Time course of cytokine, corticosterone, and tissue injury responses in mice during heat strain recovery.

Elevated circulating cytokines are observed in heatstroke patients, suggesting a role for these substances in the pathophysiological responses of this syndrome. Typically, cytokines are determined at end-stage heatstroke such that changes throughout progression of the syndrome are poorly understood. We hypothesized that the cytokine milieu changes during heatstroke progression, correlating with thermoregulatory, hemodynamic, and tissue injury responses to heat exposure in the mouse. We determined plasma IL-1alpha, IL-1beta, IL-2, IL-4, IL-6, IL-10, IL-12p40, IL-12p70, IFN-gamma, macrophage inflammatory protein-1alpha, TNF-alpha, corticosterone, glucose, hematocrit, and tissue injury during 24 h of recovery. Mice were exposed to ambient temperature of 39.5 +/- 0.2 degrees C, without food and water, until maximum core temperature (T(c,Max)) of 42.7 degrees C was attained. During recovery, mice displayed hypothermia (29.3 +/- 0.4 degrees C) and a feverlike elevation at 24 h (control = 36.2 +/- 0.3 degrees C vs. heat stressed = 37.8 +/- 0.3 degrees C). Dehydration ( approximately 10%) and hypoglycemia ( approximately 65-75% reduction) occurred from T(c,Max) to hypothermia. IL-1alpha, IL-2, IL-4, IL-12p70, IFN-gamma, TNF-alpha, and macrophage inflammatory protein-1alpha were undetectable. IL-12p40 was elevated at T(c,Max), whereas IL-1beta, IL-6, and IL-10 inversely correlated with core temperature, showing maximum production at hypothermia. IL-6 was elevated, whereas IL-12p40 levels were decreased below baseline at 24 h. Corticosterone positively correlated with IL-6, increasing from T(c,Max) to hypothermia, with recovery to baseline by 24 h. Tissue lesions were observed in duodenum, spleen, and kidney at T(c,Max), hypothermia, and 24 h, respectively. These data suggest that the cytokine milieu changes during heat strain recovery with similarities between findings in mice and those described for human heatstroke, supporting the application of our model to the study of cytokine responses in vivo.     

Acute heat stress protects rats against endotoxin shock.

The purpose of this study was to determine 1) whether prior (24-h) heat stress could render rats cross-resistant to the lethal activity of bacterial lipopolysaccharide (LPS) and 2) whether this acquired state of resistance is associated with endotoxemia during the heat stress event. Four groups (n = 7/group) of rats were examined: 1) saline treated, 2) LPS treated, 3) heat stressed and saline treated, and 4) heat stressed and LPS treated. Saline or LPS (Escherichia coli, serotype 0111:B4, 20 mg/kg body wt) was given intravenously 24 h after exposure to heat (ambient temperature 47-50 degrees C, relative humidity 30%) for heat-stressed rats and at the same time of day for nonheated rats; survival was monitored for 48 h. Thermal responses were similar (P > 0.05); values for maximum core temperature (Tc) and time above Tc of 40 degrees C were 42.7 +/- 0.1 and 42.6 +/- 0.1 degrees C (SE) and 44.0 +/- 2.1 and 47.9 +/- 3.7 (SE) min for the heat-stressed saline-treated and heat-stressed LPS-treated rats, respectively. Administration of LPS to nonheated rats resulted in 71.4% (5 of 7 rats) lethality. In contrast, all (7 of 7) rats subjected to a single nonlethal heat stress event 24 h before LPS treatment survived (P < 0.05). Endotoxin was not detected in arterial plasma immediately after heat stress in rats (n = 6) exposed to a Tc of 42.9 +/- 0.1 degrees C. These findings demonstrate that acute heat stress can protect rats from the lethal activity of LPS.     

