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Am J Physiol Regul Integr Comp Physiol 279: R196-R201, 2000;
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Vol. 279, Issue 1, R196-R201, July 2000

Role of adenosine in the hypoxia-induced hypothermia of toads

Luiz G. S. Branco1, Alexandre A. Steiner1, Glenn J. Tattersall2, and Stephen C. Wood3

1 Faculdade de Odontologia de Ribeirão Preto, Universidade de São Paulo, 14040-904, Ribeirão Preto, São Paulo, Brasil; 2 Department of Biological Sciences, Kent State University, Kent 44242; and 3 Research Foundation, Summa Health System, Akron, Ohio 44304


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

The concept that hypoxia elicits a drop in body temperature (Tb) in a wide variety of animals is not new, but the mechanisms remain unclear. We tested the hypothesis that adenosine mediates hypoxia-induced hypothermia in toads. Measurements of selected Tb were performed using a thermal gradient. Animals were injected (into the lymph sac or intracerebroventricularly) with aminophylline (an adenosine receptor antagonist) followed by an 11-h period of hypoxia (7% O2) or normoxia exposure. Control animals received saline injections. Hypoxia elicited a drop in Tb from 24.8 ± 0.3 to 19.5 ± 1.1°C (P < 0.05). Systemically applied aminophylline (25 mg/kg) did not change Tb during normoxia, indicating that adenosine does not alter normal thermoregulatory function. However, aminophylline (25 mg/kg) significantly blunted hypoxia-induced hypothermia (P < 0.05). To assess the role of central thermoregulatory mechanisms, a smaller dose of aminophylline (0.25 mg/kg), which did not alter hypoxia-induced hypothermia systemically, was injected into the fourth cerebral ventricle. Intracerebroventricular injection of aminophylline (0.25 mg/kg) caused no significant change in Tb under normoxia, but it abolished hypoxia-induced hypothermia. The present data indicate that adenosine is a central and possibly peripheral mediator of hypoxia-induced hypothermia.

thermoregulation; aminophylline; body temperature; behavior; anapyrexia


    INTRODUCTION
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

HYPOXIA IS KNOWN TO REDUCE body temperature (Tb), a response that has been found to be extremely widespread among animal taxa (28). Evidence has accumulated that hypoxia-induced hypothermia is likely produced by a downward resetting of the thermoregulatory set point (7, 10, 16, 25). This response seems to be beneficial to hypoxic animals, because it reduces oxygen consumption, produces a leftward shift of the oxyhemoglobin dissociation curve with a resulting improvement of oxygen loading in the lungs, and decreases energetically costly ventilatory responses to hypoxia (see Ref. 28). The importance of this response is emphasized by reports showing an increase in survival of the tested species if they are allowed to become hypothermic during hypoxia exposure (16, 21). Although this protective response has been extensively studied, little is known about the mechanisms and mediators involved.

A potential biochemical or neurochemical mediator of hypoxia-induced hypothermia is adenosine (11, 28). First of all, adenosine is a purine nucleoside synthesized within cells and released into the extracellular fluid during conditions of hypoxic stress (22, 27). As well, adenosine and adenosine agonists have been reported to elicit hypothermia in experimental animals (1, 11, 32). Furthermore, changes in the extracellular concentration of adenosine in the brain and carotid bodies appear to be involved in the regulation of pulmonary ventilation (31), a response that is known to be altered by hypoxia. It would be remarkable if adenosine could exert its "retaliatory" role on thermoregulation during hypoxia much as it does in the cardiovascular and respiratory systems during ischemic and hypoxic episodes (13).

