Hypothermia in hypoxic animals: Mechanisms, mediators, and functional significance

ISSN 0305-04911961515.00 SSDI 0305-0491(95)02045-4

Comp. Biochem. Physiol. Vol. 113B, No. l, pp. 37-43, 1996 Copyright © 1996 Elsevier Science Inc.

ELSEVIER

Hypothermia in Hypoxic Animals: Mechanisms, Mediators, and Functional Significance Stephen C. Wood and Rayna Gonzales DEPARTMENTOF PHYSIOLOGY,EASTCAROLINAUNIVERSITY,SCHOOLOF MEDICINE, GREENVILLE,NC 27858, U.S.A.

ABSTRACT. A basic tenet of biology is that body temperature (Tb) has a marked effect on oxygen uptake of resting animals. For most animals, the temperature coefficient (Q10) is ~ 2.5; e.g., resting oxygen uptake changes about 11% per 0(2 change in T b. An important consequence of this dependence is that hyperthermia could be deleterious for hypoxic animals, particularly for oxygen sensitive organs, e.g., heart and brain. Conversely, a moderate degree of hypothermia could be beneficial during hypoxia. This concept is not new. Forced hypothermia is sometimes used in surgical procedures, particularly for heart and brain surgery. However, in many situations where hypothermia might have benefits, e.g., pediatric intensive care, it is not permitted. This is due in part to dogma and in part to the real and potential disadvantages of hypothermia, even in severely hypoxic animals. Among these is ventricular fibrillation. This is apparently preventable if blood pH is allowed to rise following the "Buffalo Curve." Another important disadvantage, were it to occur, is elevation of oxygen demand due to a thermogenic responses. However, at least in some species, the thermogenic response is blunted during hypoxia; e.g., in young rats. Furthermore, even if a thermogenic response occurs, this takes place primarily in muscles (shivering) and brown fat (non-shivering) and not in the O2-sensitive organs, heart and brain. A third disadvantage, for prolonged hypothermia, might be impairment of the immune response, a serious problem if hypoxia is combined with infection. This paper will review four aspects of behavioral fever and hypothermia: the occurrence among animals, the mechanisms and mediators that might trigger behavioral responses, and the functional significance, coMP BIOCHEMPHYSIOL113B, 37-43, 1996. KEY WORDS. Hypoxia, thermoregulation, brain, respiration, hypothermia

INTRODUCTION Body temperature (Tb) has a marked effect on oxygen uptake (V 02) of resting animals (Krogh, 1914). For most animals, the temperature coefficient (Q10) is >> 1.5, so resting ~ / 0 2 changes about 11% per °(2 change in T b. Consequently, hyperthermia could be deleterious for hypoxic animals, particularly for oxygen sensitive organs, e.g. heart and brain. Conversely, and the subject of this paper, a moderate degree of hypothermia could be beneficial. The concept is not new. Hypothermia is used in surgical procedures, particularly for heart and brain surgery. There are real and potential disadvantages of forced hypothermia, even in severely hypoxic animals. Among these are ventricular fibrillation. This is apparently preventable if blood pH is allowed to rise following the "Buffalo Curve" (Kroncke et al., 1986). Another potential disadvantage, certainly during hypoxia, is elevation of V O 2 due to a thermogenic responses. In some species, the thermogenic response is blunted during hypoxia; e.g. in young rats (DupE6 et al., 1988). Early studies

Correspondence to: S. C. Wood, Department of Physiology, East Carolina University, School of Medicine, Greenville, NC, 27858, U.S.A. Received 30 June 1995; accepted 28 July 1995.

provided evidence that neonates are more tolerant of hypothermia than adults (Adolph, 1951). Furthermore, even if a thermogenic response occurs, this takes place primarily in muscles (shivering) and brown fat (non-shivering) and not in the O2-sensitive organs, heart and brain. A third disadvantage, for prolonged hypothermia, might be impairment of the immune response, a serious problem if hypoxia is combined with infection. This paper will review four aspects of hypoxiainduced hypothermia: the occurrence among animals, the mechanisms of hypothermia, mediators that might trigger hypothermic responses, and the functional significance of hypothermia.