Increased heat-escape/cold-seeking behavior following hypertonic saline injection in rats

We examined the effect of hypertonic saline injection on heat-escape/cold-seeking behavior in desalivated rats. Rats were exposed to 40 degrees C heat after normal (154 mM NaCl, control) or hypertonic saline (2,500 mM NaCl) injection (1 ml/100 g body wt). The rats received a 0 degrees C air for 30 s when they entered a specific area in an experimental box. Core temperature (T(c)) surpassed 40 degrees C in both conditions when 0 degrees C air was not available. Hypertonic saline injection produced a lower baseline T(c) than control [36.9 +/- 0.2 and 37.9 +/- 0.2 degrees C (means +/- SE), P < 0.05] and a greater number of 0 degrees C air rewards during the 2-h heat with lower T(c) at the end (48 +/- 1 and 34 +/- 2, 37.6 +/- 0.1, and 37.3 +/- 0.1 degrees C in the control and hypertonic saline injection trial, respectively, P < 0.05, n = 6). However, T(c) was similar (37.7 +/- 0.2 and 37.6 +/- 0.4 degrees C in the control and hypertonic saline injection trial, n = 5) when 0 degrees C air was automatically and intermittently (35 times) given during the heat. Rats augment heat-defense mechanisms in response to osmotic stress by lowering the baseline T(c) and increasing heat-escape/cold-seeking behavior.     

Thermoregulatory responses of rats to conventional preparations of lipopolysaccharide are caused by lipopolysaccharide per se-- not by lipoprotein contaminants

LPS preparations cause a variety of body temperature (T(b)) responses: monophasic fever, different phases of polyphasic fever, and hypothermia. Conventional (c) LPS preparations contain highly active lipoprotein contaminants (endotoxin proteins). Whereas LPS signals predominantly via the Toll-like receptor (TLR) 4, endotoxin proteins signal via TLR2. Several TLR2-dependent responses of immunocytes to cLPS in vitro are triggered by endotoxin proteins and not by LPS itself. We tested whether any T(b) response to cLPS from Escherichia coli 055:B5 is triggered by non-TLR4-signaling contaminants. A decontaminated (d) LPS preparation (free of endotoxin proteins) was produced by subjecting cLPS to phenol-water reextraction. The presence of non-TLR4-signaling contaminants in cLPS (and their absence in dLPS) was confirmed by showing that cLPS (but not dLPS) induced IL-1beta expression in the spleen and increased serum levels of TNF-alpha and IL-1beta of C3H/HeJ mice; these mice bear a nonfunctional TLR4. Yet, both cLPS and dLPS caused cytokine responses in C3H/HeOuJ mice; these mice bear a fully functional TLR4. We then studied the T(b) responses to cLPS and dLPS in Wistar rats preimplanted with jugular catheters. At a neutral ambient temperature (30 degrees C), a low (0.1 microg/kg iv) dose of cLPS caused a monophasic fever, whereas a moderate (10 microg/kg iv) dose produced a polyphasic fever. In the cold (20 degrees C), a high (500 microg/kg iv) dose of cLPS caused hypothermia. All T(b) responses to dLPS were identical to those of cLPS. We conclude that all known T(b) responses to LPS preparations are triggered by LPS per se and not by non-TLR4-signaling contaminants of such preparations.     

The physiological strain index applied to heat-stressed rats.

A physiological strain index (PSI) based on heart rate (HR) and rectal temperature (Tre) was recently suggested to evaluate exercise-heat stress in humans. The purpose of this study was to adjust PSI for rats and to evaluate this index at different levels of heat acclimation and training. The corrections of HR and Tre to modify the index for rats are as follows: PSI = 5 (Tre t - Tre 0). (41.5 - Tre 0)-1 + 5 (HRt - HR0). (550 - HR0)-1, where HRt and Tre t are simultaneous measurements taken at any time during the exposure and HR0 and Tre 0 are the initial measurements. The adjusted PSI was applied to five groups (n = 11-14 per group) of acclimated rats (control and 2, 5, 10, and 30 days) exposed for 70 min to a hot climate [40 degrees C, 20% relative humidity (RH)]. A separate database representing two groups of acclimated or trained rats was also used and involved 20 min of low-intensity exercise (O2 consumption approximately 50 ml. min-1. kg-1) at three different climates: normothermic (24 degrees C, 40% RH), hot-wet (35 degrees C, 70% RH), and hot-dry (40 degrees C, 20% RH). In normothermia, rats also performed moderate exercise (O2 consumption approximately 60 ml. min-1. kg-1). The adjusted PSI differentiated among acclimation levels and significantly discriminated among all exposures during low-intensity exercise (P < 0.05). Furthermore, this index was able to assess the individual roles played by heat acclimation and exercise training.     

Heat storage in horses during submaximal exercise before and after humid heat acclimation.

