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An isolated rat heart preparation was used to characterize the temperature dependence of the calcium paradox and also to assess the validity of various indices of hypothermic protection. Hearts were subjected to 10-min periods of calcium depletion at various degrees of hypothermia followed by 20 min of normothermic calcium repletion. Using enzyme or protein leakage during calcium repletion as an index of hypothermic protection during calcium depletion, paradox injury was reduced extensively by relatively moderate hypothermia. Thus, depletion at 29 degrees C reduced total creatine kinase leakage by 57 +/- 4% from 1585 +/- 24 IU/g dry wt to 677 +/- 63 IU/g dry wt and at 25 degrees C leakage was reduced by 85 +/- 4% from 1585 +/- 24 IU/g dry wt to 237 +/- 71 IU/g dry wt. However, upon calcium repletion there was no recovery of contractile function. It was not until the myocardial depletion temperature was reduced to 20 degrees C that some functional recovery occurred. Under these circumstances cumulative creatine kinase leakage was reduced to below 88 IU/g dry wt, 6% of its normothermic value and protein leakage was undetectable. Functional recovery was not complete until the temperature was reduced to 15 degrees C or below. Correlation of cumulative enzyme leakage with functional recovery suggested a narrow release threshold (50 to 100 IU/g dry wt) above which no recovery occurred and below which a full recovery could be confidently predicted. Morphological assessments an all-or-none phenomenon; thus although increasingly severe hypothermia progressively reduced the percent of cells that sustained damage (as opposed to the degree of damage in all cells), it was not until 100% of cells appeared ultrastructurally undamaged that functional recovery was observed. Calcium-free perfusion at 4 degrees C protected the intercalated discs from gross lesions and prevented the separation of the external lamina from the surface coat. Our results also stress the heterogeneity of tissue injury and hypothermic protection and in addition shed further light upon the component mechanisms contributing to calcium injury.
J Mol Cell Cardiol 1983 Jun
PMID:The temperature dependence of the calcium paradox: enzymatic, functional and morphological correlates of cellular injury. 687 88

We have previously shown that somatostatin (SS) immunoreactive (-i) neurons, located in the rat dentate hilus, are vulnerable to cerebral ischemia (Johansen et al., 1987). Within 40 h after ischemia, the cells show clear signs of cell death. At the same time, we observed that dying cells, located in the projection field of the mossy fibers (dentate hilus and CA3 mossy fiber layer), accumulate free zinc. We now demonstrate that the hilar cells, accumulating zinc after ischemia, are SS-i cells. Since it is known that hypothermia can ameliorate ischemic brain damage, we furthermore studied whether hypothermia (29 degrees C) protects the vulnerable SS-i neurons in hilus from zinc accumulation and ischemic cell death. We found that hypothermia both prevented ischemia-induced neuronal zinc accumulation and cell death. We speculate that hilar SS-i cells are highly vulnerable to ischemia, and develop rapid ischemic cell death, because they accumulate zinc shortly after ischemia.
Mol Chem Neuropathol
PMID:Hypothermia protects somatostatinergic neurons in rat dentate hilus from zinc accumulation and cell death after cerebral ischemia. 768 76

We have previously demonstrated that a single administration of ethanol induces the expression of c-fos mRNA in the hypothalamic paraventricular nucleus (PVN). However, Fos protein must interact with a member of the Jun family to form functional heterodimers. To determine whether ethanol may have differential effects on c-fos and c-jun expression, we injected male rats acclimated to a 25 degrees C environment with ethanol (3 g/kg b.wt.) or saline. Using in situ hybridization histochemistry with oligonucleotide probes, we found that ethanol increased c-fos mRNA in the PVN, but decreased c-jun mRNA both in the PVN and in hippocampus. Considering that ethanol produces hypothermia and that the PVN contains neurons activated during hypothermia, we evaluated the effect of cold on c-fos and c-jun mRNA. Both cold and ethanol increased c-fos mRNA, and the effects were additive. However, c-jun mRNA levels in both PVN and hippocampus were unaffected by temperature. Finally, c-jun mRNA levels in the hippocampus were significantly reduced by chronic ethanol exposure, and this trend was also observed in the PVN. These findings demonstrate that a single injection of ethanol has opposite effects on the expression of nuclear transcription factors which interact to regulate gene expression in the nervous system.
Brain Res Mol Brain Res 1994 Jul
PMID:A single administration of ethanol simultaneously increases c-fos mRNA and reduces c-jun mRNA in the hypothalamus and hippocampus. 796 56