OCCURRENCE OF HYPOXIA-INDUCED HYPOTHERMIA Hypothermia is a normal and presumably adaptive response of hypoxic animals. Figure 1 illustrates the pattern of body temperature changes in response to graded hypoxia in animals ranging phylogenetically from protozoans to mammals. The means by which temperature changes in these examples are behavioral, physiological, or both. The main points are the ubiquity of this type of behavioral response across the animal kingdom and the fact that there is a threshold for the hypo-

38

S. C. Wood and R. Gonzales Paramecia

Goldfish

30.

6-

26.

C 0

20. 15.

-10.

10. $

o:1 oh 0:3 0:,

' 2~-~s

-Is

1'5

Lizards

Toads

O

1'0

40.

30.

o

25.

35.

G)

20.

30.

qD

15.

25.

(J

10

Q.

E f.-

m

q) u)

t'o

Cs

2'0

2's

20 10

Alligators

1'5

210

215

1~

2b

is

FIG. 1. Patterns of behavioral thermoregulatory response to graded hypoxia in various ani. mals. Modified from Wood, 1995.

Mice

35.

40

30.

36.

2G.

30, 20.

25.

15.

10

20 1'0

1'5

210

2'5

Ib

Ambient Oxygen %

thermic response. The only animal we have found to not show a behavioral response to hypoxia is the tarantula spider, a species with a definite thermal preference but one that is unaffected by even severe hypoxia (unpublished results). MECHANISM OF HYPOXIA-INDUCED H Y P O T H E R M I A Animals lose heat by moving to a cooler environment where conductive, radiant, or evaporative heat loss occurs (behavioral) or by increasing these means of heat loss if they are in a cooler environment (physiological). Behavioral thermoregulation occurs in almost all animals, even unicellular ones (Malvin and Wood, 1992). In mammals, the mechanisms are primarily physiological but the rate of drop in T b is affected by behavioral hypothermia (Dupr~ and Owen, 1989; Gordon and Watkinson, 1989). Recent data for mice (Fig. 2) show a degree of behavioral hypothermia during hypoxia that closely parallels the pattern seen in ectotherms. The threshold for a behavioral response in both mice and lizards is at an inspired 02 of >> 10%.

For more anoxia tolerant species (e.g. goldfish, alligators) the threshold occurs at a lower inspired oxygen level. This begs the question, is the threshold proportional to blood oxygen affinity? This is a ripe area for experimental analysis. Physiological mechanisms of hypoxia-induced hypothermia in mammals are decreased heat production and increased heat loss (Lintzel, 1931; Gellhorn and Janus, 1936; Adolph, 1957; Miller and Miller, 1966; Lister, 1984; Dupr~ et al., 1988). Decreased heat production is due, in part, to redistribution of blood away from brown fat in rats (Szelenyi and Donhoffer, 1968) and human infants (Schubring, 1986). Normal responses to hypothermia, shivering and non-shivering thermogenesis, increase V O2 and heat production. The relationships among heat production (~' O2), T b, and ambient temperature change with species and developmental stage. For example, kittens are ectotherms for the first day or two (Fig. 3). With increasing age, the thermogenic response to cold becomes greater and the rate of drop in core temperature becomes less. In the rat, the adult pattern of T b regulation is attained at about 25 days after birth. In human infants, all thermoregulatory responses can be triggered at birth. Human neonates rely

Hypothermia in Hypoxic Animals: Mechanisms, Mediators and Functional Significance

40.

POTENTIAL

Mice Core

35.

selected

g

30.

E o 25

20-

g

39

1'0

is

2'0

2's

Inspired 02, %

FIG. 2. Physiological and behavioral thermoregulation in response to hypoxia in mice. Data from Gordon and Fogelson, 1991.

