strains of rat.
During forced exercise the tail of male rat vasodilates at a
lower core temperature, a response which may be responsible for the
higher core temperature of the female rat when exercising (Thompson
and Stevenson, 1965). During the nocturnal phase core temperature in
the estrus female rat is significantly higher than that recorded
during proestrus (Yochim and Spencer, 1976; Yanase et al., 1989). When
female rats are forced to exercise the threshold core temperature for
the elevation in tail temperature was higher in the estrus stage
compared to proestrus. Otherwise, there were no differences in the
control of core temperature during exercise as a function of the
estrus cycl'e (Yanase et al., 1989).
XIII. GENETIC DIFFERENCES
Some of the effects of strain of rat on thermoregulation are
apparent in the earlier data summaries (Table 1). Otherwise, there
have been a few attempts to determine the effect of genetic strain on
thermoregulatory response in the rat. There are occasional differences
in thermoregulatory response from one strain to the next; however, in
general there are few notable differences in parameters such as
metabolic rate, evaporation, thermal conductance, etc with the
exception to strains such as the corpulant Zucker and spontaneously
hypertensive rat. A general summary of reported differences in
thermoregulatory response and capacity to thermal stress of the
various strains of rat has been developed (Table 6). This table should
be used for means of general comparison.
62
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XIV. EFFECT OF RESTRAINT
Except where indicated, most of the papers cited and discussed in
this review have generally dealt with thermoregulatory responses in
the unrestrained rat. Restraint is used to permit a possible means of
collecting data normally not accesible in the unrestrained animal.
However, the stress from restraint in the naive rat can lead to severe
perturbations of the thermoregulatory system and can alter the
animal's response to physical and chemical stimuli. For example,
Martin et al., (1977) clearly demonstrated how restraint in the rat
alters it's thermoregulatory response to morphine and heroin.
Metabolic heat production increases approximately 28% along with
a 0.6 "C elevation in colonic temperature (Nagasake et al., 1979). The
restraint-induced elevation in metabolism appears to be mediated
through an activation in nonshivering thermogenesis of brown adipose
tissue (Shibata and Nagasaka, 1982). Considering the large increase in
restraint-induced thermogenesis, it is not surprisingly that
restrained rats die in less than half the time of unrestrained rats
during exposure to a Ta of 40 °C (Frankel, 1959). Paradoxically,
shivering and a concomitant drop in body temperature occurs in the
naive rat restrained at a Ta of 2 "C. However, rats adapted to the
restraint procedure continue to shiver in the cold (Shimada and Stitt,
1983).
XV. COMPUTER SIMULATION OF THERMOREGULATION
This field of study has been useful in predicting human
thermophysiological responses to various hazardous stimuli, but 'user
friendly', multipurpose computer models of have not been developed for
63
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predicting thermoregulatory responses in other species such as the
rat. Computer simulation of the rat thermoregulatory system could be
quite useful for a variety of pharmacological and toxicological
studies, especially when one considers that body temperture is most
susceptible to change following treatment with drugs and other
chemical agents (e.g., Clark and Clark, 1981; Clark and Lipton,
1985,1986; Gordon et al., 1988).
Sato et al., (1986) developed a simple, compartmentalized model
of the rat to predict rectal and skin temperture, metabolic rate, and
evaporative water loss as a function of changes in Ta. Giacchino et
al., (1979) reported on a computer simulation of thermoregulation in
the rat during cold and gravitational stimulation. A circulatory model
of blood flow in the rat tail has been developed which permits
studying effects of core and tail temperature on the control of heat
loss from the tail (Raman et al., 1987).
XVI. MISCELLANEOUS STIMULI AND THERMOREGULATION
The rat thermoregulatory system is sensitive to an array of
physical and chemical factors in the environment. With exception to
pharmaceutical agents and other chemical substances, which have been
well covered in other review articles (cf. Introduction), I have
summarized the effects of biological and physical stimuli on the rat
thermoregulatory system (Table 7). It is quite apparent from this
brief summary that body temperature of the rat may be quite labile in
the face of unusual environmental circumstances. One must remain
cognizant of these thermoregulatory effects when studying the impact
64
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of these stimuli on specific physiological and behavioral systems of
the rat.
