Endoplasmic Reticulum Stress in Heat- and Shake-Induced Injury in the Rat Small Intestine.

We investigated the mechanisms underlying damage to rat small intestine in heat- and shake-induced stress. Eighteen Sprague-Dawley rats were randomly divided into a control group and a 3-day stressed group treated 2 h daily for 3 days on a rotary platform at 35°C and 60 r/min. Hematoxylin and eosin-stained paraffin sections of the jejunum following stress revealed shedding of the villus tip epithelial cells and lamina propria exposure. Apoptosis increased at the villus tip and extended to the basement membrane. Photomicrographs revealed that the microvilli were shorter and sparser; the nuclear envelope invaginated and gaps in the karyolemma increased; and the endoplasmic reticulum (ER) swelled significantly. Gene microarray analysis assessed 93 differentially expressed genes associated with apoptosis, ER stress, and autophagy. Relevant genes were compiled from the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. Forty-one genes were involved in the regulation of apoptosis, fifteen were related to autophagy, and eleven responded to ER stress. According to KEGG, the apoptosis pathways, mitogen-activated protein kinase(MAPK) signaling pathway, the mammalian target of rapamycin (mTOR) signaling pathway, and regulation of autophagy were involved. Caspase3 (Casp3), caspase12 (Casp12), and microtubule-associate proteins 1 light chain 3(LC3) increased significantly at the villus tip while mTOR decreased; phosphorylated-AKT (P-AKT) decreased. ER stress was involved and induced autophagy and apoptosis in rat intestinal damage following heat and shake stress. Bioinformatic analysis will help determine the underlying mechanisms in stress-induced damage in the small intestine.

Multiple triggers for hyperthermic fatigue and exhaustion.

It has been proposed that a critical body temperature exists at which muscle activation is impaired through a direct effect of high brain temperature decreasing the central drive to exercise, but other factors may also inhibit performance in the heat. An integrative physiological model is presented to stimulate research into mechanisms of hyperthermic fatigue and exhaustion.

[Effects of heat stress on DA mediated PI signal transduction system in rat striatum].

Objective. To study the effects of heat stress on dopamine (DA) and related phosphatidylinositol (PI) signal transduction system members: PLA2, PI, Ca2+ in rat striatum. Method. Male Wistar rats were randomly divided into control group and heat stressed group. Heat stressed rats were placed in small hot chambers and taken out as soon as their rectal temperatures (Tr) reached the preset temperature. Then the animals were killed and their striatums were taken out. Fluorospectrophotometry, HPLC, Fura-2/AM fluoresence labelled method and acidalkaline titration were used to measure the content of DA, PI, [Ca2+]i and the enzyme activity of PLA2. Result. During heat stress, when rats' Tr reached 41.0 degrees C or higher, with increase of Tr, DA content increased continuously. When Tr = 43.0 degrees C, DA content was significantly higher than control. When Tr = 41.0 degrees C PLA2 activity was higher than control significantly, PI content of heat stressed group decreased significantly than control. [Ca2+]i increased significantly when Tr = 42.0 degrees C as compared with control. But if DA receptor2 (D2R) antagonist was given an hour before heat stress, [Ca2+]i decreased and Tr took a longer time to get to 42.0 degrees C. Conclusion. During heat stress, DA mediated PI signal transduction system was activated. The increase of [Ca 2+]i might be mediated by D2R, and D2R antagonist may improve thermotolerance.

Exercise in the heat: effects of an adenosine antagonist.

The purpose of this experiment was to examine the effects of an adenosine antagonist on cardiovascular, thermoregulatory, and exercise performance in the heat. Two doses (1 mg/kg and 10 mg/kg) of a selective adenosine A1 antagonist (1,3-di-n-propyl-8-[4-hydroxyphenyll]xanthine) (DPHPX) were tested in a rat model of exercise exhaustion, treadmill 11 m/min, 6 degrees incline, in the heat 30 degrees C. Pretreatment with the experimental adenosine antagonist caused a slight improvement p > 0.05 in run time (41+/-4 vs. 44+/-3 mm) at a low dose but reduced performance (41+/-4 vs. 29+/-3 mm) at a high dose despite elevated plasma lactate (6.41+/-0.82 vs. 9.91+/-1.0 and 12.42+/-1.1 micromole/L) levels in both dosage groups. At the low dose the antagonist provided a clear benefit in thermoregulation as evidenced by reduced heating rates (0.079+/-0.005 vs. 0.050+/-0.009 degrees C/min). Heart rate and blood pressure tended to be preserved in the low dose group also. Blood gases remained closer to normal with either dosage of drug with arterial PO2 being remarkably preserved after exercise whereas venous PO2 was not different suggesting increased oxygen delivery and extraction. The results of this investigation indicate that antagonizing the effects of adenosine at a low dose with this agent did improve cardiovascular and thermoregulatory responses but did not provide a substantial overall benefit in exercise performance in the heat.

