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Further
Quick links to online content Annu. Rev. Physiol. Copyright
© 1991
1991. 53:71--85
by Annual Reviews Inc. All rights reserved
INTERACTIONS BETWEEN HYPOXIA Annu. Rev. Physiol. 1991.53:71-85. Downloaded from www.annualreviews.org by University of Illinois - Chicago on 06/06/12. For personal use only.
AND HYPOTHERMIA Stephen C. Wood Oxygen Transport Program, Lovelace Medical Foundation, Albuquerque,
New Mexico 87108 KEY WORDS:
thermoregulation, hypoxia, behavior
INTRODUCTION Hypoxia elicits a variety of compensatory responses in animals. Physiologic responses, including increased ventilation and cardiac output, increase O2 supply. Hypoxia also elicits hypothermia, a response that decreases O2 demand. Altered thermoregulatory behavior is involved in hypoxia-induced hypothermia in both poikilothermic and homeothermic vertebrates. This re view discusses the interactions between hypoxia and thermoregulation. Some related stresses that induce hypothermia are also described. All vertebrates have a brain region specialized for thermoregulation. The sensory and integrative circuits are similar for ectothermic and endothermic vertebrates (15). Most or all thermoregulatory functions can be interpreted by single or dual set point models (31, 4). The outputs of the thermoregulatory center, behavioral and physiologic, provide feedback control of core body temperature (Tb). Ectotherms need behavioral mechanisms for Tb control. Physiologic mech anisms available to ectotherms are limited to color changes and autonomic control of cutaneous blood flow. Endotherms also use behavior for Tb control, but need physiologic mechanisms unavailable to ectotherms (shivering and non-shivering thermogenesis, sweating, panting, and so on) when ambient temperatures are outside of the thermoneutral zone. The distinction between ectotherms and endotherms is often blurred by examples of facultative en-
0066-4278/91/0315-0071$02.00
71
Annu. Rev. Physiol. 1991.53:71-85. Downloaded from www.annualreviews.org by University of Illinois - Chicago on 06/06/12. For personal use only.
72
WOOD
dothermy of ectotherms (e.g. brooding pythons, honey bee colonies, warm muscled tunas) and facultative ectothermy of endotherms (e.g. torpor,hypox ic m ammals). Most ectotherms have a distinct thermal preference,detectable in thermal gradients. Pyrogens cause selection of a higher than normal Tb (behavioral fever) in fish, amphibians, and reptiles (40, 58). This response enhances survival via increased production of T cells and increased effectiveness of interferon, an antiviral agent. On the other hand,a number of factors induce selection of lower than normal Tb• The following sections review the mech anisms and importance of behavioral hypothermia as a stress response. HYPOXIA AND THERMOREGULATION
Body temperature (Tb) has a marked effect on oxygen uptake (Vo) of resting animals (42). For most animals,the temperature coefficient (Q1O) is = 2.5,so resting iroz changes about 11% peroC change in Tb. Consequently,hyperther mia is deleterious for hypoxic animals. Conversely, hypothermia could be beneficial,particularly for O2 sensitive organs, e.g. heart and brain. Indeed, most studies reviewed below show that hypothermia is a normal and adaptive response to hypoxia in both ectotherms and endotherms. Physiologic Hypothermia
It is well established that heat loss occurs in hypoxic mammals from periph eral vasodilation (45,24, I, 50a). The recent finding of behavioral hypother mia in hypoxic mammals (see below) is significant because selection of a lower ambient temperature will accelerate the rate of heat loss. There is also decreased heat production in hypoxic mammals. This is due to redistribution of blood away from brown fat (69, 64). Within a range of ambient temperatures (thermoneutral zone), homeo therms maintain Tb without supplementary heat production or sweat secre tion. At ambient temperatures below thermoneutrality, Tb of homeotherms is maintained by thermogenic responses. Therefore, it is possible that hypo thermia could interact with hypoxia by eliciting a thermogenic response. This could be deleterious because of the increasing O2 demand of tissues involved in shivering and non-shivering thermogenesis. In hypoxic rats, however, the normal thermogenic response to reduced temperature is de pressed (23). A-reduced thermogenic response to cold also occurs in hy poxic and hypercapnic hamsters (44). Other evidence that the drop in Tb results from a change in central regulation includes a decrease impulse frequency of cold receptors during hypoxia (18) and a change in the set point of preoptic neurons during hypoxia (70). Thus, hypothermia during hypoxia can be interpreted by using the set point model (31) as a widening of the
Annu. Rev. Physiol. 1991.53:71-85. Downloaded from www.annualreviews.org by University of Illinois - Chicago on 06/06/12. For personal use only.