XVII. CONCLUSION
An overall summary of the thermal biology of the laboratory rat
may best be made graphically (Figure 3). The rat is unusual amongst
other rodents in that it prefers Ta's much cooler than that associated
with minimal energy expenditure. Normothermia is maintined up to Ta's
of 30 °C and down to Ta's of approximately 10 °C. The thermoneutral
zone is extremely narrow (-28 to 30 °C) and the rise in metabolic rate
below the lower critical Ta does not follow the typical pattern
predicted by Newton's Law of Cooling (cf. Figure 1 and 2). Increase in
blood flow to the feet and tail occur at Ta's within the thermoneutral
zone; as Ta increases above this point the rat increases evaporative
water loss through autonomic and behavioral mechanisms. The rat is
most efficient at defending body temperature during extreme cold
stress rather than heat stress. The Ta range of optimal growth in the
rat appears to coincide with that of its behavioral preferrence.
65
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ACKNOWLEDGEMENTS
I'm most grateful to C. Martin, J. LaRocco, and A. Ingram for
their excellent work in running the computerized literature searches
I'm also most appreciative to the following for their review of the
manuscript: Drs. F.S. Mohler, E. Berman, A. Rezvani, S. Trautwein,
W.P. Watkinson, and R. Refinetti.
66
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Table 1. Summary of values of thermoregulatory parameters reported for
the laboratory rat.
A. BASAL (BMR) AND RESTING (RMR) METABOLIC RATE (M) AT THERMONEUTRALITY
AND STANDARD ROOM TEMPERTURE
Strain M, ml 02/(kg.min) Mass, kg Ta, °C Reference
S
ii
H
SD
Strain
NS
It
Strain
NS
A
A (f)
WKY (rstr)
SHR (rstr)
W
17.0 (BMR)
17.8 (RMR)
20.8 "
27.1 "
18.3 "
M, W/kg
4.54 (RMR)
7.43 "
M, W/m2
37.4 (RMR)
38.7 "
34.8 "
48.9 "
62.9 "
53.9 "
0.3
0.3
0.2
0.1
0.39
Mass, kg
0.32
0.32
Mass, kg
0.31-0.38
0.26-0.29
0.18-0.2
0.38
0.30
0.29
28
ii
n
ii
30
Ta, °C
31
21.5
Ta, °C
30-31
28
H
29
n
25
Bramente, 1968
n
n
n
Depocas, 1957
Reference
Swift, 1939
II
Reference
Herrington, 1940
Benedict, 1929
n
Collins, 1987
n
Nagasaka, 1979
B. CHARACTERISTICS OF THERMONEUTRAL ZONE
1. Lower Critical (LCT) Ta, °C
Strain
NS
SD
NS
W
W
SD, FCH, LE
SD
NS
A
LCT
29.2
27.0
26.5
28.0
25.0
28.0
22.0
30.0
28.0
Reference
Herrington, 1940
Depocas, 1957
Pace, 1983
Poole, 1977
Banet, 1988
Gordon, 1987
Gwosdow, 1985
Swift, 1939
Benedict, 1929
67
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Table 1 (cont).
2. Upper Critical Ta (UCT), °C
Strain UCT, "C Reference
NS 31.0 Herrington, 1940
NS 26.5 Pace, 1983
W 32.0 Poole, 1977
SD, FCH 30-32 Gordon, 1987
LE 32-34 Gordon, 1987
SD 27.0 Gwosdow, 1985
NS 33.0 Swift, 1939
'//////////
C. RESPIRATORY FREQUENCY (f)
Strain f, breaths/min Reference
NS (anes; normothermic) 84 Richards, 1968
" (anes; Tcoi=40.1 °C) 152
SD (Ta= 30 'C) 123 Nattie, 1979
11 (Ta= 35 °C) 188
'//
D. RESPIRATORY QUOTIENT (RQ)
Strain Ta, "C RQ Reference
W 25 0.85 Nakatsuka, 1983
1-5 for 4 days 0.76
SD
NS
20 (ad libitum
feeding; 24 h
mean) 0.87
20 (fasted; 24 h
mean) 0.73
21.5 (fasted 17 h) 0.72
7.5 " 0.71
35.0 " 0.77
24.0 (prefeeding) 0.83
24.0 (feeding) 0.93
SD (rstr)
28.0
0.72
Lackey, 1970
n
Swift, 1939
n
Sugano, 1983
ii
Caldwell, 1966
68
-------
Table 1 (cont).