The effects of substrate and fluid provision on thermoregulatory and metabolic responses to prolonged exercise in a hot environment.

A high ambient temperature reduces the capacity to perform prolonged exercise. Total carbohydrate oxidation is less, and thus glycogen depletion is not limiting. Fluid ingestion in the heat should, therefore, focus on maintenance of hydration status rather than on substrate provision. Six healthy males cycled to exhaustion at 60% of maximum oxygen consumption (VO2max) with no drink, ingestion of a 15% carbohydrate-electrolyte drink (1.45+/-0.29 litres) or ingestion of a 2% carbohydrate-electrolyte drink (3.12+/-0.47 litres). The ambient temperature was 30.2+/-0.6 degrees C (mean +/- s), with a relative humidity of 71+/-1% and an air speed of approximately 0.7 m x s(-1) on all trials. Weighted mean skin temperature, rectal temperature and heart rate were recorded and venous samples drawn for determination of plasma volume changes, blood metabolites, serum electrolytes and osmolality. Expired gas was collected to estimate rates of fuel oxidation. Exercise capacity was significantly (P < 0.05) different in all trials. The median (range) time to exhaustion was 70.9 min (39.4-97.4 min) in the no-drink trial, 84.0 min (62.7-145 min) in the 15% carbohydrate trial and 118 min (82.6-168 min) in the 2% carbohydrate trial. The 15% carbohydrate drink resulted in significantly (P < 0.05) elevated blood glucose and total carbohydrate oxidation compared with the no-drink trial. The 2% carbohydrate drink restored plasma volume to pre-exercise values by the end of exercise. No differences were observed in other thermoregulatory or cardiorespiratory responses between trials. These results suggest that fluid replacement with a large volume of a dilute carbohydrate drink is beneficial during exercise in the heat, but the precise mechanisms for the improved exercise capacity are unclear.

HSP70 expression in the CNS in response to exercise and heat stress in rats.

We have previously documented the regional distribution of 70-kDa heat shock protein (HSP70) in brains of rats made hyperthermic by brief exposure to high-powered microwaves (HPM; 2.06 GHz). We now compare HSP70 expression induced by HPM exposure to that induced by exertional and/or environmental heat stress. Rats were chronically implanted with a temperature probe guide in the hypothalamic region of the brain (Tbr). After recovery, the following treatment groups were examined: HPM; sham exposed; treadmill exercise at room temperature (24 degreesC; Ex-1); treadmill exercise in a warm environment (34 degreesC; Ex-2); and sedentary groups (Sed-1 and Sed-2), in which ambient temperature was adjusted so that the Tbr mimicked the Tbr in the corresponding exercise groups. Significant HSP70 expression occurred only in the hyperthermic (Ex-2, Sed-2, and HPM) groups. The pattern of HSP70 expression was similar among Ex-2 and Sed-2 rats but differed from that in HPM rats. We conclude that 1) the pattern of HSP70 expression differs between HPM and nonmicrowave heating, and 2) exercise alone was not sufficient to induce central HSP70 expression.

The biochemistry of heat illness.

The two common forms of heat illness in the Services are heatstroke and heat exhaustion. Biochemical predisposing factors are considered for each. Susceptibility to malignant hyperthermia should be tested for in cases of heat stroke. The heterozygote status for cystic fibrosis should be established in cases of heat exhaustion.

Hypothalamic dopamine release and local cerebral blood flow during onset of heatstroke in rats.

BACKGROUND AND PURPOSE: Brain dopamine has been implicated as a mediator of brain neuronal damage resulting from ischemic injury. Augmented interleukin-1 production and cerebral ischemia occurred during onset of heatstroke. This study has attempted to ascertain whether heatstroke resulting from hyperthermia causes an increase in hypothalamic dopamine release and to assess whether the administration of an interleukin-1 receptor antagonist (IL-1ra) can attenuate heat-stroke formation. METHODS: Both local cerebral blood flow and hypothalamic dopamine release during onset of heatstroke were assessed in saline-treated rats and in rats treated with an IL-1ra. Heat-stroke was induced by exposing the animals to a high ambient temperature. Hypothalamic dopamine release was determined by carbon fiber electrodes combined with in vivo differential pulse amperometry. RESULTS: During onset of heatstroke, rats with heatstroke displayed higher values of colonic temperature, higher values of hypothalamic dopamine release, and lower values of blood flow in different brain regions compared with normothermic control rats. In another separate experiment in which IL-1ra (200 micrograms/kg IV) was injected 30 minutes before onset of heatstroke, both the augmented hypothalamic dopamine release and diminished cerebral blood flow during onset of heatstroke were significantly attenuated. In addition, the survival time (interval between onset of heatstroke and death) of the rats with heatstroke was prolonged by pretreatment with IL-1ra. CONCLUSIONS: These results suggest that an increase in hypothalamic dopamine release and a decrease in local cerebral blood flow occur during onset of heatstroke. Pretreatment with IL-1ra attenuates the heatstroke formation resulting from cerebral ischemia by reducing hypothalamic dopamine release.