Previous data on the role of adenosine in hypoxia-induced hypothermia are from systemic administration of adenosine antagonists in anesthetized mammals (9, 11, 19, 22). In the present study we tested the hypothesis that adenosine is a central mediator of hypoxic hypothermia. Ectothermic species have emerged as a suitable model to investigate mechanisms of thermoregulation, because their control of Tb is primarily behavioral. As well, core Tb would not be affected by the vasoactive effects of adenosine, as it would in endotherms, because Tb is determined primarily by the temperature of the environment. Furthermore, hyperventilation and an accompanying heat loss are not complicating issues in working with hypoxia-induced hypothermia in ectotherms, because their hypoxic ventilatory drive is severely blunted at lower temperatures (18). The fact that the preferred Tb in ectotherms is believed to reflect the hypothalamic set point(s) for thermoregulation (8, 12, 15), analogous to the mammalian Tb set point, makes behavioral thermoregulation in ectotherms a useful approach to investigating the control of Tb. In fact, lesions in the hypothalamic region of the brains of ectotherms lead to alterations in preferred Tb (8) analogous to those seen in birds and mammals, suggesting that the neurological control of behavioral thermoregulation in lower vertebrates is similar to the physiological control seen in higher vertebrates. Thus, in the present study, we chose to examine the thermoregulatory responses of the toad Bufo paracnemis to hypoxia. Numerous thermoregulatory and ventilatory studies on this species have been performed in the past (4, 18), making it a very suitable animal model.


    METHODS
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Animals

Animal source and maintenance. Adult toads (Bufo paracnemis) of either sex, weighing 179.2 ± 18.4 g (means ± SE), were collected on the Campus of the University of São Paulo at Ribeirão Preto from February to April. The toads were maintained in plastic containers with free access to water and basking areas (temperature 25-27°C) for 2-5 wk before experimentation. Food (earthworms) was withheld for 1 wk before surgery.

Surgery. For anesthesia, the toad was submerged in 0.3% MS-222 (Sigma, St. Louis, MO). For measurements of preferred Tb, a thermistor probe was secured 2 cm into the cloaca with skin sutures. Similar preferred temperature profiles have been observed in this laboratory (unpublished observations) using toads with implanted telemeters. Thus, to minimize surgical interventions, the cloacal thermistor was used. Experiments were initiated 24 h after surgery (similar temperature preferences were observed whether 1, 2, or 4 days were allowed to elapse after surgery).

The fourth cerebral ventricle of the toads was cannulated as described previously (6). Briefly, during anesthesia (induced by submergence in 0.3% MS-222), the skin covering the caudal half of the skull was removed, and a hole was formed by cutting out a circular piece of connective tissue between the first vertebra and the occipital bone. This hole provided access to the fourth ventricle. A catheter was stereotaxically placed inside the hole with tips protruding into the cerebrospinal fluid (CSF) of the fourth ventricle. The opening was sealed with bone wax followed by application of dental acrylic, which secured the assembly in place. Screws had been drilled in the occipital bone and first vertebra to provide a firm contact after fusion with the acrylic. A tight-fitting mandril was kept inside the guide cannula to avoid its occlusion. This preparation allowed intracerebroventricular injections. All animals recovered from surgery, and 48 h later they were placed in the middle of the temperature gradient. The ionic composition of the mock CSF (mCSF) solution was (in meq/l) 56.6 NaCl, 2.7 KCl, 0.9 CaCl2, 0.45 MgSO4, and 27.0 NaHCO3.

Experiments Carried Out to Assess the Effect of Aminophylline on Selected Tb

Behavioral temperature selection was determined in a thermal gradient chamber (1.0 × 0.5 m) with an aluminum floor. One end was cooled to 10°C with a copper pad placed under the floor and connected to a refrigerated water bath (VWR Scientific, 1160A. Niles, IL). An electrical resistor heated the other end to 40°C. Petri dishes filled with tap water throughout the chamber provided access to water at all temperatures. An animal bearing the cloacal temperature probe was placed in the center of the temperature gradient, and the thermistor output was displayed on a chart recorder (Narcotrace 80). The thermogradient chamber was supplied with humidified air (normoxia) throughout the measurements.

The toad was placed in the middle of the temperature gradient and left undisturbed for 4 h. This period of time was adequate to observe a preferred Tb in toads, which does not change over a 24-h period (7, 29). At the 5th h, aminophylline was injected subcutaneously into the dorsal lymph sac (systemically) at the doses of 0.25 or 25 mg/kg body wt or injected into the fourth cerebral ventricle at the dose of 0.25 mg/kg body wt. Control toads were treated with the same volume of sterile, pyrogen-free Ringer (for lymph sac injections) or mCSF (for intracerebroventricular injections). Ringer or mCSF was the vehicle in which aminophylline was dissolved. The volume of each injection was 200 µl in the dorsal lymph sac or 2 µl in the fourth ventricle using a 705-LT, 10-µl Hamilton syringe.