heavily on non-shivering thermogenesis (mainly from brown fat), which can elevate heat production by 100-200% (Bruck, 1978). In infants and adults, there is no drop in core temperature until an environmental temperature below the maximum thermogenic capacity is reached. Under normal conditions, metabolism is maintained at a basal level without supplementary heat production or sweat secretion, over a range of ambient temperatures called the thermoneutral zone (TNZ). In adults, T b is maintained at ambient temperatures below the TNZ by thermogenic responses. However, in neonates of most species, T b falls at temperatures below the TNZ although heat production (and V 02) increase sharply. The maximum thermogenic response occurs at about 24°C in neonates and 0°C for adult humans. In neonates the lower end of the TNZ is 34-36°C versus 26°C for adults). Clearly, cold exposure could worsen hypoxia by eliciting a thermogenic response and increasing 02 demand. As mentioned above, two factors permit hypothermia to be a viable response to hypoxia. First, there is evidence that, hypoxic animals do not show a normal thermogenic response (Dupr6 et al., 1988). Second, the thermogenic response, even if full blown, occurs in hypoxia tolerant tissues, e.g. brown fat and skeletal muscle. Thus, the brain and heart, if cooled, should show a Ql0 dependent decrease in "V 02. In ectotherms, the mechanism of hypothemia is primarily behavioral but the rate of drop in T b may be augmented by physiological means, i.e. control of cutaneous blood flow therefore heat flux. Under normoxic conditions, lizards cool more slowly than they heat, indicating decreased peripheral blood flow. Hypoxia abolishes this hysteresis of heating and cooling curves in the iguana (Hicks and Wood, 1985). This increases the rate of cooling during hypoxia, shortening the time required for T b to drop after hypoxic animals select a lower ambient temperature. In amphibians, the role of cutaneous flow in thermoregulation is relatively unknown. As skin breathers, the control of cutaneous blood flow may be a key component of cutaneous gas exchange as well as heat conductance.

MEDIATORS

OF HYPOTHERMIA

Stimuli that elicit hypothermia are diverse and often unrelated, except by the denominator of being associated with stress. For example, ethanol, urine, morphine, prostaglandins, histamine, hypoxia, dry air, anemia, pesticides, food deprivation and heavy metals have all been associated with hypothermic responses (Gordon, 1988; Wood, 1991). There are also diverse pyrogens that, without crossing the blood brain barrier, also alter central thermoregulation (Dascombe, 1985). There are a host of potential mediators of hypothermia, including endogenous opioid peptides (Kavaliers et al., 1984). Several candidates have been studied to date. Arginine vasopressin, AVP, (arginine vasotocin, AVT, in ectotherms) is one of these. Rationales for this hypothesis were: 1. Hypoxia stimulates the release of AVP in rats (Walker, 1986); in fetal sheep (Stegner et al., 1984), and in human infants born after hypoxic distress (Ruth et al., (1988). Wilson et al. (1987) showed in dogs that hypoxic hypoxia, reducing arterial [02] to 8% vol., caused a 250% increase in blood flow to the neurohypophysis and a concurrent rise in plasma AVP from 8 to 52 pg/ml. 2. AVP is an endogenous antipyretic peptide in mammals. Centrally administered AVP elicits specific thermoregulatory actions (Naylor et al., 1986). AVP is a central neurotransmitter that coordinates responses to homeostatic perturbations (Riphagen and Pittman, 1986). AVT is involved in thermoregulation of birds (Robinzon et al., 1988). A vasotocin neurosecretory system has been identified in lizards by Bons (1983). 3. There is enhanced AVP release in response to hypercapnic acidosis in rats (Walker, 1987). Hypercapnia induces behavioral hypothermia in toads (Riedel and Wood, 1988). 4. Water deprivation is known to increase the release of AVP in response to increased extracellular tonicity and diminished plasma volume in mammals (Wade et al., 1983) and in amphibians (reviewed by Shoemaker and Nagy, 1977). 40.0.

I kittens I

37.5.

P E

0 I--

35.0.

0 0

30.01 20

2*5

30

35

4'o

Ambient Temp., °C FIG. 3. Scheme of heat production and body temperature related to ambient temperature in a neonatal m a m m a l (Data shown are for a newborn kitten at various ages. Hill, 1961).