Clinical and biochemical characteristics of collapsed ultra-marathon runners.

To evaluate the characteristics of runners with exercise-associated collapse (EAC), we studied the time of onset of collapse, rectal temperatures, cardiovascular status, and incidence of readily identifiable medical conditions in 46 male athletes who collapsed during or after a 56-km ultramarathon footrace run on a cool day. Data were compared with 65 control runners who did not collapse in the same race. Weight changes during recovery were studied in a subsample of both groups. The majority (85%) of runners with EAC collapsed after they had completed the race; rectal temperatures (38.5 +/- 1.3 degrees C, mean +/- SD; range 35.5-42.0 degrees C) and supine heart rates (87.5 +/- 17.2 min-1; range 60-138) were only modestly elevated. Postrace serum sodium concentrations, changes in plasma volume, and mass during recovery were not significantly different from values in control runners. We conclude that: (i) most cases of EAC (85%) occur after the finish line; (ii) runners collapsing during the race are more likely to have a readily identifiable medical condition than runners collapsing after the finish line; (iii) runners collapse most frequently near cutoff times for medals and race closure times; and (iv) 16% of EAC casualties and 19% of control runners have identifable biochemical abnormalities.

Interleukin-1 beta production during the onset of heat stroke in rabbits.

During the onset of heat stroke, rabbits displayed hyperthermia (42.8 degrees C), decreased arterial blood pressure, increased intracranial pressure, decreased cerebral perfusion pressure and increased interleukin-1 beta production (in both the hypothalamus and plasma), compared to those of normothermic, control rabbits. In addition, the heat-stroke animals which received an i.v. injection of interleukin 1-receptor antagonist (200 micrograms/kg) had a survival time (interval between onset of heat stroke and death) longer than that of the heat-stroke animals which received control-vehicle solution. The data indicate that interleukin-1 production plays a role in pathogenesis of heat stroke in rabbits.

Induction of heat-shock proteins enhances myocardial and endothelial functional recovery after prolonged cardioplegic arrest.

The aim of this study was to investigate the role of heat-shock proteins after heat-shock stress on the post-ischemic recovery of cardiac mechanical and endothelial function following a prolonged cardiac arrest. Isolated working rat hearts were subjected to a cardioplegic arrest for 4 hours at 4 degrees C. Three groups (n = 8 in each) were studied: (1) control, (2) sham-treated, and (3) heat-shocked rats. Postischemic recovery of cardiac output and endothelial function (as percent of preischemic control values) was 57.8% +/- 2.8% and 20.8% +/- 3.9% in group 1, 50.9% +/- 4.0% and 26.3% +/- 5.9% in group 2, and 74.0% +/- 2.4% and 51.2% +/- 8.0% in group 3, respectively. Both postischemic myocardial and endothelial function were improved by heat stress.

Possible central role of nitric oxide in conditions clinically similar to cerebral malaria.

The changes in mental status during cerebral malaria, heat stroke, and recovery from major surgery are clinically similar, and are associated with high circulating concentrations of cytokines that can induce nitric oxide generation in vascular walls. This vascular nitric oxide could diffuse across the blood brain barrier, causing functional changes that include inhibition of glutamate-induced calcium entry, reduced activity of the calcium-dependent nitric oxide synthase, and thus reduced nitric oxide formation, in post-synaptic neurons. Certain general anaesthetics and ethanol reduce glutamate-induced calcium entry into post-synaptic cells, and so would also reduce the rate of formation of neuronal nitric oxide. In view of the apparent importance of glutamate-induced nitric oxide in excitatory neurotransmission, a reduction in neuronal nitric oxide could help explain why these otherwise unrelated influences alter central nervous system function in a similar manner. In particular, this reduction could rationalise why heat stroke, ethanol excess, morphine poisoning, and conditions with high blood ammonia concentrations are easily confused clinically with cerebral malaria.

