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Am J Physiol Regul Integr Comp Physiol 291: R603-R607, 2006. First published April 13, 2006; doi:10.1152/ajpregu.00038.2006
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Physiology and Pharmacology of Temperature Regulation

Central angiotensin AT1-receptor blockade affects thermoregulation and running performance in rats

Laura H. R. Leite, Ana Cristina R. Lacerda, Umeko Marubayashi, and Cândido C. Coimbra

Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil

Submitted 16 January 2006 ; accepted in final form 5 April 2006


   ABSTRACT
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 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
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The effect of central angiotensin AT1-receptor blockade on thermoregulation in rats during exercise on a treadmill (18 m/min, 5% inclination) was investigated. Core (Tb) and skin tail temperatures were measured in rats while they were exercising until fatigue after injection of 2 µl of losartan (Los; 20 nmol, n = 4; 30 nmol, n = 4; 60 nmol, n = 7), an angiotensin II AT1-receptor antagonist, or 2 µl of 0.15 mol/l NaCl (Sal; n = 15) into the right lateral cerebral ventricle. Body heat rate (BHR), heat storage rate, threshold Tb for tail vasodilation (TTbV), time to fatigue, and workload were calculated. During exercise, the BHR and heat storage rate of Los-treated animals were, respectively, 40 and 53% higher (P < 0.01) than in Sal-treated animals. Additionally, rats injected with Los showed an increased TTbV (38.59 ± 0.19°C for Los vs. 38.12 ± 0.1°C for Sal, P < 0.02), a higher Tb at fatigue point (39.07 ± 0.14°C Los vs. 38.66 ± 0.07°C Sal, P < 0.01), and a reduced running performance (27.29 ± 4.48 min Los vs. 52.47 ± 6.67 min Sal, P < 0.01), which was closely related to the increased BHR. Our data suggest that AT1-receptor blockade attenuates heat dissipation during exercise due to the higher TTbV, leading to a faster exercise-induced increase in Tb, thus decreasing running performance.

tail vasodilation; fatigue; heat balance

ACTING CENTRALLY, ANGIOTENSIN II (ANG II), exerts thermoregulatory effects characterized by a decreased metabolic rate, a fall in core temperature (Tb), and an increase in tail skin temperature (Ttail) (43, 44, 46), through angiotensin type 1 (AT1) receptors. These receptors are widely spread through the central nervous system (CNS), including the preoptic area/anterior hypothalamus (POA/AH), regions of the hypothalamus considered to be the integrative centers of body temperature (5, 29, 34, 35). In addition, the subfornical organ (SFO) is critical for the central actions of ANG II (8, 14). The AT1-receptor antagonist losartan (Los) has been used to investigate the role of ANG II in Tb. Some studies have observed that intracerebroventricular (icv) injection of Los inhibited the hypothermic effect of ANG II, producing an increase in Tb of resting animals exposed to a hot environment (7, 27). In addition, Horowitz and colleagues (17, 36) showed that central administration of Los elevates the temperature threshold for peripheral vasodilation and causes a downward shift in the threshold for evaporative cooling during heat stress, indicating the involvement of hypothalamic angiotensinergic signaling in thermoregulation. Because hypothermia and increased heat dissipation may be neuroprotective, activation of central angiotensinergic transmission may exert important effects on thermoregulation during exercise, influencing running performance.

Elevated internal body temperature and increased heat storage (9, 12, 30) have been considered to be limiting factors that reduce the CNS drive for exercise performance (31, 32, 40) and precipitate feelings of fatigue, thus protecting the brain from thermal damage. It is important to emphasize that, until now, the literature has no reports on the role of thermoregulation and ANG II or Los during exercise. Therefore, the objective of this study was to assess the effects of the central administration of the AT1-receptor antagonist Los on heat balance and threshold Tb for tail vasodilation (TTbV) in untrained rats submitted to exercise until fatigue.


   METHODS
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 METHODS
RESULTS
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Animals. Male Wistar rats (240–330 g) were housed individually at a room temperature of 22 ± 2°C, under 14:10-h light-dark cycles and had free access to water and rat chow. Following anesthesia achieved using 2,2,2-tribromoethanol (1 ml/100 g body wt ip), the rats were fixed to a stereotaxic apparatus (David Kopf Instruments, M-900, Tujunga, CA), and a guide cannula (22 gauge) was implanted into the right lateral cerebral ventricle using a previously described technique (23). Also during this surgical procedure, TR3000 VM-FH temperature sensor (Mini Mitter, Sun River, OR) was implanted into the peritoneal cavity through a small incision in the linea alba. All animals were allowed to recover for at least 1 wk before being submitted to the experiments. The animals were acclimatized to exercise on the motor-driven treadmill by running at a speed of 15 m/min at 5% inclination for 5 min/day during four consecutive days before the experiments. All experiments were approved by the Ethics Committee for the Care and Use of Laboratory Animals of the Federal University of Minas Gerais and were carried out in accordance with the regulations described in the Committee's Guiding Principles Manual.