S. C. Wood and R. Gonzales

40

The toad, Bufo marinus, selects significantly lower Tbs when exposed to dry air (Malvin and Wood, 1989). 5. AVT injections can alter behavior in amphibians (reproductive behavior) and the altered behavior can be blocked by a intracerebroventricular AVP antagonist (Moore and Miller, 1983). The AVP hypothesis has been tested by administering AVP and AVT antagonist to ectotherms (toads) exposed to conditions known to elicit hypothermia. Also, the Brattleboro rat, a strain that is genetically AVP deficient has been studied. In both cases, pilot studies have produced negative results, i.e. no effect on hypoxia induced hypothermia (Malvin and Wood, unpublished results: Wood et al., unpublished results). Other potential mediators of hypoxia-induced hypothermia include histamine and adenosine. Histamine is involved in mammalian thermoregulation (e.g., Bligh, 1979). Histamine mediates radiation-induced hypothermia in rats (Kandasamy et al., 1988). Histamine infusion into either the lateral ventricle or 4th ventricle of rats induces hypothermia (Dey and Mukhopadhaya, 1986). Histamine has been implicated in behavioral thermoregulation of fish (Green and Lomax, 1976) and salamanders (Hutchison and Spriestersbach, 1986). Histamine does not readily pass the blood-brain barrier in mammals, but apparently can in ectotherms (Green and Lomax, 1976). Another mediator candidate is lai:tate. Lactate is the classical companion of hypoxic stress in mammals. Its appearance in the circulation shows a distinct threshold (the anaerobic threshold) which could conceivably be linked to the distinct behavioral threshold. Recent evidence for toads (P6rmer et al., 1994) supports the lactate hypothesis, at least partially. Injected lactate was shown to elicit behavioral hypothermia, but to a lesser extent than that observed in hypoxic or hypercapnic toads. Brain pH also plays a role in behavioral thermoregulation in toads (Branco et al., 1994) but again does not fully explain the extent of the hypothermia observed in hypoxic animals. It may be that multiple mediators are operating in a synergistic manner to trigger a full blown hypothermic response. Another potential mediator that needs to be investigated is adenosine. Rationales for the adenosine hypothesis are: 1. Adenosine possesses a hypothermic property. When injected into animals, body core temperature decreases significantly (Wang et al., 1990). Moreover, xanthines which inhibit adenosine receptors have hyperthermic properties (Wang et al., 1990). 2. The adenosine agonist 5'-N-ethylcarboxamidoadenosine (NECA) is known to produce profound (10°C) hypothermia in rats that can be blocked by caffeine, an adenosine receptor antagonist (Seale et al., 1988). 3. Adenosine is a normal product of ATP catabolism and increases during hypoxia. The role of these potential mediators in hypoxia-induced hypothermia remains to be determined.

4. Hypersensitivity to the hyperthermic effects of caffeine in specific mice strains (Seale et al., 1984) appears to be mechanistically manifest through different expression of adenosine receptors (Jarvis and Williams, 1988). It remains unclear whether the hypothermic actions of adenosine are centrally or peripherally mediated although there is evidence to support the latter mechanism (Wang et al., 1990). 5. Adenosine is a metabolically linked compound possessing a variety of physiological actions. In the cardiovascular system adenosine mediates vascular dilatation, bradycardia, cardioprotection, anti-adrenergic effects, and stimulation of substrate metabolism (Olsson and Pearson, 1990). 6. In the respiratory system it has been proposed that adenosine mediates local bronchoconstriction, central depression of respiration, and stimulation of peripheral chemoreceptors (Griffiths and Holgate, 1990). 7. In the central nervous system adenosine (among other things) inhibits neuronal firing, stimulates vasodilatation, mediates neuroprotection, inhibits convulsions, and produces analgesia and anti-nociception, etc. (Phillis and Wu, 1981; Williams, 1989). Since hypoxia produces significant hypothermia and enhances central and peripheral adenosine levels, it's feasible that adenosine may play a role in mediation of hypoxic hypothermia. This hypothesis is currently being cued up for investigation, awaiting a good graduate student. FUNCTIONAL SIGNIFICANCE OF HYPOXIA-INDUCED HYPOTHERMIA

The "upside" of hypothermia in hypoxic animals would be: • a left shift of the oxyhemoglobin dissociation curve (increased P50) with the resulting improvement of 0 2 loading in the lungs.