The effect of humid heat acclimation on thermoregulatory responses to humid and dry exercise-heat stress was studied in six exercise-trained Thoroughbred horses. Horses were heat acclimated by performing moderate-intensity exercise for 21 days in heat and humidity (HH) [34.2-35.7 degrees C; 84-86% relative humidity (RH); wet bulb globe temperature (WBGT) index approximately 32 degrees C]. Horses completed exercise tests at 50% of peak O(2) uptake until a pulmonary arterial temperature (T(pa)) of 41.5 degrees C was attained in cool dry (CD) (20-21.5 degrees C; 45-50% RH; WBGT approximately 16 degrees C), hot dry (HD 0) [32-34 degrees C room temperature (RT); 45-55% RH; WBGT approximately 25 degrees C], and HH conditions (HH 0), and during the second hour of HH on days 3, 7, 14, and 21, and in HD on the 18th day (HD 18) of heat acclimation. The ratios of required evaporative capacity to maximal evaporative capacity of the environment (E(req)/E(max)) for CD, HD, and HH were approximately 1.2, 1.6, and 2.5, respectively. Preexercise T(pa) and rectal temperature were approximately 0.5 degrees C lower (P < 0. 05) on days 7, 14, and 21 compared with day 0. With exercise in HH, there was no effect of heat acclimation on the rate of rise in T(pa) (and therefore exercise duration) nor the rate of heat storage. In contrast, exercise duration was longer, rate of rise in T(pa) was significantly slower, and rate of heat storage was decreased on HD 18 compared with HD 0. It was concluded that, during uncompensable heat stress in horses, heat acclimation provided modest heat strain advantages when E(req)/E(max) was approximately 1.6, but at higher E(req)/E(max) no advantages were observed.     

Inflammatory, hemostatic, and clinical changes in a baboon experimental model for heatstroke.

The mortality and neurological morbidity in heatstroke have been attributed to the host's inflammatory and hemostatic responses to heat stress, suggesting that immunomodulation may improve outcome. We postulated that an experimental baboon model of heatstroke will reproduce human responses and clinical outcome to allow testing of new therapeutic strategies. Eight anesthetized juvenile baboons (Papio hamadryas) were subjected to heat stress in an incubator maintained at 44-47 degrees C until rectal temperature attained 42.5 degrees C (moderate heatstroke; n = 4) or systolic arterial pressure fell to <90 mmHg (severe heatstroke; n = 4) and were allowed to recover at room temperature. Four sham-heated animals served as a control group. Rectal temperature at the end of heat stress was 42.5 +/- 0.0 and 43.3 +/- 0.1 degrees C, respectively. All heat-stressed animals had systemic inflammation and activated coagulation, indicated by increased plasma IL-6, prothrombin time, activated partial thromboplastin time, and D-dimer levels, and decreased platelet count. Biochemical markers and/or histology evidenced cellular injury/dysfunction: plasma levels of thrombomodulin, creatinine, creatine kinase, lactic dehydrogenase, and alanine aminotransferase were increased, and varying degrees of tissue damage were present in liver, brain, and gut. No baboon with severe heatstroke survived. Neurological morbidity but no mortality was observed in baboons with moderate heatstroke. Nonsurvivors displayed significantly greater coagulopathy, inflammatory activity, and tissue injury than survivors. Sham-heated animals had an uneventful course. Heat stress elicited distinct patterns of inflammatory and hemostatic responses associated with outcome. The baboon model of heatstroke appears suitable for testing whether immunomodulation of the host's responses can improve outcome.     

Acclimation of entomopathogenic nematodes to novel temperatures: trehalose accumulation and the acquisition of thermotolerance