Experimental protocol. On the day of the experiment, the animals were allowed to rest for 1 h in the rodent treadmill chamber before being submitted to the test. A needle (30 gauge) protruding 0.3 mm from the tip of the guide cannula was introduced into the right lateral cerebral ventricle by connecting it to a Hamilton syringe. Immediately before exercise, 2.0 µl of 0.15 mol/l NaCl (Sal; n = 15) or 2.0 µl of Los (Merck Sharpe & Dohme, Campinas, Brazil; 60 nmol, n = 7) were injected into the right lateral ventricle. The dose of Los used was established after a previous test performed to determine a dose-response curve for the drug. The doses examined were 20, 30, and 60 nmol (Fig. 1). The dose that showed a significant influence on thermoregulatory parameters was selected. It is important to point out that the chosen dose of Los has been shown to be ineffective in producing thermal effects when administered via peripheral route (24, 41, 49). Rats were randomly assigned to groups receiving either Sal and/or Los solution. An interval of at least 4 days was allowed for the animal to recover between the tests. Immediately after the icv injections, the animals were submitted to running exercise until fatigue. Exercise was performed on a motor-driven treadmill (Columbus Instruments, Modular Treadmill, serial number 96002–2) between 1000 and 1400 at a room temperature of 22 ± 2°C. The intensity of exercise (18 m/min and 5% inclination) corresponded to an oxygen uptake of ~66% of maximal oxygen uptake (2, 18). Fatigue was defined as the point at which the animals were no longer able to keep pace with the treadmill (33, 39). Time to fatigue (TTF; min) and workload (kgm) were considered indexes of exercise performance.


Figure 1
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  		Fig. 1. Effect of intracerebroventricular injection of 2 µl of losartan (Los; 20 nmol, n = 4; 30 nmol, n = 4; 60 nmol, n = 7) or 0.15 mol/l NaCl (Sal, n = 15) on core temperature (Tb) at fatigue point. Data are expressed as means ± SE. r = 0.989, P < 0.01.

 
Tb was measured by telemetry. Ttail was measured using a probe, series 409-B (Yellow Springs Instruments), taped to the dorsal surface of the skin, ~10 mm from the base of the tail. Tb and Ttail were used to determine the TTbV, i.e., the Tb that corresponds to the moment at which Ttail clearly begins to increase (vasodilation). Tb and Ttail were recorded at rest, every minute during the first 20 min of exercise, and from this period on every 5 min until fatigue.

Calculations. Body heat rate (BHR; °C/min), i.e., rate of increase in Tb, was calculated as BHR = {Delta}Tb/(running time interval), where {Delta}Tb is the change in Tb (Tf – Ti), where Tf is Tb at fatigue point, and Ti is initial Tb measured before exercise.

Heat storage rate (HSR; cal/min) was calculated (13) as: HSR = ({Delta}Tb)·m·c/(running time interval), where m is the body weight in grams, and c is the specific heat of the body tissues (0.826 cal·g–1·°C–1).

Workload (W; kgm) was calculated as W = [body weight (kg)]·(TTF)·[treadmill speed (m/min)]·[sine {theta} (treadmill inclination)] (2, 3, 26).

Statistical analysis. The data are reported as means ± SE. Differences between groups and the effect of time were evaluated using the ANOVA test, followed by the Newman-Keuls test. The data were also compared using paired or unpaired Student's t-test, as applicable. The correlation between BHR and TTF was assessed using Pearson's correlation coefficient. Significance level was set at P < 0.05.


   RESULTS
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DISCUSSION
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As illustrated in Fig. 1, during exercise, the icv injection of Los induced a dose-dependent increase in Tb at fatigue point. However, after the icv injection of Los (60 nmol/2.0 µl, n = 5) or Sal (n = 9) in normal, resting animals, Tb and Ttail remained stable in both experimental groups during a period of 60 min (Table 1). The data of all Sal-treated animals, which were used to compare different doses of Los, were plotted together, as these showed similar performance during exercise.