E. THERMAL CONDUCTANCE, WET (Cw) (minimal value, i.e., Ta < LCT)
Strain Mass, kg Cw, ml 02/(g-h-°C) Reference
NS 0.16 0.1 (accl. 0-2 °C) Bradley, 1980
0.17 0.09 Hart, 1971
0.22 0.071
0.39 0.048
///////////////
F. THERMAL CONDUCTANCE, DRY (C
-------
Table 1 (cont).
2. Site: colon
Strain Ta, °C Time Tc, °C Reference
SD 20-24 day 37.0-37.4 Gordon, 1987
FCH " " 37.4-37.6
LE " " 37.3-37.9
3. Site: abdominal cavity (telemetry)
Strain Ta, 8C Time Tc, °C Reference
HZ (f) 23 0200 hrs 38.5 Spencer, 1976
0600 hrs 37.0
1500 hrs 37.1
NS day 37.2 Thornhill, 1978
night 37.9
" 24-h mean 37.6 "
4. Site: thoracic cavity
Strain Ta, °C Tc, °C Reference
WS 23 37.0 Poole, 1977a
'/////
I. CRITICAL Ta's FOR NORMOTHERMIA
Strain Exposure Time, min Ta, "C Reference
1. Upper Ta Limit
W
SD, LE
FCH
NS
SD
-10-20
90
90
360
150
31
30
34
28
30
Poole, 1977
Gordon, 1987
Herrington, 1940
Krog, 1955
2. Lower Ta Limit
NS
SD
360
150
30-135
14-15 Herrington, 1940
10 Krog, 1955
<-5.7 "C Depocas, 1957
70
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Table 1 (cont).
J. THERMAL TOLERANCE
1. Upper Lethal Core Temperature (Tc) and Survival Time (ST)
Strain Ta, °C Tc, °C ST, min Reference
LE 42.5 44.77 68 Furuyama, 1982
SD " 44.83 152
FCH " 45.37 132
W " 44.1-44.9 -95 Isobe, 1980
NS 38-50 42.5 (LDso) 60-480 Adolph, 1947
2. Critical Thermal Maximum (CTMax)
Strain Ta, "C CTMax, °C Time to CTMax, min Reference
NS 40.0 44.22 180 Erskine, 1982
3. Lower Lethal Core Temperature (Tc)
Strain Ta, °C Tc, °C Reference
NS (rstr) 10 15.1 Adolph, 1950
NS (anes) ? 6.3 (at last heart beat) Huttunen, 1963
4. Critical Thermal Minimum (CTMin)
Strain Ta, "C CTMin, °C Time to CTMin, min Reference
NS -40 16-20 40-60 Ferguson, 1970
K. SHIVERING THERMOGENSIS
1. Threshold Ta for Initiation of Shivering
Strain Ta, °C Reference
NS (f) 23.5 (0.2-0.3 °C/min cooling
rate; partial rstr) Dawson, 1981
SD 20.0 (24% increase in EMG
compared to Ta of
30 °C) Hart, 1956
P 15-20 Stoner, 1971
71
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Table 1 (cont).
L. PERIPHERAL VASOMOTOR RESPONSES
1. Ta for Initiation of Vasodilation (Ta_V(j) and Vasoconstriction
(Ta_vc) in the Tail
Strain Ta.vc|, "C Ta.vc, °C Reference
NS (rstr) 28 24 Hellstrom, 1975
W (f; rstr) 27-30 - Rand, 1965
H (rstr) 30 - Dawson, 1979
H (rstr) 27 Clarkson, 1972
2. Core Temperature (Tc) for Initiation of Vasodilation of Tail
Strain Tc, °C Reference
W (rstr) > 37.0 Hellstrom, 1975a
NS " 39.0 (anes) Grant, 1963
Z " 38.0 (Thypothalamus) Horowitz, 1985
P " 39.8 (Tbrain; heated with
thermode) Stoner, 1972
3. Range of Tail Blood Flow (Q)
Q, ml/(100 cc tissue-min)
Strain Min. Rate (vasoconstricted) Max. Rate (heat stress) Reference
NS (rstr) 5.0 68.0 Raman, 1982
1.6 45.0 Rand, 1965
L. EVAPORATIVE WATER LOSS
1. Cutaneous Evaporative Water Loss (EWLC)
Strain EWLC, mg H20/(cm2-hr) Reference
NS (anes) 2.6 Wang, 1980
72
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Table 1 (cont).