The effect of thermal acclimation on trehalose accumulation and the acquisition of thermotolerance was studied in three species of entomopathogenic nematodes adapted to either cold or warm temperatures. All three Steinernema species accumulated trehalose when acclimated at either 5 or 35 degrees C, but the amount of trehalose accumulation differed by species and temperature. The trehalose content of the cold adapted Steinernema feltiae increased by 350 and 182%, of intermediate Steinernema carpocapsae by 146 and 122% and of warm adapted Steinernema riobrave by 30 and 87% over the initial level (18.25, 27.24 and 23.97 microg trehalose/mg dry weight, respectively) during acclimation at 5 and 35 degrees C, respectively. Warm and cold acclimation enhanced heat (40 degrees C for 8h) and freezing (-20 degrees C for 4h) tolerance of S. carpocapsae and the enhanced tolerance was positively correlated with the increased trehalose levels. Warm and cold acclimation also enhanced heat but not freezing tolerance of S. feltiae and the enhanced heat tolerance was positively correlated with the increased trehalose levels. In contrast, warm and cold acclimation enhanced the freezing but not heat tolerance of S. riobrave, and increased freezing tolerance of only warm acclimated S. riobrave was positively correlated with the increased trehalose levels. The effect of acclimation on maintenance of original virulence by either heat or freeze stressed nematodes against the wax moth Galleria mellonella larvae was temperature dependent and differed among species. During freezing stress, both cold and warm acclimated S. carpocapsae (84%) and during heat stress, only warm acclimated S. carpocapsae (95%) maintained significantly higher original virulence than the non-acclimated (36 and 47%, respectively) nematodes. Both cold and warm acclimated S. feltiae maintained significantly higher original virulence (69%) than the non-acclimated S. feltiae (0%) during heat but not freezing stress. In contrast, both warm and cold acclimated S. riobrave maintained significantly higher virulence (41%) than the non-acclimated (14%) nematodes during freezing, but not during heat stress. Our data indicate that trehalose accumulation is not only a cold associated phenomenon but is a general response of nematodes to thermal stress. However, the extent of enhanced thermal stress tolerance conferred by the accumulated trehalose differs with nematode species.     

Differential metabolic capacity of mice selected for magnitude of swim stress-induced analgesia.

Maximum oxygen consumption (Vo(2)) elicited by swimming in 20 degrees C water or by exposure to -2.5 degrees C in helium-oxygen (Helox) atmosphere is higher in mice selected for low (LA) than for high (HA) stress-induced analgesia (SIA) produced by swimming. However, this line difference is greater with respect to swim- than to cold-elicited Vo(2). To study the relationship between the analgesic and thermogenic mechanisms, we acclimated HA and LA mice to 5 degrees C or to daily swimming at 20 or 32 degrees C. Next, the acclimated mice were exposed to a Helox test at -2.5 degrees C and to a swim test at 20 degrees C to compare Vo(2) and hypothermia (DeltaT). Cold acclimation raised Vo(2) and decreased DeltaT. These effects were similar in both lines in the Helox test but were smaller in the HA than in the LA line in the swim test. HA and LA mice acclimated to 20 or 32 degrees C swims increased Vo(2) and decreased DeltaT elicited by swimming, but only HA mice acclimated to 20 degrees C swims increased Vo(2) and decreased DeltaT in the Helox test. We conclude that the between-line difference in swim Vo(2) results from a stronger modulation of thermogenic capacities of HA mice by a swim stress-related mechanism, resulting in SIA. We suggest that the predisposition to SIA observed in laboratory as well as wild animals may significantly affect both the results of laboratory measurements of Vo(2) and the interpretation of its intra- and interspecific variation.     

Neurotensin analog NT77 induces regulated hypothermia in the rat

The potential use of hypothermia as a therapeutic treatment for stroke and other pathological insults has prompted the search for drugs that can lower core temperature. Ideally, a drug is needed that reduces the set-point for control of core temperature (T(c)) and thereby induces a regulated reduction in T(c). To this end, a neurotensin analog (NT77) that crosses the blood brain barrier and induces hypothermia was assessed for its effects on the set-point for temperature regulation in the Sprague-Dawley rat by measuring behavioral and autonomic thermoregulatory responses. Following surgical implanation of radiotransmitters to monitor T(c), rats were placed in a temperature gradient and allowed to select from a range of ambient temperatures (T(a)) while T(c) was monitored by radiotelemetry. There was an abrupt decrease in selected T(a) from 29 to 16 degrees C and a concomitant reduction in T(c) from 37.4 to 34.0 degrees C 1 hr after IP injection of 5.0 mg/kg NT77. Selected T(a) and T(c) then recovered to control levels by 1.5 hr and 4 hr, respectively. Oxygen consumption (M) and heat loss (H) were measured in telemetered rats housed in a direct calorimeter maintained at a T(a) of 23.5 degrees C. Injection of NT77 initially led to a reduction in M, little change in H, and marked decrease in T(c). H initially rose but decreased around the time of the maximal decrease in T(c). Overall, NT77 appears to induce a regulated hypothermic response because the decrease in T(c) was preceded by a reduction in heat production, no change in heat loss, and preference for cold T(a)'s. Inducing a regulated hypothermic response with drugs such as NT77 may be an important therapy for ischemic disease and other insults.     