HYPOXIA AND HYPOTHERMIA
73
thermoneutral zone and downward shift of the threshold temperature for shivering thermogenesis. In ectotherms, shivering and non-shivering thermogenesis does not occur during behavioral hypothermia. As with mammals, physiologic and be havioral mechanisms act in concert to lower Tb• In ectotherms hypothermia is primarily behavioral, but the rate of drop in Tb may be augmented by control of cutaneous blood flow. Under normoxic conditions, lizards cool more slowly than they heat, which indicates decreased peripheral blood flow during cooling. Hypoxia abolishes this difference in the iguana (35) thereby increas ing the rate of cooling during hypoxia and shortening the time required for Tb to drop after hypoxic animals select a lower ambient temperature. Behavioral Hypothermia Most vertebrates, including mammals and birds, utilize behavior to regulate Tb in heterothermal environments. In nature or in laboratory thermal gra dients, most species show definite thermal preferences. Many so-called cold blooded animals, e.g. lizards, actually prefer a Tb of 35°C or higher. An interaction between hypoxia and thermoregulation of ectotherms was predicted from models of O2 transport (76). With venous admixture as a result of shunts, the arterial PO2 of normoxic ectotherms lies near the shoulder of the oxygen dissociation curve rather than on the upper flat portion as in normoxic mammals. Lacking this normal reserve for hypoxia, ectotherms were pre dicted to select a lower Tb in an hypoxic environment. This hypothesis was confirmed in lizards (34) and other ectotherms (77). Behavioral hypothermia also occurs in water breathers including crayfish, amphibian larvae, and teleost fish (20, 8, 57). Among animals how wide spread is this behavioral response to hypoxia? The answer is not yet known since only a few species of each vertebrate taxa and a few invertebrate species have been studied. We recently started a search for the simplest animal, beginning with a protozoan (48), to show this response. Paramecium caudatum were placed in an aquatic thermal gradient, exposed first to air, and then to nitrogen. The mean temperature selected by the paramecia during air exposure was, as previously shown by Mendelssohn (50), 26°C. During extreme hypoxia (P02 was no� measured but assumed to be less than 1 torr), the selected temperature was significantly reduced to = 16°C. This hypothermia was completely reversed when the gradient was returned to normoxia. These results can be incorporated into a model for temperature selection for paramecia based on the work of Hennessey et al (33). According to this model, temperature selection results from the follow ing processes: (a) Heat at the selected temperature is tranduced by a mech anism that increases ion conductance of the body membrane, presumably by opening membrane ion channels; (b) ions flowing through channels cause
Annu. Rev. Physiol. 1991.53:71-85. Downloaded from www.annualreviews.org by University of Illinois - Chicago on 06/06/12. For personal use only.