Hypothermic cardioplegic solutions are currently used to preserve cardiac function during transportation. However, it has been shown that end-diastolic compliance decreases in donor hearts during reperfusion. Excessively cold temperatures may affect membrane-bound enzymes (Ca2+ ATPase and Ca2+ uptake) which are necessary for calcium homeostasis. To study the effect of temperature on Ca2+ ATPase and Ca2+ uptake activities over the temperature range to which a donor heart is usually exposed (4 degrees-37 degrees C), sarcoplasmic reticulum (SR) was isolated from human atrial appendages. SR was also isolated from atrial appendages which had been stored in saline at 4 degrees C for 4 or 24 h or 24 h in St Thomas' cardioplegic solution (ST). Ca2+ ATPase and Ca2+ uptake from these samples were compared with those found in the SR of unstored appendages. The activity of Ca2+ uptake and Ca2+ ATPase showed great sensitivity at assay temperatures below 22 degrees C, while no such sensitivity was identified in SR NADPH/cytochrome C reductase (NCR). After storage of atrial appendages for only 4 h in saline at 4 degrees C, Ca2+ uptake activity was reduced 50% in the SR when compared to unstored controls (80 +/- 9.9 nmol/mg/min and 155.24 +/- 2.4 nmol/mg/min, respectively; P < 0.02) whereas Ca2+ ATPase was not affected until 24 h of storage, when the activity was also decreased > 50% (P = 0.0002). However, NCR was not affected. In addition, storage at 4 degrees C significantly decreased the SR protein yield (mg/g homogenate protein) at 4 or 24 h in saline as well as 24 h in ST. However, there was no decrease in the enzyme activities (Ca2+ ATPase, 229 +/- 25.3; Ca2+ uptake, 221 +/- 27.1; NCR, 24.9 +/- 0.48 nmol/mg/min). Following exposure to low temperature, alteration of Ca2+ uptake and Ca2+ ATPase may result in disruption of calcium homeostasis, thereby interrupting excitation-contraction coupling and relaxation. The damaging effects of hypothermia should be taken into account when assessing the peri-operative complications and the long-term results of cardiac transplantation.
J Mol Cell Cardiol 1993 Oct
PMID:Temperature affects human cardiac sarcoplasmic reticulum energy-mediated calcium transport. 826 50

In non-adult hearts, hypothermia influences protection of the myocardium by exerting effects on specific ion transporters, thereby altering the normal balance between ion pumps and ion leaks. We studied the effects of hypothermia on individual ion transporters in cardiac myocytes to better understand how to preserve the normal ion balance at reduced temperatures, and thereby enhance myocardial protection. Cardiocytes obtained from 11 day chick embryos were cultured for 3 days, and then equilibrated in a glucose containing HEPES-TRIS buffered salt solution at 37 degrees C (pH = 7.4). The cells were incubated at 10 +/- 2 degrees C for 5 to 360 min in the absence or presence of specific ion transport inhibitors, and ion contents were assessed by atomic absorption spectrophotometry. Intracellular Na content increased from approximately 90 nmol/mg protein (control) to 2-3 times this value within 30 min, and then returned to control levels by 60 min. This increase in Na was accompanied by a small rise in total Ca (1.5 times control). Acidotic pH (6.4) and/or ethylisopropyl amiloride (100 microM), but not bumetanide (100 microM) prevented the rise in Na content, suggesting the Na/H exchanger contributed to the initial Na influx. Ouabain (1 mM), exacerbated the Na rise and prevented its recovery to control values at 10 degrees C, although Rb flux measurements revealed only a low level of Na/K ATPase activity throughout 240 min at 10 degrees C (15% of 37 degrees C activity). Calcium content rose to 10 times control values in the presence of ouabain at 37 degrees C only, consistent with a lack of significant Na/Ca exchange activity during hypothermia. In conclusion, the effects of hypothermia on ion pumps and ion leaks in embryonic heart cells are as follows: (1) a low level of Na/K ATPase activity contributes significantly to ion regulation; (2) activity of the Na/H exchanger must be attenuated to minimize Na loading; (3) slowing of the Na/Ca exchange may reduce Ca induced cell injury. We suggest that reducing Na/H exchange activity during hypothermia, using cardioplegic solutions with a slightly acidic pH or with added ethylisopropyl amiloride, may enhance the protective effects of hypothermia in non-adult hearts.
J Mol Cell Cardiol 1993 Mar
PMID:Ion transport during hypothermia in cultured heart cells: implications for protection of the immature myocardium. 838 88