Effect of body temperature during exercise on skeletal muscle cytochrome c oxidase content.

This study determined the role of body temperature during exercise on cytochrome-c oxidase (CytOx) activity, a marker of mitochondrial content, and mitochondrial heat shock protein 70 (mtHSP70), which is required for import of nuclear-coded preproteins. Male, 10-wk-old, Sprague-Dawley rats exercised identically for 9 wk in ambient temperatures of 23 degrees C (n = 10), 8 degrees C with wetted fur (n = 8), and 4 degrees C with wetted fur and fan (n = 7). These conditions maintained exercising core temperature (T(c)) at 40.4, 39.2, or 38.0 degrees C (resting temperature), respectively. During weeks 3-9, exercisers ran 5 days/wk up a 6% grade at 20 m/min for 60 min. Animals were housed at 23 degrees C. Gastrocnemius CytOx activity in T(c)=38.0 degrees C (83.5 +/- 5.5 microatoms O x min(-1) x g wet wt(-1)) was greater than all other groups (P < 0.05), exceeding sedentary (n = 7) by 73.2%. T(c) of 40.4 and 39.2 degrees C also were higher than sedentary by 22.4 and 37.4%, respectively (P < 0.05). Quantification of CytOx content verified that the increased activity was due to an increase in protein content. In extensor digitorum longus, a nonactive muscle, CytOx was not elevated in T(c) = 38.0 degrees C. mtHSP70 was significantly elevated in gastrocnemius of T(c) = 38.0 degrees C compared with sedentary (P < 0.05) but was not elevated in extensor digitorum longus (P > 0.05). The data indicate that decreasing exercise T(c) may enhance mitochondrial biogenesis and that mtHSP70 expression is not dependent on temperature.     

AMP does not induce torpor

Torpor, a state characterized by a well-orchestrated reduction of metabolic rate and body temperature (T(b)), is employed for energetic savings by organisms throughout the animal kingdom. The nucleotide AMP has recently been purported to be a primary regulator of torpor in mice, as circulating AMP is elevated in the fasted state, and administration of AMP causes severe hypothermia. However, we have found that the characteristics and parameters of the hypothermia induced by AMP were dissimilar to those of fasting-induced torpor bouts in mice. Although administration of AMP induced hypothermia (minimum T(b) = 25.2 +/- 0.6 degrees C) similar to the depth of fasting-induced torpor (24.9 +/- 1.5 degrees C), ADP and ATP were equally effective in lowering T(b) (minimum T(b): 24.8 +/- 0.9 degrees C and 24.0 +/- 0.5 degrees C, respectively). The maximum rate of T(b) fall into hypothermia was significantly faster with injection of adenine nucleotides (AMP: -0.24 +/- 0.03; ADP: -0.24 +/- 0.02; ATP: -0.25 +/- 0.03 degrees C/min) than during fasting-induced torpor (-0.13 +/- 0.02 degrees C/min). Heart rate decreased from 755 +/- 15 to 268 +/- 17 beats per minute (bpm) within 1 min of AMP administration, unlike that observed during torpor (from 646 +/- 21 to 294 +/- 19 bpm over 35 min). Finally, the hypothermic effect of AMP was blunted with preadministration of an adenosine receptor blocker, suggesting that AMP action on T(b) is mediated via the adenosine receptor. These data suggest that injection of adenine nucleotides into mice induces a reversible hypothermic state that is unrelated to fasting-induced torpor.     

Effects of hypothermia and re-warming on the inflammatory response in a murine multiple hit model of trauma