2. Percent Total Heat Loss as a Function of Ta
Strain
W
ii
NS
W
ii
SD
W
SD
H
Ta, °C
15
20
23-25
25
30
32
35
36
40
% Heat Loss
10
12
11-16
21
26
15-20
36
80-85
90
Reference
Schmidek, 1983
H
Tennent, 1946
Schmidek, 1983
H
Hainsworth, 1970
Schmidek, 1983
Hainsworth, 1968
H
3. Threshold Ta for Elevating Evaporation above Basal Level
(dry air environment)
Strain Ta
"C
» «
SD 30-32
LE 32-34
FCH 34-36
4. Respiratory
Strain
WKY (rstr)
II
II
SD
Evaporative
Ta, °C
12.5
23.0
28.5
8
22
30
Reference
Gordon, 1987
Water Loss
•5 ^™
W/m2
8.6
8.6
8.1
(Eres)
W/kg Reference
Collins, 1987
0.18 Lin, 1979
0.4
0.82
5. Threshold Core (hypothalamic) Temperature (Tco]) for Initiation of
Salivation
Strain Tcoi, "C Reference
Z (rstr) 39.5 Horowitz, 1985
73
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Table 1 (cont).
M. BEHAVIORAL THERMOREGULATION
Strain
SD
11
LE
FCH
LE
AL
SD
SD
LE
Apparatus
gradient
ii
ti
n
ii
n
M
n
operant
n
Selected Ta, °C
27.2
24.9
19.8
23.4
31.0
30-31
20-25
19.5
19.0
21-24*
Reference
Marques, 1984
Gordon, 1987
ii
n
Refinetti, 1986
Ettenberg, 1986
Gordon, 1985
Dupre, 1989
Refinetti, 1989
Corbit, 1970
*within this range of Ta's it was predicted that there was no operant selection
for cool air or radiant heat.
Key: SD-Sprague-Dawley, FCH-Fischer 344, LE- Long-Evans, HZ-Holtzman, S-
Simonsen (Sprague-Dawley derived), W-Wistar, AL-albino, Z-Zabar (albino
related), P-Porter (albino related), WKY-Wistar-Kyoto (normotensive), SHR-
spontaneously hypertensive, NS-not specified, rstr- restrained, anes-
anesthetized, f-female (all others male)
74
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Table 2. Summary of some major physiological and morphological changes in the
laboratory rat following cold acclimation.
Parameter
(dimension)
Metabolic Rate
(ml 02/(hr-g-52)
at Ta = 30 °C
at Ta = 6 8C
Metabolic Rate
(ml 02/(min-kg)
at Ta = 25 °C
at Ta = -19 °C
Max. Metabolic
Rate; Ta = -3 °C
(ml 02/(min-kg)
Respiratory
Quotient
Body
Temperature
(•C)
Body Fat (%)
Feed Efficiency
(weight gain/
food intake)
Daily Meal
Frequency
Meal Size
(g/meal )
Food Intake
(9/day)
Caloric Intake
(W/kg)
Tail Temperature
at Ta = 6 'C
Acclimation T, 8C
control cold
30 6
30 6
28 6
28 6
30 6
25 1
30 10
23 2
25 1
24 5
24 5
24 5
RT 3-8
30 6
Parameter Value
control cold
22.8 26.7
38.2 43.4
16.9 21.1
50.9 58.7
72.9 89.9
0.85 0.81
no change
9.9 6.8
0.35 0.12
11.0 9.0
2.7 4.6
28.4 40.4
8.6 17.8
10.4 11.2
Reference
Depocas, 1957
ii
Foster, 1979
H
Pasquis, 1970
Nakatsuka, 1983
Pinto, 1987
Nakatsuka, 1983
H
Leung, 1976
H
»
Page, 1953
Depocas, 1957
75
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Table 2 (cont).