100

75

4°

38°C

25

2'5 Inspired 02 (%)

FIG. 4. Survival of male rats exposed to graded hypoxia while being kept at normal body temperature (temperature clamped) or allowed to become hypothermic (Tb ca. 33-34°C). Unpublished data.

Hypothermia in Hypoxic Animals: Mechanisms, Mediators and Functional Significance

inspired 0 2. As seen in Fig. 4, rats which were all6wed to become hypothermic (down to 34°C) could survive considerable lower levels of hypoxia than control (temperature clamped) rats.

300.

Toads J= .~ 200. O o

32"C

C O N T R O L OF B R E A T H I N G

tO

100. 25 °

C

0

t5"

0

m---.___ =

g

o

I'0 1'5 Inspimd 0 2 , %

2'0

FIG. 5. Ventilatory response of toads, Bufo paracnemis, to graded hypoxia at three different body temperatures. Data from Kruheffer et a/., 1987.

• decreased V O 2 according to the Ql0 effect; e.g. ~' 02 would decrease some 11% per °C. • energetically costly responses to hypoxia e.g. increased cardiac output and ventilation may be avoided. As of result of these primary changes due to temperature, both global and regional benefits should be measurable, as summarized below: Survival

Neonatal mammals (Miller and Miller, 1966) and anemic rabbits (Gollan and Aono, 1973) have increased survival if allowed to become hypothermic. Dunn and Miller (1969) showed that asphyxiated neonates treated by hypothermia had a mortality rate of 11.5% compared to 48% in 288 cases not using hypothermia. Hicks and Wood (1985) found 100% survival of lizards allowed to cool during hypoxia versus 100% mortality of animals prevented from cooling down. A recent study with rats showed a pronounced survival advantage of hypothermia during exposure to graded hypoxia (24 to 4% 1200

Rats ¢e

:~ m

800

o'= = x E---

41

400 34oc

lb

2'0 I n s p i r e d O2 (%)

FIG. 6. Ventilatory response of rats to graded hypoxia at two different body temperatures. Unpublished data.

In amphibians and reptiles, hypothermia during hypoxia reduces the ventilatory response to hypoxia (Glass and Wood, 1983; Glass et al., 1983; Kruh0ffer et al., 1987). At 25°C, there is a brisk ventilatory response to hypoxic gas mixtures but at 15°C, the ventilatory response to hypoxia is absent. These temperatures approximate the normal selected temperature and hypoxia-selected temperatures in Bufo marinus. Data for Bufo paracnemis, are shown in Fig. 5. The ventilatory response of hypothermic mammals (nonhibernators) to hypoxia is less well documented. We recently studied the ventilatory response of rats to graded hypoxia and compared temperature clamped with hypothermic animals, using both female and male rats (Gonzales and Wood, 1994). As shown in Fig. 6, hypothermia significantly attenuated the ventilatory response to hypoxia in rats. Brain Metabolism and Function Hypoxia presents neurons with two problems: acidosis due to lactic acid, and energy depletion due to 02 lack. 3lP-NMR spectroscopy can be used to examine CNS adaptations to each of these stresses individually. The frequency of the inorganic phosphate signal is sensitive to pH variations in the physiological range. The concentrations of the phosphorus metabolites are proportional to the areas under their signals. This allows metabolic processes to be monitored by measuring signal areas as a function of time. Intracellular phosphate metabolism and pH can be measured sequentially during normoxia and hypoxia at different body temperatures. This data will provide information on general cerebral metabolism. One of the common causes of CNS damage in childhood is perinatal hypoxia. The consequences include motor disturbances, behavioral abnormalities, and learning disabilities (Kreussler and Volpe, 1984). The hyp0xic/ischemic neural degeneration is apparently mediated by endogenous excitatory amino acids, glutamate and aspartate (Rothman and Olney, 1986). In our laboratory, brain function of rats is being assessed as spatial learning ability using a Morris water maze. An important brain region for spatial learning is the hippocampus, a structure that is particularly sensitive to hypoxia (Misgeld and Frotscher, 1982; Aitken and Schiff, 1986). Previous studies with rats have shown that postnatal exposure to 10% 02 causes significant structural changes in the hippocampus (Pokomy et al., 1982). Stafanovich et al. (1988) exposed 1 day old rats to hypobaric hypoxia (PO 2 >> 70 mm Hg) 10 hr daily for 5 days. Of the 41 cerebral structures they examined 3 months later, only the hippocampus was found to have significantly impaired glucose utilization.