INTRODUCTION: Although, hypothermia is a frequent event after trauma, it is unclear whether its beneficial or detrimental effects are more important. This study aims to quantify the effects of hypothermia and re-warming on the inflammatory response after fracture/hemorrhage and subsequent fracture stabilization with resuscitation. MATERIALS AND METHODS: Eighty-one male C57Bl/6 mice (aged 8-10 weeks, weighing 22.0+/-3.0 g) underwent femoral fracture and hemorrhage followed by resuscitation and splint fixation of the fracture. Animals were sacrificed 3h after induction of hemorrhage and fracture. Besides a sham group (n=6), four experimental groups were created: A: normothermia (n=12), B: hypothermia after trauma (n=21), C: re-warming after resuscitation and before stabilization (n=21), and D: hypothermia before trauma (n=21). Groups B-D were further subdivided into three subgroups according to the degree of hypothermia (subgroup 1: 35-33 degrees C, subgroup 2: 32.9-30.0 degrees C, and subgroup 3: 29.9-27.0 degrees C). Plasma cytokine (TNF-alpha, IL-6, and IL-10) and chemokine (MCP-1) concentrations were determined by ELISA, pulmonary permeability changes were quantified, and histological analysis of lung and liver tissues was performed. RESULTS: Normothermia resulted in a significantly increased early mortality rate. A significantly increased pro-inflammatory and decreased anti-inflammatory responses were also observed in normothermia as compared to hypothermia. The extent of these changes was most pronounced in the severe hypothermic group. Re-warming after mild hypothermia resulted in a pro-inflammatory response comparable to normothermia. CONCLUSION: Hypothermia has a beneficial effect on early survival after trauma, which appears to be independent of the level of hypothermia and re-warming. Re-warming, however, enhanced the pro-inflammatory response. Further studies with a longer posttraumatic observation period are required to investigate the long term effects of the hypothermia and re-warming-induced changes on the pro- and anti-inflammatory responses.     

Effects of hypothermia on neuronal-vascular function after cerebral ischemia in piglets

We determined whether cerebral arteriolar dilation to N-methyl-d-aspartate (NMDA), a response dependent on stimulation of cortical neurons and inhibited by anoxic stress, would be preserved by hypothermia during and following ischemia. Pial arteriolar diameters in anesthetized piglets were determined via intravital microscopy. Arteriolar responses to NMDA (10, 50, and 100 micromol/l) were measured before and 1 h after 10 min of global ischemia. Piglets were exposed to either total body or selective brain cooling (33-34 degrees C). Arteriolar dilation to lower doses or to 100 micromol/l NMDA was not affected by hypothermia alone (51 +/- 3 vs. 46 +/- 7%, normothermia vs. hypothermia; n = 7) in nonischemic animals. However, arteriolar responses to 100 micromol/l NMDA were clearly attenuated after ischemia despite body cooling during ischemia (53 +/- 3 vs. 32 +/- 6%; n = 8), hypothermia during ischemia and early reperfusion (49 +/- 10 vs. 20 +/- 3%; n = 8), or selective brain cooling (48 +/- 5 vs. 20 +/- 5%; n = 10). In contrast, pretreatment with indomethacin resulted in complete preservation of NMDA-induced vasodilation after ischemia. Thus, hypothermia fails to protect against neuronal dysfunction during ischemia.     

Heat acclimation and physical training adaptations of young women using different contraceptive hormones

Although endogenous and exogenous steroid hormones affect numerous physiological processes, the interactions of reproductive hormones, chronic exercise training, and heat acclimation are unknown. This investigation evaluated the responses and adaptations of 36 inactive females [age 21 +/- 3 (SD) yr] as they undertook a 7- to 8-wk program [heat acclimation and physical training (HAPT)] of indoor heat acclimation (90 min/day, 3 days/wk) and outdoor physical training (3 days/wk) while using either an oral estradiol-progestin contraceptive (ORAL, n = 15), a contraceptive injection of depot medroxyprogesterone acetate (DEPO, n = 7), or no contraceptive (EU-OV, n = 14; control). Standardized physical fitness and exercise-heat tolerance tests (36.5 degrees C, 37% relative humidity), administered before and after HAPT, demonstrated that the three subject groups successfully (P < 0.05) acclimated to heat (i.e., rectal temperature, heart rate) and improved muscular endurance (i.e., sit-ups, push-ups, 4.6-km run time) and body composition characteristics. The stress of HAPT did not disrupt the menstrual cycle length/phase characteristics, ovulation, or plasma hormone concentrations of EU-OV. No between-group differences (P > 0.05) existed for rectal and skin temperatures or metabolic, cardiorespiratory, muscular endurance, or body composition variables. A significant difference post-HAPT in the onset temperature of local sweating, ORAL (37.2 +/- 0.4 degrees C) vs. DEPO (37.7 +/- 0.2 degrees C), suggested that steroid hormones influenced this adaptation. In summary, virtually all adaptations of ORAL and DEPO were similar to EU-OV, suggesting that exogenous reproductive hormones neither enhanced nor impaired the ability of women to complete 7-8 wk of strenuous physical training and heat acclimation.     