Parameter Acclimation T, "C
(dimension) control cold
Cardiac Output
(ml/kg)
Ta = 25 °C 28
Ta = -19 °C 28
Heart Mass
(mg/100 g) 20
Adrenal Mass
(mg/100 g) 20
Interscapular
BAT Mass (g) 28
BAT Blood Flow
(ml/min)
Ta = 25 °C 28
Ta = 19 eC 28
Myoglobin (mg/g)
quadriceps 25
heart 25
Pelt Insulation
(°C/(W-m2) 30
Body Hair (g)
at 15 days accl . 25
at 65 days accl . 25
Operant Thermoregulatory
Behavior
Latency to activate
Heat Lamp 25
Reinforcements from
Heat Lamp 22
6
6
5
5
6
6
6
5
5
6
5
5
2
5
Parameter Value
control cold
413 459
751 882
259 319
16.6 23.5
0.67 1.03
2.1 2.3
25 56
0.08 0.27
1.52 1.95
0.27 0.27
0.5 1.45
0.5 0.8
increase with cold
acclimation
decrease with cold
acclimation
Reference
Foster, 1979
ii
Harri, 1984
"
Foster, 1979
H
ii
Ohno, 1986
ii
Depocas, 1957
Joy, 1968
M
Laties, 1960
Mogenson, 1971
RT = "room temperature"
76
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Table 3. Summary of principal physiological and morphological changes in the
laboratory rat following heat acclimation.
Parameter Acclimation
(dimension) control
Body Temperature
CO
at Ta = 35 °C 22
at Ta = 32.5 °C 24.5
Evaporative Water Loss
(mg/(g-hr))
at Ta = 32.5 °C 24.5
Metabolic Rate
(ml 02/g) 28
(ml 02/min 25
Food Consumption
(g/day) 25
Growth Rate
(g/day) 25
Cardiac Output (anes)
(ml/min) RT
Stroke Volume (anes)
(ill ) RT
BAT Mass
(mg/100 g) 25
Salivary Gland Mass
(mg/100 g;dw) 22
RT
T, 'C
heat
35
32.5
32.5
34
34
34
34
34
34
34
35
34
Parameter
control
-39
37.6
4.9
-1.6
5.4
23.2
4.0
24.5
65
65
21
17.6
Value
heat
-40
38.2
3.5
-1.3
4.0
15.2
2.3
28.1
73
46
27
24.2
Reference
Sod-Mori
Gwosdow,
"
Yousef,
Rousset,
H
11
Horowit
Habara,
Horowit
Elmer,
ah, 1973
1985
1967
1984
z, 1985a
1983
z, 1976
1970
77
-------
Table 3 (cont).
Parameter
(dimension)
Acclimation T, "C
control heat
Parameter Value
control heat
Reference
Vascular Compliance
w/ Hyperthermia
(ml/mm Hg) 24
Core Temperature
for Tail Vasodilation
(°C) 24
Core Temperature
for Salivation
32
34
3.2
38.0
2.0 Horowitz, 1988
37.5 Horowitz, 1985
(°C)
Saliva Flow
(/il/min)
Urine Flow
(ml/24 hr)
Urea Clearance
(ml/min-kg))
Inulin Clearance
(ml/(min-kg)
24
24
23
23
23
34
34
35
35
35
39.5
24.5
16.3
1.98
3.28
38.8
5.4
11.8 Chayoth, 1984
0.56
1.08
RT = "room temperature"; dw = dry weight.
78
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Table 4. Principal autonomic and behavioral characteristics of the
thermoregulatory system of the developing rat.
Parameter
(dimension)
Metabolic Rate
single pups
(ml 02/(kg-min))
Metabolic Rate
single pups
(W/m2)
Metabolic Rate
6-7 pups
(ml 02/(kg-min))
Insulation
single pups
CC/(W-cm2))
Core Temperature
CC)
Lower Critical Ta
CC)
Age, days
5
9
15
5-7
9-11
13-15
17-19
< 1
< 1
2-4
6-7
13-16
18-21
5
12
21
5-7
9-11
13-15
17-19
Ta, °C
30
30
30
TNZ
TNZ
TNZ
TNZ
TNZ
30
30
30
30
30
in nest
ii H
H H
Value
52.4
59.6
37.5
25.5
29.3
32.5
32.4
19.7
0.10
0.11
0.19
0.27
0.40
35.5
36.5
37.1
34.5
34.0
32.2
32.0
Reference
Alberts, 1978
H
H
Conklin, 1971
H
H
H
Taylor., 1960
Takano, 1979
H
H
H
H
Conklin, 1971
H
H
Spiers, 1987
H
H
H
79
-------
Table 4 (cont).