42 Results of our studies of spatial learning indicate a pronounced impairment of spatial learning in temperature clamped rats following exposure to severe hypoxia (7% inspired 02). T h e important experiments yet to be completed are to assess the putative protection of hypothermia on this measure of brain function in post hypoxic rats.

Research of the authors was supported by NIH grant HL 40537.

References Adolph, E. F. Tolerance to cold and anoxia in infant rats. Am. J. Physiol. 155:366-377;1951. Adolph, E. F. Ontogeny of physiological regulations in the rat. Quart. Rev. Biol. 32:89-137;1957. Aitken, P. G.; Schiff, S. J. Selective neuronal vulnerability to hypoxia. Neurosci. Lett. 67:92-96;1986. Bligh, J. The central neurology of mammalian thermoregulation. Neuroscience 4:1213-1216; 1979. Bons, N. Immunocytochemical identification of the mesotocin and vasotocin-producing systems in the brain of temperate and desert lizard species and their modifications by cold exposure. Gen. Comp. Endocrinol. 52:56-66;1983. Branco, L.; Wood, S. C. Role of central chemoreceptors in behavioral thermoregulation of the toad, Bufo marinus. Am. J. Physiol. 266:R1483-1487;1994. Bruck, K. Heat production and temperature regulation. In Perinatal Physiology, (Edited by Stave, U.) Plenum Press, New York, 1978. Dascombe, M. J. The pharmacology of fever. Prog. Neurobiol. 25: 327-373;1985. Dey, P. K.; Mukhopadhaya N. Involvement of histamine receptors in mediation of histamine induced thermoregulatory response in rats. Indian J. Physiol. Pharmacol. 30:300-306;1986. Dunn, J. M.; Miller, J. A., Jr. Hypothermia combined with positive pressure ventilation in resuscitation of the asphyxiated neonate. Am. J. Obstet. Gynecol. 104:58;1969. Duprd, R. K. ; Romero, A. M.; Wood, S. C. Thermoregulation and metabolism in hypoxic animals. In Oxygen Transfer from Environ. ment to Tissues, (Edited by Fed&, R., and Gonzalez, N.), Plenum Press, New York 1988: pp. 347-351. Duprd, R. K. ; Owen, T. L. Behavioral thermoregulation in hypoxic rats. Fed. Proc. 3:A838;1989. Gellhorn, E.; Janus, A. The influence of partial pressures of 02 on body temperature. Am. J. Physiol. 116:327-329;1936. Glass, M. L.; Wood, S. C. Gas exchange and control of breathing in reptiles. Physiol. Rev. 63:232-259;1983. Glass, M. L.; Boutelier, R. G.; Heisler, N. Ventilatory control of arterial PO 2 in the turtle, Chrysemys picta bellii: Effects of temperature and hypoxia. J. Comp. Physiol. 151:145-153;1983. Gonzales, R.; Wood, S. C. Effect of gender and body temperature on the ventilatory response to hypoxia in hooded rats. Fed. Proc. 8:A840; 1984. Gollan, F.; Aono, M. The effect of temperature on sanguinous rabbits. CryoBiology 10:321-327; 1973. Gordon, C. J.; Watkinson, W. P. Effect of nickel chloride on body temperature and behavioral thermoregulation in rats. Fed. Proc. 3:A701;1989. Gordon, C. J. Temperature regulation in laboratory mammals following acute toxic insult. Toxicology 53:161-178; 1988. Gordon, C. J.; Fogelson, L. Comparative effects of hypoxia on behavioral thermoregulation in rats, hamsters, and mice. Am. J. Physiol. 260:R120-125; 1991. Green, M. D.; Lomax, P. Behavioral thermoregulation and neuroamines in fish (Chromus chromus). J. Therm. Biol. 1:237-240;1976.