Ambient temperature modulates hypoxic-induced changes in rat body temperature and activity differentially

When rats, acclimated to an ambient temperature (T(a)) of 29 degrees C, are exposed to 10% O(2) for 63 h, the circadian rhythms of body temperature (T(b)) and level of activity (L(a)) are abolished, T(b) falls to a hypothermic nadir followed by a climb to a hyperthermic peak, L(a) remains depressed (Bishop B, Silva G, Krasney J, Salloum A, Roberts A, Nakano H, Shucard D, Rifkin D, and Farkas G. Am J Physiol Regulatory Integrative Comp Physiol 279: R1378-R1389, 2000), and overt brain pathology is detected (Krasney JA, Farkas G, Shucard DW, Salloum AC, Silva G, Roberts A, Rifkin D, Bishop B, and Rubio A. Soc Neurosci Abstr 25: 581, 1999). To determine the role of T(a) in these hypoxic-induced responses, T(b) and L(a) data were detected by telemetry every 15 min for 48 h on air, followed by 63 h on 10% O(2) from rats acclimated to 25 or 21 degrees C. Magnitudes and rates of decline in T(b) after onset of hypoxia were inversely proportional to T(a), whereas magnitudes and rates of T(b) climb after the hypothermic nadir were directly proportional to T(a). No hyperthermia, so prominent at 29 degrees C, occurred at 25 or 21 degrees C. The hypoxic depression of L(a) was least at 21 degrees C and persisted throughout the hypoxia. In contrast, T(a) was a strong determinant of the magnitudes and time courses of the initial fall and subsequent rise in T(b). We propose that the absence of hyperthermia at 21 and 25 degrees C as well as a persisting hypothermia may protect the brain from overt pathology.     

A physiological systems approach to modeling and resetting of mouse thermoregulation under heat stress

Heat stroke (HS) is a serious civilian and military health issue. Due to the limited amount of experimental data available in humans, this study was conducted on a mouse mathematical model fitted on experimental data collected from mice under HS conditions, with the assumption there is good agreement among mammals. Core temperature (T(c)) recovery responses in a mouse model consist of hypothermia and delayed fever during 24 h of recovery that represent potential biomarkers of HS severity. The objective of this study was to develop a simulation model of mouse T(c) responses and identify optimal treatment windows for HS recovery using a three-dimensional predictive heat transfer simulation model. Several bioenergetic simulation variables, including nonlinear metabolic heat production (W/m3), temperature-dependent convective heat transfer through blood mass perfusion (W/m3), and activity-related changes in circadian T(c) were used for model simulation. The simulation results predicted the experimental data with few disparities. Using this simulation model, we tested a series of ambient temperature treatment strategies to minimize hypothermia and delayed fever to accelerate HS recovery. Using a genetic algorithm, we identified eight time segments (ambient temperature = 27, 30, 31, 29, 28, 28, 27, 26°C) of 110 min total duration that optimized HS recovery in our model simulation.     

Acetaminophen: antipyretic or hypothermic in mice? In either case, PGHS-1b (COX-3) is irrelevant

Acetaminophen (AC) reduces the core temperatures (T(c)) of febrile and non-febrile mice alike. Evidence has been adduced that the selectively AC-sensitive PGHS isoform, PGHS-1b (COX-3), mediates these effects. PGHS-1b, however, has no catalytic potency in mice. To resolve this contradiction, AC was injected intravenously (i.v.) into conscious PGHS-1 gene-sufficient (wild-type (WT)) and -deficient (PGHS-1(-/-)) mice 60 min before or after pyrogen-free saline (PFS) or E. coli LPS (10 microg/kg) i.v. T(c) was monitored continuously; brain and plasma PGE(2) levels were determined hourly. AC at <160 mg/kg did not affect T(c) when given before PFS or LPS; at 160 mg/kg, it caused a approximately 2.5 degrees C T(c) fall in 60 min. LPS given after AC (all doses) induced a approximately 1 degrees C fever, not different from that in AC-untreated mice. But this rise was insufficient to overcome the hypothermia of the 160 mg/kg-treated mice; their T(c) culminated 1 degrees C below baseline. LPS given before AC similarly elevated T(c) approximately 1 degrees C. This rise was reduced to baseline in 30 min by 80 mg AC/kg; T(c) rebounded to its febrile level over the next 30 min. At 160 mg/kg, AC reduced T(c) to 4 degrees C below baseline in 60 min, where it remained until the end of the experiment. WT and PGHS-1(-/-) mice responded similarly to all the treatments. The basal brain and plasma PGE(2) levels of PFS mice and the elevated plasma levels of LPS mice were unchanged by AC at 160 mg/kg; but the latter's brain levels were reduced at 1h, then recovered. Thus, AC could exert an anti-PGHS-2 effect when this enzyme is upregulated in the brain of febrile mice. The hypothermia it induces in non-febrile mice, therefore, is due to another mechanism. PGHS-1b is not involved in either case.     