Activation of muscarinic acetylcholine (ACh) receptors contributes to the pathophysiological consequences of moderate experimental traumatic brain injury (TBI). Hypothermia (30 degrees C) provides protection in experimental TBI. We measured ACh levels in CSF and plasma 5 min after moderate fluid percussion TBI under normothermic or hypothermic conditions, because ACh in the CSF has been correlated with the severity of behavioral deficits after TBI. Three groups were examined: TBI with hypothermic brain (30 degrees C), TBI with normothermic brain (37 degrees C), or sham TBI with normothermic brain (37 degrees C). ACh concentrations in CSF were significantly higher in 37 degrees C TBI rats, but not in 30 degrees C TBI rats compared to shams. ACh concentrations in plasma did not differ between groups. These results suggest that a contributing factor to the neuroprotective effects of moderate hypothermia in TBI may be related to the reduction of excessive ACh levels in the central nervous system following injury.
Mol Chem Neuropathol 1993 Apr
PMID:Hypothermia blunts acetylcholine increase in CSF of traumatically brain injured rats. 850 3

The protective effect of regional epidural spinal cord cooling was evaluated in a rabbit spinal cord ischemia model. Hypothermia was performed by the continual perfusion of 2-4 degrees C cold saline in the epidural space around the ischemic lumbar segments, 4 min before and during ischemia. The spinal cord was deeply hypothermic (21 degrees C) throughout the whole ischemic period. Ischemia was induced by the occlusion of the abdominal aorta for 40 min under normothermic or hypothermic conditions. Recovery of motor and sensory functions, spinal cord-evoked potentials, and motor-evoked potentials were then evaluated up to 24 h postischemia. After this period, choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) activities were measured, in particular, zones of the lumbar spinal cord. AChE was also investigated histochemically. Animals in the normothermic group displayed fully developed spastic paraplegia with near complete loss of spinal somatosensory and motor-evoked potentials. AChE histochemistry showed extensive necrotic changes affecting lumbosacral gray matter. These changes corresponding with the pronounced losses of ChAT and AChE activities indicated irreversible injury of the spinal cord. In contrast, after hypothermic ischemia, animals survived without any sign of neurological impairment with almost full recovery of the spinal cord-evoked potentials. ChAT and AChE activities in the gray matter showed near control values corresponding with histochemical analysis of fully preserved gray matter. Hypothermia under the present experimental conditions efficiently protected the spinal cord against ischemic injury.
Mol Chem Neuropathol
PMID:Epidural perfusion cooling protects against spinal cord ischemia in rabbits. An evaluation of cholinergic function. 853 29