Exertional heatstroke and muscle metabolism: an in vivo 31P-MRS study.

An impairment of muscle energy metabolism has been suggested as a predisposing factor for, as well as a consequence of exertional heatstroke (EHS). Thirteen young men were investigated 6 months after a well-documented EHS using 31Phosphorus Magnetic Resonance Spectroscopy (31P-MRS). The relative concentrations of ATP, phosphocreatine (PCr), inorganic phosphate (Pi), phosphomonoesters (PME), and the intracellular pH (pHi) were determined at rest, during a graded standardized exercise protocol (360 active plantar flexions) and during recovery. Also the leg tissue blood flow was determined by venous occlusion plethysmography during the MRS procedure. Sixteen age-matched healthy male volunteers served as control group. In resting muscle, there were no significant differences between the groups as regards pHi, Pi/PCr, and ATP/PCr+Pi+PME ratios. During steady state exercise conditions, effective power outputs were similar for both groups at each level of exercise: 20, 35, and 50% of maximal voluntary contraction (MVC) of the calf muscle. No significant differences were shown between the two groups in Pi/PCr, pHi, or changes of leg blood flow at each level of exercise. At 50% MVC, Pi/PCr was 0.48 +/- 0.08 vs 0.47 +/- 0.05 (P = 0.96), pHi was 6.94 +/- 0.03 vs 6.99 +/- 0.02, respectively (P = 0.13). Finally, the rate of PCr resynthesis during recovery was not significantly different between the two groups: t1/2 PCr = 0.58 +/- 0.07 vs 0.50 +/- 0.05 min, respectively (P = 0.35). Therefore, no evidence of an impairment of muscle energy metabolism was shown in the EHS group during a standardized submaximal exercise using 31P-MRS performed 6 months after an EHS.

[Radionuclide studies on the hormonal manifestations of heat stress in cancer patients under controlled total hyperthermia]. / Radionuklidnye issledovaniia gormonal'nykh proiavlenii teplovogo stressa u onkologicheskikh bol'nykh pri obshchei upravliaemoi gipertermii.

The results of the investigations of ACTH, HGH, hydrocortisone, glucagon, C-peptide, insulin in 180 patients with advanced and metastatic melanomas, soft tissue sarcomas, lung cancers and renal cell carcinomas testify to the development of the syndrome of endocrine hyperfunction in patients under whole-body guided hyperthermia as well as of functional pancreas insufficiency. The data presented form a biochemical basis for working out measures to optimally carry out whole-body hyperthermia treatment, aimed at increasing the range of indications for its use in clinical oncology.

[The effect of ionol on oxidative-reductive processes in the kidney during heat stroke]. / Vliianie ionola na okislitel'no-vosstanovitel'nye protsessy v pochke pri teplovom udare.

Heat stroke was induced in intact rats in a thermal chamber (45 degrees C) and simultaneously a group of animals was subjected to overheating for the same time but was given intraperitoneal injections of ionol (120 mg/kg) for 2 days and 30 minutes before exposure in the chamber. Significant increase of the concentration of intermediates--lactate, pyruvate, malate, glutamate, ammonia--and decrease of the alpha-ketoglutarate content occurred in the renal tissue in animals of both groups. The NAD/NADH ratio in the cytoplasm and mitochondria reduced essentially, to a greater degree in animals given ionol injections. The last named were distinguished by higher survival and lower degree of hyperthermia.

Hyperthermic syndromes and impairment of the dopaminergic system: a clinical study.

We present 8 cases of centrally-originating hyperthermic syndrome, the initial cause being either neuroleptic malingnant syndrome, hyperthemia after discontinuance of antiparkinsonian therapy or heatstroke. We review the physiological and neurochemical mechanisms involved in thermoregulation, emphasizing the role of dopamine. A single mechanism, consistent with pharmacological or neuropathological impairment of the dopaminergic system, could be responsible for all the cases of hyperthermic syndrome presented.

[Relation between energy metabolism, Na+ and K+ levels, and Na,K-ATPase activity in erythrocytes and their volume and shape during overheating]. / Sootnoshenie énergeticheskogo obmena, soderzhaniia Na+ i K+, aktivnosti Na,K-ATFazy v éritrotsitakh s ikh ob''emom i formoi v usloviiakh peregrevaniia organizma.

Development of heat stroke led to a decrease in main reactions of energy production and energy potential in erythrocytes, to a decrease in activity of Na+, K+-ATPase and in content of sodium and potassium as well as to alterations in forms and to decrease in volume of these cells.