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  		Table 1. Effect of intracerebroventricular injection of 2 µl of losartan (60 nmol) or 0.15 mol/l NaCl on resting core temperature and resting tail temperature

 
The icv injection of Los in untrained, normal rats (n = 7) induced a 48 and 50% decrease, respectively, in TTF (P < 0.01) and W (6.89 ± 1.16 kgm Los vs. 13.70 ± 1.87 kgm Sal, P < 0.01) compared with Sal-treated rats (n = 15) (Fig. 2, A and C). Exercise induced a rapid increase in Tb in both groups (Fig. 2A). Such increase was more intense during the first 15 min, but remained constant thereafter until the fatigue point. However, the Los animals exhibited a greater increase in Tb (38.52 ± 0.18°C Los vs. 38.24 ± 0.09°C Sal; P < 0.02). The differences in Tb between the treatments were already observed at 7 min and remained different until fatigue. The highest difference between treatments occurred at 25 min after exercise had started (39.06 ± 0.14°C Los vs. 38.54 ± 0.09°C Sal; P < 0.01). Additionally, Los-treated rats showed a higher Tb at fatigue point (39.07 ± 0.14°C Los vs. 38.66 ± 0.07°C Sal; P < 0.01).


Figure 2
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  		Fig. 2. Effect of intracerebroventricular injection of 2 µl of Los (60 nmol, n = 7) or 0.15 mol/l Sal (n = 15) on Tb (A), body heat rate and heat storage rate (BHR/HSR; B), skin tail temperature (Ttail; C), and on vasodilation threshold (TTbV; D) during exercise. Time to fatigue (TTF) is indicated by the horizontal bar at bottom of A and C: Sal (open bar) and Los (solid bar). Values are expressed as means ± SE. *P < 0.05 compared with Sal group. +P < 0.05 compared with corresponding basal value. {phi}P < 0.05 compared with corresponding nadir.

 
To compare the total thermal effects of exercise in both treatment groups, BHR and HSR (Fig. 2B) were calculated. During exercise, the BHR and HSR of Los-treated animals were, respectively, 40 and 53% higher (P < 0.01) than in the Sal-treated group. We also observed a close correlation between BHR and TTF (Fig. 3, r = 0.748, P < 0.01).


Figure 3
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  		Fig. 3. Correlation between BHR and TTF during exercise in rats treated with 2 µl of Los (60 nmol, n = 7; solid circles) or 2 µl of 0.15 mol/l Sal (n = 15; open circles).

 
As illustrated in Fig. 2C, Ttail increased within 14–16 min of exercise in both groups, indicating that heat loss mechanisms had been activated. Thereafter, Ttail remained stable in both groups. To assess whether Los affected the heat loss mechanism, TTbV was calculated, and results showed that values were 0.47°C higher in Los-treated rats compared with Sal-treated animals (Fig. 2D, P < 0.02).


   DISCUSSION
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In the present study, AT1-receptor blockade by Los produced an increase in TTbV, which was associated with elevated BHR and HSR in exercising rats. These data suggest that central angiotensin-mediated pathways are involved in thermoregulatory heat loss. Such pathways are probably responsible for the resetting of thresholds for heat balance during exercise. These findings also indicated a stronger inhibition of heat dissipation mechanisms in Los-treated rats, which produced a marked increase in BHR and HSR, leading to higher Tb during exercise and precipitating fatigue. This is the first demonstration that central angiotensin AT1 receptors are involved in thermoregulation and central fatigue during exercise.

The increase in body temperature that occurs in response to continuous exercise results from the temporary imbalance in the rates of heat production and dissipation during the early stage of exercise (4, 11, 20, 42). Vasoconstriction mediated by the sympathetic nervous system during this stage of exercise (15, 28) impairs heat loss. Consequently, Tb increases rapidly until it reaches the threshold for peripheral thermal vasodilation, thereby improving heat dissipation. Thereafter, Tb plateaus at a high level and remains high until fatigue.

Some studies provide evidence that central angiotensinergic pathways play an important role in thermoregulation by increasing heat dissipation through skin vasodilation as well as decreasing metabolic rate and Tb (43, 44, 46). This mechanism prevents high levels of heat storage and excessive hyperthermia. Elevated internal body temperature and increased heat storage have been considered to be limiting factors (9, 12, 30) that reduce the CNS drive for exercise performance (31, 32, 40) and precipitate feelings of fatigue, thus protecting the brain from thermal damage. The dissipation of heat from the body is thought to be more important than the control of heat production in the regulation of body temperature during exercise (10, 42). In exercising rodents, tail skin vasodilation is an essential route of heat loss from the body (12, 20, 35), and rat tails dissipate an equivalent of 25% of resting heat production (47), and, during exercise, the tail skin vasodilation is the primary heat loss mechanism (37, 45). Therefore, any imbalance in this mechanism provides severe heat loss impairment, leading to hyperthermia. Thus, as Los treatment raised TTbV, i.e., vasodilation was induced at a higher Tb than in untreated rats, the Los-treated rats have their heat dissipation through the tail delayed and have increased BHR and HSR as a consequence. On the other hand, as changes in absolute values of Ttail did not differ between the groups, and ANG II has an inhibitory effect on metabolic rate, we cannot exclude the possibility that icv injection of Los resulted in an increase in metabolic rate, leading in part to the enhanced hyperthermia seen in the running rats. Similar to the hyperthermic effect of central Los observed during heat exposure (22), it is possible that the blockade of central AT1 receptors prevented the increase in splanchnic nerve activity and the redistribution of blood flow to the skin during body heating induced by exercise. The increased TTbV and the delayed vasodilation observed in Los-treated rats point in this direction.