Experiments Carried Out to Assess the Effect of Aminophylline on Hypoxia-Induced Hypothermia

The same temperature gradient chamber was used as in the normoxic exposure. At the 5th h, aminophylline was injected subcutaneously into the lymph sac (systemically) at the doses of 0.25 or 25 mg/kg body wt or injected into the fourth cerebral ventricle at the dose of 0.25 mg/kg body wt, and the chamber was ventilated with a hypoxic mixture (7% inspired O2).

Experiments Carried Out to Assess the Effect of Aminophylline on Blood Gases

Blood gases were determined in normoxic toads injected with saline or with aminophylline to ensure that the drug itself did not alter blood gases. Because hypoxemia or hyperoxemia could potentially alter the preferred temperatures, it was imperative that these controls be carried out. Blood (0.5 ml) withdrawn from the arterial cannula was analyzed for arterial PO2 (PaO2) and arterial pH (pHa) using an O2 analyzer (FAC, São Carlos, Brazil, model 204A) and a pH meter (Metrohm, Switzerland, model 654). The electrode was calibrated at 25°C with Radiometer precision buffer solutions (S1510 and S1500). The O2 electrodes were calibrated at 25°C using standard gas mixtures (CCS gas, Radiometer). All blood samples were analyzed immediately after withdrawal.

A set of experiments was then performed at 25°C, in which PaO2 and pHa were measured before and 2 h after aminophylline was administered subcutaneously (25 mg/kg) or intracerebroventricularly (0.25 mg/kg). Saline and mCSF were used as the respective controls. This was done as a control for possible aminophylline-induced changes in Tb from an indirect effect of this substance altering blood gases.

Data Analysis

Mean selected Tb was determined every hour in all experiments. The effect of drug administration on Tb was assessed by calculating the mean Tb for each experimental period and then comparing these means by a paired t-test. Values of P < 0.05 were considered to be significant. All results are presented as means ± SD.


    RESULTS
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Effect of Systemic Injection of Aminophylline on Selected Tb

Subcutaneous injection of aminophylline at the doses of 0.25 and 25 mg/kg caused a transitory reduction in the preferred Tb of the toads, similar to the effect of Ringer (Fig. 1).


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  		Fig. 1.   Effect of systemic injection of aminophylline on preferred body temperature (Tb) of toads. Mean ± SE preferred Tb was plotted over a 16-h period (n = 5). At the 5th h, aminophylline was injected subcutaneously into the lymph sac (ls). Room air or hypoxia (7% O2) was continuously flushed through the temperature-gradient chamber.

Hypoxia itself (7% inspired O2) caused a drop of Tb from 24.8 ± 0.3 to 19.5 ± 1.1°C, which was prevented by administration of 25 mg/kg aminophylline into the lymph sac but not 0.25 mg/kg (Fig. 1). Additional experiments showed that severe hypoxia (3% inspired O2) reduced (P < 0.05; n = 8) Tb from 26.6 ± 2.8 to 16.0 ± 4.1°C. Aminophylline (25 mg/kg into the lymph sac) combined with severe hypoxia (3% inspired O2) was lethal to the toads (80% mortality if hypoxia duration was >11 h).

Effect of Intracerebroventricular Injection of Aminophylline on Selected Tb

Intracerebroventricular injection of aminophylline at the dose of 0.25 mg/kg produced a transient reduction in the preferred Tb of the toads, similar to that observed when mCSF was injected. Hypoxia reduced Tb in toads injected with mCSF, but not after injection of 0.25 mg/kg aminophylline. These data are shown in Fig. 2. Table 1 shows the mean Tb for each experimental period.


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  		Fig. 2.   Effect of intracerebroventricular injection of aminophylline on preferred Tb of toads. Mean ± SD preferred Tb was plotted over a 16-h period (n = 5). At the 5th h, aminophylline was injected. Room air or hypoxia (7% O2) was continuously flushed through the temperature-gradient chamber. CSF, cerebrospinal fluid.