74
WOOD
depolarization if resting membrane voltage is less than -20 mY; (c) de polarization triggers opening of a voltage-dependent calcium channel in ciliary membranes, thus initiating an action potential; (d) the action potential (Ca influx) causes a change in the beat direction of the ciliary axoneme and backward swimming. Under severe hypoxia, we postulate that this sequence occurs at a lower temperature since the resting membrane potential at a given temperature will be decreased. Paramecium caudatum may provide a useful model for studies of mechanisms and significance of thermoregulation at the single-cell level. Hypoxia-induced hypothermia for representative vertebrates is shown in Figures 1 and 2. In each case there is a distinct threshold for the behavioral 2
0
::J .... . L
••
-2
0
Q) 0. -4 E Q) -6 I-0 -8 Q) .... . 0 Q) -10 Q) VJ -12 -. -0 20 0 m -0 Q)
0
T
T
II
Goldfish
L
0
f
h 1"
0
ID
Bufo marinus
15
Q)
Q) VJ 10 5
10
15
20
25
Inspired Oxygen, % Figure 1
Top: Effect of inspired water Po, on temperature selection of goldfish and rainbow
trout in a thermal gradient. Midpoint analysis indicates a breakpoint (hypoxic threshold) of about
35 torr for the goldfish. Data from (55). Bottom: Effect of inspired % oxygen on temperature selection of the toad, Bufo marinus. Data from S. C. Wood, unpublished.
HYPOXIA AND HYPOTHERMIA
75
40 u Q) ....
:J -+-' 5 Q) 0.
E
3
Lizard'i (4 .pecie.)
�
Q) I-0
Annu. Rev. Physiol. 1991.53:71-85. Downloaded from www.annualreviews.org by University of Illinois - Chicago on 06/06/12. For personal use only.
�
30
u Q)
Q) (fJ 20
15
10
25
Inspired Oxygen, % 40
U
35
� ::l
-+-'
� � E
�
0 3 25
A r+-+-+ ,+-: / T Til II Selected Temp . • Core Temp.
•
.
T 1
iii-iii ... , ,T//'1'
_./..L
•
CBA/J
Mice
�
• ./1
20 L....L�"---'��'-..L��-'-��-' 20 25 15 10 5
Inspired Oxygen, % Figure 2
Top: Selected body temperature of four species of lizards during graded hypoxia. Data
from (34). Bottom: Selected temperature and body temperature of mice during exposure to graded hypoxia. Data from C. Gordon, personal communication.
response to hypoxia. Behavioral hypothennia in hypoxic mammals is a recent finding that further blurs the distinction between ectothenns and homeothenns (7, 22, C. Gordon, personal communication). Data for mice (Figure 2) show a degree of behavioral hypothennia during hypoxia that closely parallels the pattern seen in ectothenns. The threshold for a behavioral response in both mice and lizards is at an inspired O2 of 10%. =
Mechanisms and Mediators NEURAL MECHANISMS Behavioral thennoregulation of terrestrial ecto thenns is modeled according to minimum and maximum temperatures based on the early work of Cowles & Bogert (13). Experiments with shuttle
76
WOOD
boxes, in which animals are forced to choose between boxes either too cold or too hot to allow their normal preferred Tb, revealed oscillations of Tb between reproducible limits (32). These limits, or exit temperatures, are normally distributed, which suggests a dual threshold control system (32, 4). Several lines of evidence suggest that behavioral hypothermia is a regulated response to hypoxia (vs random movement to a cold area where animals
Annu. Rev. Physiol. 1991.53:71-85. Downloaded from www.annualreviews.org by University of Illinois - Chicago on 06/06/12. For personal use only.
become immobile). First, the response is rapidly reversible. Second, the
hypoxic ectotherms show a frequency distribution of selected temperature similar to normoxic animals, but shifted to lower temperatures. Third, there is a resetting of exit temperatures in shuttle-box experiments (34, 35). The
behavioral hypothermia of the iguana lizard, shown in Figure 3, illustrates the
exit temperature mechanism of regulated hypothermia. When iguanas were exposed to 10% O2 after 24 hr of normoxia, they quickly moved to the cold end of the thermal gradient. In a separate shuttle-box experiment, the upper (hot) and lower (cold) exit temperatures were determined under normoxic and hypoxic conditions. These are drawn as horizontal lines in Figure 3. Under hypoxic conditions, the upper exit temperature is reduced from = 37 to 31°C.