S. C. Wood and R. Gonzales

Griffiths, T. L.; Holgate, S. T. The role of adenosine in respiratory physiology. In Adenosine and Adenosine Receptors (Edited by Williams, M.), Humana Press, Clifton, NJ, 1990: pp. 381-422. Hicks, J. W. ; Wood, S. C. Temperature regulation in lizards: effects of hypoxia. Am. J. Physiol. 248:R595-R600;1985. Hutchison, V. H.; Spriesterbach, K. K. Histamine and histamine receptors: behavioral thermoregulation in the salamander. Necturus maculosus. Comp. Biochem. Physiol. 85:199-206;1986. Jarvis, M. F.; Williams, M. Differences in adenosine A1 and A2 receptor density revealed by autoradiography in methylxanthinesensitive and insensitive mice. Pharmacol. Biochem. Behav. 30: 707-714; 1988. Kandasamy, S. B.; Hunt, W. A.; Mickley, G. A. Implication of prostaglandin and histamine H1 and H2 receptors in radiationinduced temperature responses of rats. Radiat. Res. 114:4253;1988. Kavaliers, M. ; Courtenay, S. ; Hirst, M. Opiates influence behavioral thermoregulation in the curly-tailed lizard, Leiocephalus carinatus. Physiol. Behav. 32:221-224;1984. Krogh, A. The quantitative relation between temperature and standard metabolism in animals. Intern. Z. Physik-chem. Biol. 1:491508;1914. Kroncke, G. M.; Nichols, R. D.; Mendenshall, J. T.; Myerowitz, P. D. ; Starling, J. R. Ectothermic philosophy of acid base balance to prevent fibrillation during hypoxia. Arch. Surg. 121:303304;1986. Kreussler, K. L.; Volpe, J. J. The neurological outcome of perinatal asphyxia. Early Brain Damage 1:151-167; 1984. Kruh¢ffer, M.; Glass, M. L.; Abe, A. S.; Johansen, K. Control of breathing in an amphibian, Bufo paracnemius: effects of temperature and hypoxia. Respir. Physiol. 69:267-275;1987. Lintzel, W. Uber die Wirkung der Luftverdunnung auf Tiere. V. Mitteilung Gaswechsel weisser Ratten. Pfugers. Arch. ges Physiol. 227:673-708; 1931. Lister, G. Oxygen transport in the intact hypoxic newborn lamb: acute effects of increasing P50. Ped. Res. 18:172-177;1984. Malvin, G. M.; Wood, S. C. Effect of air humidity on behavioral thermoregulation of the toad, Bufo marinus. J. Exp. Zoology 258: 322-326. Malvin, G. M.; Wood, S. C. Behavioral hypothermia and survival of hypoxic protozoans, Paramecium caudatum. Science 255:14231425; 1992. Miller, J. A.; Miller, F. S. Interactions between hypothermia and hypoxia-hypercapnia in neonates. Federation Proc. 25:13381341;1966. Misgeld, U.; Frotscher, M. Dependence of the viability of neurons in hippocampal slices on oxygen supply. Brain Res. Bull. 8:9931003;1982. Moore, F. L.; Miller, L. J. Arginine vasotocin induces sexual behavior on newts by acting on cells in the brain. Peptides 4:97102;1983. Naylor, A. M.; Ruwe, W. D.; Veale, W. L. Thermoregulatory actions of centrally administered vasopressin in the rat. Neuropharm. 25:787-794; 1986. Olsson, R. A.; Pearson, J. D. Cardiovascular purinoceptors. Physiol. Rev. 70:761-845;1990. Phillis, J. W.; Wu, P. H. The role of adenosine and its nucleotides in central synamptic transmission. Prog. Neurobiol. 16:187239;1981. Pokorny, J.; Trojan, S.; Fisher, J. Changes in the structure of the rat hippocampus after prolonged postnatal hypoxia. Physiol. Bohemoslov. 3 l: 193-202;1982. P6rtner, H. O.; Branco, L. S.; Malvin, G. M.; Wood, S. C. A new role for lactate in the toad, Bufo marinus. J. Applied Physiol., 76:2405-2410;1994.