Los-treated rats showed a reduced exercise performance that was closely associated with BHR. The decrease in TTF observed in our study might have resulted from hyperthermic action of central Los not compensated by heat loss. The elevated HSR and the higher Tb at fatigue point showed by rats injected with Los support this hypothesis. The brain angiotensin-mediated pathways may have a thermolytic effect during exercise, improving heat loss mechanisms, protecting the brain from excessive hyperthermia, and improving physical performance. It is known that part of the metabolic energy consumed during exercise is dissipated as heat, and the other part is used to perform mechanical work. The balance between heat production and heat loss determines internal body temperature in homeothermic animals. To maintain the thermal balance, heat production by exercising muscles should be counteracted by increased heat loss. Otherwise, activity results in greater body temperature. Furthermore, hyperthermia reduces physical performance in many mammalian species, including rodents (9, 30, 40).

The exact location and precise pathways involved in the angiotensinergic mediation of normal thermoregulation during exercise still require clarification. However, hypothalamic regions expressing ANG II, such as the POA and paraventricular nucleus, are possible sites at which ANG II may influence thermoregulation during exercise (14). Therefore, we hypothesized that infusion of Los into the cerebral ventricle would perfuse to the SFO and other thermoregulatory centers situated in the hypothalamus, inhibiting the heat loss response and accelerating the BHR and HSR during prolonged exercise. The POA/AH is thought to be the primary locus for body temperature regulation (1, 5, 34, 35) due to the fact that it contains both warm-sensitive and cold-sensitive neurons that respond to small changes in temperature (19, 48). Moreover, lesions or pharmacological blockade of the POA/AH has been shown to produce a severe impairment in thermoregulation (5, 6, 34, 35). It has been established that the POA/AH is an integrative region for the maintenance of metabolic, vasomotor, and thermal homeostasis (5, 6, 34, 35). It is important to point out that POA/AH cell groups project to the sympathetic outflow of the tail artery involved in heat loss in the rat (38), producing tail vasodilation when the POA is warmed (19, 21, 48). In addition, it has recently been shown that inhibition of the POA/AH by local infusion of tetrodotoxin impairs heat loss in running rats (16). A variety of studies have suggested that SFO and other adjacent areas are critical for the central actions of ANG II (7, 14) and that SFO afferent communication with paraventricular nucleus utilizes ANG II as a neurotransmitter within this hypothalamic region (25). Moreover, lesion of the SFO resulted in abolished ANG II-mediated temperature response (7). These results indicate that the POA/AH and SFO are important mediators of heat loss as opposed to heat production during exercise and might be possible sites for Los action.

In summary, icv infusion of Los induced a significant increase in BHR, which rapidly produced hyperthermia 0.41°C higher than in controls, with a significant increase in TTbV. In addition, treatment with Los reduced exercise performance that was closely associated with BHR. Therefore, our results provide the first evidence that central angiotensinergic transmission has important effects on thermoregulation during exercise by increasing heat dissipation through peripheral vasodilation, preventing high levels of heat storage and protecting the brain against excessive hyperthermia.


   GRANTS
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The authors are indebted to Coordenadoria de Apoio ao Pessoal de Nível Superior, Conselho Nacional de Desenvolvimento Científico e Tecnológico, and Fundação de Amparo à Pesquisa de Estado de Minas Gerais for financial support.


   ACKNOWLEDGMENTS
 
The technical assistance of André Luis Pimenta de Faria is acknowledged.


   FOOTNOTES
 

Address for reprint requests and other correspondence: C. C. Coimbra, Departamento de Fisiologia e Biofísica, Instituto de Ciências Biológicas/UFMG, Av. Antônio Carlos, 6627, 31270-901 Belo Horizonte, MG, Brazil (e-mail: coimbrac{at}icb.ufmg.br)

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


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