Behavioral Thermoregulation
Core (Tc) and Skin (Tsk) Temperature
after Placement in a Temperature Gradient
Age, days Tc, °C Ts|<, °C Reference
4-5
6-7
8-9
10-11
12-13
30.5
32.5
34.5
35.5
36.0
28.5
30.5
32.0
33.5
34.0
Fowler, 1975
H
ii
H
H
80
-------
Table 5. Maximum or near maximum metabolic rates (V02 max) reported for the
laboratory rat under conditions of forced exercise and/or cold exposure.
Mass,
kg
0.37
0.21
0.21
?
6.28
0.34
0.26
Running Speed,
m/min*
67
40
35
27
7
27-32
42
Ta,
°C
24
22-25
33-35
18-24
6
?
?
V02 max,
ml 02/(min-kg)
95.1
110.0
102.0
85.0
81.2
93.0
71.6
Reference
Shepard, 1976
Shell ock, 1984
"
Bedford, 1979
Pasquis, 1970
Gleeson, 1981
Patch, 1980
*grade of treadmill is elevated in some studies to achieve maximum exertion.
81
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Table 6. Summary of studies which have shown distinct differences in behavioral
or autonomic function of the thermoregulatory system of specific strains of the
laboratory rat.
Parameter Reference
A.Survival to Acute Heat Stress
SD>LE Furuyama, 1982
SHRSD Kiang-Ulrich, 1984
C. Preferred Environmental Temperture
SD=FCH>LE Gordon, 1987
SHR>NT Wilson, 1977
D. Core Temperature
SHR>NT • Collins, 1987
Hajos, 1986
fa/faNT
Collins, 1987
key: FCH-Fischer 344, SD-Sprague-Dawley, LE-Long-Evans, SHR-spontaneous
hypertensive, fa/fa-obese Zucker rat, Fa/--lean Zucker rat.
82
-------
Table 7. Summary of the effects of various physical and biological stimuli on
core and skin temperature, metabolic rate, and preferred Ta of the rat. Results
generally include responses measured at ambient tempertures equal to or below
standard laboratory room temperture. D-decrease; I-increase; ?-no data.
Environmental
Stimulus
Hypercapnia
Hypergravity
Hyperoxia/
Hyperbaria
Hypoxia
Ionizing
Radiation
Limb
Ischemia
Core Skin
Temp Temp
D D
D I
D I*
D ?
I/D ?
D ?
Metabolic Preferred
Rate Temp
D ?
D ?
D ?
D I
? ?
D ?
Reference
Szelenyi, 1968
Chapin, 1963
Stuppel, 1960
Fuller, 1977
Ohara, 1982
Martini, 1989
Kowalski, 1971
Puglia, 1974
Szelenyi, 1968
Dupre, 1988
Dupre, 1989
Bahatia, 1969
Kandasamy, 1988
Stoner, 1969
Microwave
(nonionizing)
Radiation
Open-Field
Stress I
Skin Burns D
Semi-Starvation D
Starvation D
Tumor-Bearing D
D
D
D
Gordon, 1986
Gordon, 1987a,b
Stern, 1979
Singer, 1986
Kluger, 1987
Stoner, 1986
Heim, 1965
Swift, 1944
Markussen, 1986
Hamilton, 1959
Kampschmidt, 1970
83
-------
*indirect evidence based on increase in thermal conductance (Martini et al.,
1989).
84
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FIGURE LEGENDS
Figure 1. Idealized relationship between ambient temperature and the magnitude
of key thermoregulatory effectors; metabolic rate, skin blood flow, and
evaporative water loss. Principal patterns in this figure have been adapted from
several general reviews (Folk, 1974; Elizondo, 1977; Schmidt-Nielsen, 1975;
Cossins and Bowler, 1987).
Figure 2. Relationship between Ta and percent increase in metabolic rate at
Ta's below the lower critical Ta (LCT) as reported in several investigations of
the laboratory rat. Note that for all studies, metabolism regression line does
not intersect with normal body temperature (dashed lines) at point where MR = 0
as is predicted by Newton's Law of Cooling (cf. Figure 1).
Figure 3. General summary of the effect of Ta on activation of various
thermoregulatory effectors and other temperature related phenomena in the
laboratory rat. Most data for this figure were taken from Table 1.
85
-------
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