Hypothermia in Hypoxic Animals: Mechanisms, Mediators and Functional Significance

Riedel, C.; Wood, S. C. Effects of hypercapnia and hypoxia on temperature selection of the toad, Bufo marinus. Fed. Proc. 2: A500;1988. Riphagen, C. L.; Pittman, Q. J. Arginine vasopressin as a central neurotransmitter. Fed. Proc. 45:2318-2322;1986. Robinzon, B.; Koike, T. I.; Neldon, H. L.; Kinzler, S. L.; Hen&y, I. R.; el-Halawani, M. E. Physiological effects of arginine vasotocin and mesotocin in cockerels. Brit. Poultry Sci. 29:639652;1988. Rothman, S. M.; Olney, J. W. Glutamate and the pathophysiology of hypoxic-ischemic brain damage. Ann. Neurol. 19:105111;1986. Ruth, V.; Fyhrquist, F. ; Clemons, G.; Raivio, K. O. Cord plasma vasopressin, erythropoietin, and hypoxanthine as indices of asphyxia at birth. Ped. Res. 24:490-494;1988. Schubring, C. Temperature regulation in healthy and resuscitated newborns immediately after birth. J. Perinat. Med. 14:2733;1986. Seale, T. W.; Johnson, P.; Carnety, J. M.; Rennert, O. M. Interstrain variation in acute toxic responses to caffeine among inbred mice. Pharmacol. Biochem. Behav. 20:567-573;1984. Seale, T. W.; Abla, K. A. ; Shamim, M. T.; Carney, J. M.; Daly, J. W. 3,7-dimethyl-l-propargylxanthine: A potent and selective in vivo antagonist of adenosine analogs. Life Sci. 43:16711684;1988. Shoemaker, V. W. ; Nagy, K. A. Osmoregulation in amphibians and reptiles. Ann. Rev. Physiol. 39:449-471;1977. Snyder, S. H. Adenosine as a neuromodulator Annu. Rev. Neurosci. 8:103-124;1985. Stefanovich, V.; Lunn, A; Gross, J. The effect of early postnatal hypoxia on the regional cerebral utilization of glucose in adult rats. Metabolic Brain Disease 3:311-315;1988.

43

Stegner, H.; Leake, R. D.; Palmer, S. M.; Oakes, G.; Fisher, D. A. The effect of hypoxia on neurohypophyseal hormone release in fetal and maternal sheep. Ped. Res. 18:188-191;1984. Szelenyi, Z. ; Donhoffer, S. The thermogenic function of brown adipose tissue and the response of body temperature to hypoxia and hypercapnia in the cold- and warm-adapted rat. Acta Physiol. Acad. Sci. Hungaricae 33:31-39;1968. Wade, C. E.; Keil, L. C. ; Ramsey, D. J. Role of volume and osmolality in the control of plasma vasopressin in dehydrated dogs. Neuroendocrinology 37:349-353; 1983. Walker, B. A. Role of vasopressin in the cardiovascular response to hypoxia in the conscious rat. Am. J. Physiol. 251:H1316H1323;1986. Walker, B. A. Cardiovascular effects of Vlf vasopressinergic blockade during acute hypercapnia in conscious rats. Am. J. Physiol. 252:R127-R133;1987. Wang, X. L., Lee, T. F.; Wang, L. C. H. Do adenosine antagonists improve cold tolerance by reducing hypothalamic adenosine activity in rats. Brain Res. Bull. 24:389-391;1990. Williams, M. Adenosine: the prototypic neuromodulator. Neurochem. Int. 14:249-264;1989. Wilson, D. A.; Hanley, D. F.; Feldman, M. A.; Traystman, R. J. Influence of chemoreceptors on neurohypophyseal blood flow during hypoxic hypoxia. Circ. Res. 61:94-101;1987. Wood, S. C. Interactions between hypoxia and hypothermia. Ann. Rev. Physiol. 53:71-85;1991. Wood, S. C. Interrelationships between hypoxia and thermoregulation. In Advances in Environmental and Comparative Physiology: Mechanisms of Systemic Regulation in Lower Vertebrates. (Edited by Heisler, N.) Springer, Berlin, 1995: pp. 209-23l.