Amphetamines (AMPs) can cause long-term depletions in striatal dopamine (DA) and serotonin (5-HT), and these decrements are often accepted as prima facie evidence of AMP-induced damage to the dopaminergic and serotonergic projections to striatum. Rarely are indices linked to neural damage used to evaluate the neurotoxicity of the AMPs. Here, we determined the potential neurotoxic effects of two substituted AMPs, d-methylenedioxymethamphetamine (d-MDMA) and d-fenfluramine (d-FEN) in group-housed female C57BL6/J mice. Astrogliosis, assessed by quantification of glial fibrillary acidic protein (GFAP), was the main indicator of d-MDMA-induced neural damage. Assays of tyrosine hydroxylase (TH), DA, and 5-HT were used to determine effects on DA and 5-HT systems. Since AMPs are noted for both their stimulatory and hyperthermia-inducing properties, activity, as well as core temperature, was monitored in several experiments. To extend the generality of our findings, these same end points were examined in singly housed female C57bL6/J mice and in group-housed male C57BL6/J or female B6C3F1 mice after treatment with d-MDMA. Mice received either d-MDMA (20 mg/kg) (singly housed mice received dosages of 20, 30, or 40 mg/kg) or d-FEN (25 mg/kg) every 2 h for a total of four sc injections. d-MDMA caused hyperthermia, whereas d-FEN induced hypothermia. d-MDMA cause a large (300%) increase in striatal GFAP that resolved by 3 wk and a 50-75% decrease in TH and DA that was still apparent at 3 wk, d-FEN did not affect any parameters in striatum. d-MDMA is a striatal dopaminergic neurotoxicant in both male and female C57BL6/mice, as evidenced by astrogliosis and depletions of DA in this area in both sexes. The greater lethality to males suggests they may be more sensitive, at least to the general toxicity of d-MDMA, that females. d-MDMA (20 mg/kg) induced the same degree of damage whether mice were housed singly or in groups. Higher dosages in singly housed mice induced greater lethality, but not greater neurotoxicity. d-MDMA was also effective in inducing striatal damage in mice of the B6C3F1 strain. Significant increases in activity were induced by d-MDMA, and these increases were not blocked by pretreatment with MK-801, despite the profound lowering of body temperature induced by this combination. A lowering of body temperature, whether by a 15 degree C ambient temperature (approx 2 degree drop), pretreatment with MK-801 (1.0 mg/kg prior to the first and third d-MDMA injections; approx 5-6 degrees C drop) or restraint (approx 5-6 degrees C drop) was effective in blocking the neurotoxicity of d-MDMA in both C57BL6/J and B6C3F1. The stimulatory effects of d-MDMA appeared to have little impact on the neurotoxicity induced by d-MDMA or the protection conferred by MK-801. These data suggest that in the mouse, the neurotoxic effects of d-MDMA, and most likly other AMPs, are linked to an effect on body temperature.
Mol Neurobiol
PMID:The role of temperature, stress, and other factors in the neurotoxicity of the substituted amphetamines 3,4-methylenedioxymethamphetamine and fenfluramine. 856 61

The role of the glutathione (GSH) system in vivo or in drug resistance has received much attention, since GSH is a major component of the cellular detoxification system. We Studied the effect of GSH depletion by buthionine sulfoximine (BSO), a potent inhibitor of gamma-glutamylcysteine synthetase, on doxorubicin (DOX) toxicity in mice. The administration of BSO (30 mM in drinking water for 5 days) significantly decreased the tissue GSH. The GSH depletion in various tissues by BSO was associated with a decrease in the detoxification of DOX in mice. A single dose of 20 mg/kg of DOX significantly reduced body weight and rectal temperature in mice 3 days after injection. The combination with BSO and cepharanthine (biscoclaurine alkaloid), a P-glycoprotein (P-gp) inhibitor, significantly potentiated decrease in body and hypothermia induced by DOX. The study demonstrates that BSO markedly increases the toxicological effect of DOX with the alterations in GSH of tissues and Suggests that the intracellular accumulation of DOX is not a factor.
Res Commun Mol Pathol Pharmacol 1995 Sep
PMID:Effect of glutathione depletion by buthionine sulfoximine on doxorubicin toxicity in mice. 868 Aug 8

The significance of mild hypothermia as a therapeutic measure for ischemic brain damage is presented on the basis of different experimental results. An extracellular glutamate surge, a sustained activation of N-methyl-D-aspartate (NMDA) receptors, and an enhancement of DNA binding activity to transcription factor AP-1, all being key items directly linked to excitotoxic neuronal damage, are deeply affected by slightly lowering temperature (mild hypothermia [MH]). The cellular mechanism of MH seems rather nonspecific but tends to collectively involve these key items rendering neurons resistant to ischemic damage. Clinical application of MH should be a great challenge to relieve deadly effects on central neurons.
Mol Chem Neuropathol
PMID:Ischemic neuronal damage. How does mild hypothermia modulate it? 887 59


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