                              
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  		Table 1.   Effects of the injection of aminophylline into the lymph sac or intracerebroventricularly on preferred body temperature

Effects of Systemic Injections of Aminophylline on PaO2 and pHa

In toads kept at 25°C, neither systemic (25 mg/kg) nor intracerebroventricular (0.25 mg/kg) administration of aminophylline caused any significant change in PaO2 or pHa. Similarly, vehicle injections also had no significant effect on blood gases. These data are shown in Table 2.

                              
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  		Table 2.   Effects of the injection of aminophylline into the lymph sac or intracerebroventricularly on blood gases


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

The present study provides the first evidence that adenosine is an important mediator of hypoxia-induced behavioral hypothermia acting on the central nervous system (CNS).

Effects of Hypoxia on Tb

Our toads showed a drop in Tb during hypoxia exposure of ~5.5°C. It is well established that hypothermia is a beneficial response to hypoxia in many animal species (30). This is supported by the facts that 1) hypoxic-hypothermia has a marked protective effect on survival (30) and that 2) a 1°C drop in brain temperatures of rats is adequate to prevent a fall in brain ATP levels at a low PO2 (20 mmHg; Ref. 3).

Effects of Aminophylline on Tb Under Normoxia and Hypoxia

In the present study, neither systemic nor intracerebroventricular injection of aminophylline alone altered Tb of toads, indicating that adenosine does not have a tonic effect on the control of Tb. In fact, available literature data led us to conclude that adenosine could act as a neuromodulator when its concentration in the CNS is elevated by specific conditions such as hypoxia (31), asphyxia, (27) and injection of adenosine analogs (17). Administration of adenosine antagonists only, such as aminophylline, theophylline, or caffeine, at optimal doses, has been reported to have no effect on the Tb of mammals (11). In contrast, at higher doses, these antagonists increased heat production and Tb, which were always associated with behavioral excitation (20).

In our study, central aminophylline abolished hypoxia-induced hypothermia. Because systemic injections of aminophylline (which is known to cross the blood-brain barrier in rats; Ref. 14) at the same dose (0.25 mg/kg) failed to block hypoxic hypothermia, this supports the central role for adenosine in the thermoregulatory response to hypoxia. However, recent data indicate that the role of the CNS in thermoregulation during hypoxia is subjected to numerous modifiers (see Ref. 5). In addition to adenosine (11), lactate (7, 23) and opioids (11) have been suggested as neuromodulators of hypoxic hypothermia. Among them, nitric oxide seems to be a common mediator of several hypothermic stimuli, including hypoxia (5), hypercapnia (2), and systemic AVP injection (24). It is possible that all of the candidates, and others that will still be discovered, are necessary to trigger a full-blown hypoxia-induced hypothermia. However, the nature of this interaction remains unknown.

An interesting point about the role of adenosine in hypoxic hypothermia is that intracerebroventricular injection of an adenosine analog (2-chloroadenosine) causes a dose-related fall in Tb of mice (32), resembling the progressive Tb drop caused by hypoxia exposure. This raises the possibility that adenosine released during hypoxic stress may play a modulatory role in central thermoregulation by either promoting heat loss or inhibiting heat production. Because the preoptic anterior hypothalamus is the recognized major site for Tb control, one would expect this to be the area affected by adenosine during hypoxia. Wang et al. (26) used intrahypothalamic injections of aminophylline to assess the role of adenosine in cold tolerance in rats, and, in this condition, aminophylline alone did not elicit any enhancement in heat production compared with control animals exposed to cold. However, the hypothalamus may be affected by aminophylline during hypoxia because adenosine is increased in this condition (27, 31), a fact that does not seem to occur during cold exposure. Further studies are needed to assess the role of adenosine in the hypothalamus during hypoxic stress. Nevertheless, our data indicate that the presence of adenosine in the CNS during hypoxic exposure is important for a normal behavioral thermoregulatory response, perhaps because it causes a reduction of the thermoregulatory set point. In this context, our data strengthen this hypothesis, because, if adenosine is a mediator of hypoxia-induced hypothermia by acting on the CNS of toads, whose changes in preferred Tb have been shown to be related to changes in the thermoregulatory set point, it is likely that adenosine acts centrally by reducing this set point.