40
()
Further
Quick links to online content Annu. Rev. Physiol. Copyright
© 1991
1991. 53:71--85
by Annual Reviews Inc. All rights reserved
INTERACTIONS BETWEEN HYPOXIA Annu. Rev. Physiol. 1991.53:71-85. Downloaded from www.annualreviews.org by University of Illinois - Chicago on 06/06/12. For personal use only.
AND HYPOTHERMIA Stephen C. Wood Oxygen Transport Program, Lovelace Medical Foundation, Albuquerque,
New Mexico 87108 KEY WORDS:
thermoregulation, hypoxia, behavior
INTRODUCTION Hypoxia elicits a variety of compensatory responses in animals. Physiologic responses, including increased ventilation and cardiac output, increase O2 supply. Hypoxia also elicits hypothermia, a response that decreases O2 demand. Altered thermoregulatory behavior is involved in hypoxia-induced hypothermia in both poikilothermic and homeothermic vertebrates. This re view discusses the interactions between hypoxia and thermoregulation. Some related stresses that induce hypothermia are also described. All vertebrates have a brain region specialized for thermoregulation. The sensory and integrative circuits are similar for ectothermic and endothermic vertebrates (15). Most or all thermoregulatory functions can be interpreted by single or dual set point models (31, 4). The outputs of the thermoregulatory center, behavioral and physiologic, provide feedback control of core body temperature (Tb). Ectotherms need behavioral mechanisms for Tb control. Physiologic mech anisms available to ectotherms are limited to color changes and autonomic control of cutaneous blood flow. Endotherms also use behavior for Tb control, but need physiologic mechanisms unavailable to ectotherms (shivering and non-shivering thermogenesis, sweating, panting, and so on) when ambient temperatures are outside of the thermoneutral zone. The distinction between ectotherms and endotherms is often blurred by examples of facultative en-
0066-4278/91/0315-0071$02.00
71
Annu. Rev. Physiol. 1991.53:71-85. Downloaded from www.annualreviews.org by University of Illinois - Chicago on 06/06/12. For personal use only.
72
WOOD
dothermy of ectotherms (e.g. brooding pythons, honey bee colonies, warm muscled tunas) and facultative ectothermy of endotherms (e.g. torpor,hypox ic m ammals). Most ectotherms have a distinct thermal preference,detectable in thermal gradients. Pyrogens cause selection of a higher than normal Tb (behavioral fever) in fish, amphibians, and reptiles (40, 58). This response enhances survival via increased production of T cells and increased effectiveness of interferon, an antiviral agent. On the other hand,a number of factors induce selection of lower than normal Tb• The following sections review the mech anisms and importance of behavioral hypothermia as a stress response. HYPOXIA AND THERMOREGULATION
Body temperature (Tb) has a marked effect on oxygen uptake (Vo) of resting animals (42). For most animals,the temperature coefficient (Q1O) is = 2.5,so resting iroz changes about 11% peroC change in Tb. Consequently,hyperther mia is deleterious for hypoxic animals. Conversely, hypothermia could be beneficial,particularly for O2 sensitive organs, e.g. heart and brain. Indeed, most studies reviewed below show that hypothermia is a normal and adaptive response to hypoxia in both ectotherms and endotherms. Physiologic Hypothermia
It is well established that heat loss occurs in hypoxic mammals from periph eral vasodilation (45,24, I, 50a). The recent finding of behavioral hypother mia in hypoxic mammals (see below) is significant because selection of a lower ambient temperature will accelerate the rate of heat loss. There is also decreased heat production in hypoxic mammals. This is due to redistribution of blood away from brown fat (69, 64). Within a range of ambient temperatures (thermoneutral zone), homeo therms maintain Tb without supplementary heat production or sweat secre tion. At ambient temperatures below thermoneutrality, Tb of homeotherms is maintained by thermogenic responses. Therefore, it is possible that hypo thermia could interact with hypoxia by eliciting a thermogenic response. This could be deleterious because of the increasing O2 demand of tissues involved in shivering and non-shivering thermogenesis. In hypoxic rats, however, the normal thermogenic response to reduced temperature is de pressed (23). A-reduced thermogenic response to cold also occurs in hy poxic and hypercapnic hamsters (44). Other evidence that the drop in Tb results from a change in central regulation includes a decrease impulse frequency of cold receptors during hypoxia (18) and a change in the set point of preoptic neurons during hypoxia (70). Thus, hypothermia during hypoxia can be interpreted by using the set point model (31) as a widening of the
Annu. Rev. Physiol. 1991.53:71-85. Downloaded from www.annualreviews.org by University of Illinois - Chicago on 06/06/12. For personal use only.