Human exposure to 2450 MHz CW energy at levels outside the IEEE C95.1 standard does not increase core temperature

Permission was received from the Brooks AFB Institutional Review Board and the AF Surgeon General's Office to exceed the peak power density (PD = 35 mW/cm(2)) we had previously studied during partial body exposure of human volunteers at 2450 MHz. Two additional peak PD were tested (50 and 70 mW/cm(2)). The higher of these PD (normalized peak local SAR = 15.4 W/kg) is well outside the IEEE C95.1 guidelines for partial body exposure, as is the estimated whole body SAR approximately 1.0 W/kg. Seven volunteers (four males, three females) were tested at each PD in three ambient temperatures (T(a) = 24, 28, and 31 degrees C) under our standard protocol (30 min baseline, 45 min RF exposure, 10 min baseline). The thermophysiological data (esophageal and six skin temperatures, metabolic heat production, local sweat rate, and local skin blood flow) were combined with comparable data at PD = 0, 27, and 35 mW/cm(2) from our 1999 study to generate response functions across PD. No change in esophageal temperature or metabolic heat production was recorded at any PD in any T(a). At PD = 70 mW/cm(2), skin temperature on the upper back (irradiated directly) increased 4.0 degrees C in T(a) = 24 degrees C, 2.6 degrees C in T(a) = 28 degrees C, and 1.8 degrees C in T(a) = 31 degrees C. These differences were primarily due to the increase in local sweat rate, which was greatest in T(a) = 31 degrees C. Also at PD = 70 mW/cm(2), local skin blood flow on the back increased 65% over baseline levels in T(a) = 31 degrees C, but only 40% in T(a) = 24 degrees C. Although T(a) becomes an important variable when RF exposure exceeds the C95.1 partial body exposure limits, vigorous heat loss responses of blood flow and sweating maintain thermal homeostasis efficiently. It is also clear that strong sensations of heat and thermal discomfort will motivate a timely retreat from a strong RF field, long before these physiological responses are exhausted. Published 2001 Wiley-Liss, Inc.     

Role of neuronal nitric oxide synthase in hypoxia-induced anapyrexia in rats.

Anapyrexia (a regulated decrease in body temperature) is a response to hypoxia that occurs in organisms ranging from protozoans to mammals, but very little is known about the mechanisms involved. Recently, it has been shown that the NO pathway plays a major role in hypoxia-induced anapyrexia. However, very little is known about which of the three different nitric oxide synthase isoforms (neuronal, endothelial, or inducible) is involved. The present study was designed to test the hypothesis that neuronal nitric oxide synthase (nNOS) plays a role in hypoxia-induced anapyrexia. Body core temperature (T(c)) of awake, unrestrained rats was measured continuously using biotelemetry. Rats were submitted to hypoxia, 7-nitroindazole (7-NI; a selective nNOS inhibitor) injection, or both treatments together. Control animals received vehicle injections of the same volume. We observed a significant (P < 0.05) reduction in T(c) of approximately 2.8 degrees C after hypoxia (7% inspired O(2)), whereas intraperitoneal injection of 7-NI at 25 mg/kg caused no significant change in T(c). 7-NI at 30 mg/kg elicited a reduction in T(c) and was abandoned in further experiments. When the two treatments were combined (25 mg/kg of 7-NI and 7% inspired O(2)), we observed a significant attenuation of hypoxia-induced anapyrexia. The data indicate that nNOS plays a role in hypoxia-induced anapyrexia.