It is unlikely that aminophylline produces hypothermia by affecting blood gases. Although we did not measure blood bicarbonate, it is also unlikely that changes in arterial CO2 (i.e., a lower CO2) would have affected the behavioral response to hypoxia. Previous work has shown that the respiratory alkalosis brought about by hyperventilation during hypoxia does not affect the development of hypoxia-induced behavioral hypothermia (25, 29). As well, any changes in peripheral blood flow due to adenosine blockade would not have altered the Tb in toads. Our data showing that intracerebroventricular injections of aminophylline had no significant effects on PaO2 and pHa 2 h after administration (Table 2) indicate that hypothermia does not result from drug-induced changes in blood gases.

In conclusion, the present study indicates that although central adenosine does not play a major role in thermoregulation of normoxic toads, it seems to account, among other potential mediators, for hypoxic hypothermia. Because we used intracerebroventricular administration of aminophylline, we cannot ensure the exact site of action of the drug into the brain, although if the temperature set point has been altered by hypoxia, we would expect the preoptic area of the anterior hypothalamus to be a likely site for adenosine neuromodulation of Tb.

Perspectives

Future work in this field should examine the specific adenosine receptor types responsible for this behavior, their localization in the brain, and determine if the same neurophysiological control is observed in endotherms. If adenosine is indeed acting on the hypothalamus to lower the set point for Tb, this would be significant, as it could provide evidence for an association between the control of Tb and ventilation, because both are influenced by adenosine blockade. The importance of understanding how Tb is reduced during hypoxic stress could easily extend to clinical situations where pharmacological interventions to reduce Tb in a controlled rather than an uncontrolled fashion are desired. By understanding the pharmacology of Tb control, we may be able to manipulate Tb without causing harm. The significance of this study was that it examined this response in an ectotherm where the preferred temperature reflects the set point control and is not influenced by heat production or even heat loss. The other advantage of using an ectotherm for this study is that probable vasoactive effects of adenosine do not alter Tb as they would in an endotherm; i.e., altered peripheral blood flow would only alter the rate of heating or cooling but not cause a change in Tb.


    ACKNOWLEDGEMENTS

This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo, Conselho Nacional de Desenvolvimento Científico e Tecnológico, and Summa Health System of Akron, Ohio.


    FOOTNOTES

Address for reprint requests and other correspondence: S. C. Wood, Research Foundation, Summa Health System, 41 Arch St., Akron, OH 44306 (E-mailwoodsc{at}summa-health.org).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Received 3 September 1999; accepted in final form 16 February 2000.


    REFERENCES
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4.   Branco, LGS Effects of 2-deoxy-D-glucose and insulin on plasma glucose levels and behavioral thermoregulation of the toad, Bufo paracnemis. Am J Physiol Regulatory Integrative Comp Physiol 272: R1-R5, 1997[Abstract/Free Full Text].

5.   Branco, LGS, Carnio EC, and Barros RCH Role of nitric oxide pathway in hypoxia-induced hypothermia of rats. Am J Physiol Regulatory Integrative Comp Physiol 273: R967-R971, 1997[Abstract/Free Full Text].

6.   Branco, LGS, Glass ML, Wang T, and Hoffmann A. Temperature and central chemoreceptor drive to ventilation in toad (Bufo paracnemis). Respir Physiol 93: 337-346, 1993[ISI][Medline].

7.   Branco, LGS, and Steiner AA. Central thermoregulatory effects of lactate in the toad Bufo paracnemis. Comp Biochem Physiol A Physiol 122: 457-461, 1999.

8.   Berk, ML, and Heath JE. Effects of preoptic, hypothalamic, and telencephalic lesions on thermoregulation in the lizard, Dipsosaurus dorsalis. J Therm Biol 1: 65-78, 1975.

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Am J Physiol Regul Integr Comp Physiol 279(1):R196-R201
0363-6119/00 $5.00 Copyright © 2000 the American Physiological Society


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