HYPOXIA AND HYPOTHERMIA
73
thermoneutral zone and downward shift of the threshold temperature for shivering thermogenesis. In ectotherms, shivering and non-shivering thermogenesis does not occur during behavioral hypothermia. As with mammals, physiologic and be havioral mechanisms act in concert to lower Tb• In ectotherms hypothermia is primarily behavioral, but the rate of drop in Tb may be augmented by control of cutaneous blood flow. Under normoxic conditions, lizards cool more slowly than they heat, which indicates decreased peripheral blood flow during cooling. Hypoxia abolishes this difference in the iguana (35) thereby increas ing the rate of cooling during hypoxia and shortening the time required for Tb to drop after hypoxic animals select a lower ambient temperature. Behavioral Hypothermia Most vertebrates, including mammals and birds, utilize behavior to regulate Tb in heterothermal environments. In nature or in laboratory thermal gra dients, most species show definite thermal preferences. Many so-called cold blooded animals, e.g. lizards, actually prefer a Tb of 35°C or higher. An interaction between hypoxia and thermoregulation of ectotherms was predicted from models of O2 transport (76). With venous admixture as a result of shunts, the arterial PO2 of normoxic ectotherms lies near the shoulder of the oxygen dissociation curve rather than on the upper flat portion as in normoxic mammals. Lacking this normal reserve for hypoxia, ectotherms were pre dicted to select a lower Tb in an hypoxic environment. This hypothesis was confirmed in lizards (34) and other ectotherms (77). Behavioral hypothermia also occurs in water breathers including crayfish, amphibian larvae, and teleost fish (20, 8, 57). Among animals how wide spread is this behavioral response to hypoxia? The answer is not yet known since only a few species of each vertebrate taxa and a few invertebrate species have been studied. We recently started a search for the simplest animal, beginning with a protozoan (48), to show this response. Paramecium caudatum were placed in an aquatic thermal gradient, exposed first to air, and then to nitrogen. The mean temperature selected by the paramecia during air exposure was, as previously shown by Mendelssohn (50), 26°C. During extreme hypoxia (P02 was no� measured but assumed to be less than 1 torr), the selected temperature was significantly reduced to = 16°C. This hypothermia was completely reversed when the gradient was returned to normoxia. These results can be incorporated into a model for temperature selection for paramecia based on the work of Hennessey et al (33). According to this model, temperature selection results from the follow ing processes: (a) Heat at the selected temperature is tranduced by a mech anism that increases ion conductance of the body membrane, presumably by opening membrane ion channels; (b) ions flowing through channels cause
Annu. Rev. Physiol. 1991.53:71-85. Downloaded from www.annualreviews.org by University of Illinois - Chicago on 06/06/12. For personal use only.
74
WOOD
depolarization if resting membrane voltage is less than -20 mY; (c) de polarization triggers opening of a voltage-dependent calcium channel in ciliary membranes, thus initiating an action potential; (d) the action potential (Ca influx) causes a change in the beat direction of the ciliary axoneme and backward swimming. Under severe hypoxia, we postulate that this sequence occurs at a lower temperature since the resting membrane potential at a given temperature will be decreased. Paramecium caudatum may provide a useful model for studies of mechanisms and significance of thermoregulation at the single-cell level. Hypoxia-induced hypothermia for representative vertebrates is shown in Figures 1 and 2. In each case there is a distinct threshold for the behavioral 2
0
::J .... . L
••
-2
0
Q) 0. -4 E Q) -6 I-0 -8 Q) .... . 0 Q) -10 Q) VJ -12 -. -0 20 0 m -0 Q)
0
T
T
II
Goldfish
L
0
f
h 1"
0
ID
Bufo marinus
15
Q)
Q) VJ 10 5
10
15
20
25
Inspired Oxygen, % Figure 1
Top: Effect of inspired water Po, on temperature selection of goldfish and rainbow
trout in a thermal gradient. Midpoint analysis indicates a breakpoint (hypoxic threshold) of about
35 torr for the goldfish. Data from (55). Bottom: Effect of inspired % oxygen on temperature selection of the toad, Bufo marinus. Data from S. C. Wood, unpublished.
HYPOXIA AND HYPOTHERMIA
75
40 u Q) ....
:J -+-' 5 Q) 0.
E
3
Lizard'i (4 .pecie.)
�
Q) I-0
Annu. Rev. Physiol. 1991.53:71-85. Downloaded from www.annualreviews.org by University of Illinois - Chicago on 06/06/12. For personal use only.
�
30
u Q)
Q) (fJ 20
15
10
25
Inspired Oxygen, % 40
U
35
� ::l
-+-'
� � E
�
0 3 25
A r+-+-+ ,+-: / T Til II Selected Temp . • Core Temp.
•
.
T 1
iii-iii ... , ,T//'1'
_./..L
•
CBA/J
Mice
�
• ./1
20 L....L�"---'��'-..L��-'-��-' 20 25 15 10 5
Inspired Oxygen, % Figure 2
Top: Selected body temperature of four species of lizards during graded hypoxia. Data
from (34). Bottom: Selected temperature and body temperature of mice during exposure to graded hypoxia. Data from C. Gordon, personal communication.
response to hypoxia. Behavioral hypothennia in hypoxic mammals is a recent finding that further blurs the distinction between ectothenns and homeothenns (7, 22, C. Gordon, personal communication). Data for mice (Figure 2) show a degree of behavioral hypothennia during hypoxia that closely parallels the pattern seen in ectothenns. The threshold for a behavioral response in both mice and lizards is at an inspired O2 of 10%. =
Mechanisms and Mediators NEURAL MECHANISMS Behavioral thennoregulation of terrestrial ecto thenns is modeled according to minimum and maximum temperatures based on the early work of Cowles & Bogert (13). Experiments with shuttle
76
WOOD
boxes, in which animals are forced to choose between boxes either too cold or too hot to allow their normal preferred Tb, revealed oscillations of Tb between reproducible limits (32). These limits, or exit temperatures, are normally distributed, which suggests a dual threshold control system (32, 4). Several lines of evidence suggest that behavioral hypothermia is a regulated response to hypoxia (vs random movement to a cold area where animals
Annu. Rev. Physiol. 1991.53:71-85. Downloaded from www.annualreviews.org by University of Illinois - Chicago on 06/06/12. For personal use only.
become immobile). First, the response is rapidly reversible. Second, the
hypoxic ectotherms show a frequency distribution of selected temperature similar to normoxic animals, but shifted to lower temperatures. Third, there is a resetting of exit temperatures in shuttle-box experiments (34, 35). The
behavioral hypothermia of the iguana lizard, shown in Figure 3, illustrates the
exit temperature mechanism of regulated hypothermia. When iguanas were exposed to 10% O2 after 24 hr of normoxia, they quickly moved to the cold end of the thermal gradient. In a separate shuttle-box experiment, the upper (hot) and lower (cold) exit temperatures were determined under normoxic and hypoxic conditions. These are drawn as horizontal lines in Figure 3. Under hypoxic conditions, the upper exit temperature is reduced from = 37 to 31°C.
40
()
