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Raising intracellular calcium levels can induce apoptosis or programmed cell death in many cells. While early rises in intracellular calcium are not universally associated with apoptotic cell death, calcium clearly plays a key role in many of the biochemical events which occur during apoptosis. In this paper we have determined intracellular calcium rises induced by 2, 10, and 100 nM thapsigargin in mouse thymocytes. These concentrations cause increases in cytosolic calcium of 100-250, 400-600, and > 1000 nM, respectively. These rises are sustained for at least 85 min and the ratio between the maximum rise caused by 10 nM compared to 2 nM thapsigargin is 2.1 +/- 0.4 (n = 6). Both 2 and 10 nM thapsigargin cause apoptosis at 24 h as shown by DNA fragmentation and morphology when examined by electron microscopy. Cyclosporin A (CsA) inhibits apoptosis caused by 2 nM thapsigargin but not that caused by 10 nM thapsigargin. Electron microscopy of thymocytes treated with 2 nM thapsigargin at 24 h shows intact mitochondria although with altered morphology. There is no loss of ATP or decrease in the ATP/ADP ratio in these cells over 12 h. Mitochondria in cells treated with 10 nM thapsigargin, however, are swollen by 6 h and many are lost by 24 h. These cells show greatly diminished ATP content by 12 h and a decrease in ATP/ADP ratio. Examination of the effects of PMA, an activator of the plasma membrane calcium ATPase pump, on cells treated with 10 nM thapsigargin suggests that two pools of calcium may be responsible for the differential effects of the two calcium levels in the cells. Probing of the mitochondrial membrane potential (MMP) by rhodamine 123 staining of live cells shows that the collapse of the MMP caused by 10 nM thapsigargin is unaffected by CsA. The MMP is also reduced in cells treated with 2 nM thapsigargin but this is restored by CsA. Cells are also rescued from apoptosis caused by 2 nM thapsigargin by incubation with FK506. This immunosuppressive agent has no effect on the membrane permeability transition induced in isolated mitochondria. These results suggest that very low rises in intracellular calcium in thymocytes cause activation-induced cell death inhibited by CsA and FK506 and are without effect on ATP levels and therefore do not involve irreversible mitochondrial damage. Exceeding these calcium levels by only two-fold results in apoptosis accompanied by reduced ATP levels and mitochondrial damage, although apoptotic cell death in this instance is unaffected by the classic inhibitor of mitochondrial permeability transition, CsA.
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PMID:Cyclosporin A rescues thymocytes from apoptosis induced by very low concentrations of thapsigargin: effects on mitochondrial function. 883 65

Rewarming from accidental hypothermia is associated with fatal circulatory derangements. To investigate potential pathophysiological mechanisms involved, we examined heart function and metabolism in a rat model rewarmed after 4 h at 15-13 degrees C. Hypothermia resulted in a significant reduction of left ventricular (LV) systolic pressure, cardiac output, and heart rate, whereas stroke volume increased. The maximum rate of LV pressure rise decreased to 191 +/- 28 mmHg/s from a control value of 9,060 +/- 500 mmHg/s. Myocardial tissue content of ATP, ADP, and glycogen was significantly reduced, whereas lactate content remained unchanged. After rewarming, heart rate returned to control value, whereas LV systolic pressure, cardiac output, and stroke volume all remained significantly depressed. The posthypothermic maximum rate of LV pressure rise was 5,966 +/- 1.643 mmHg/s. The posthypothermic myocardial lactate content was significantly increased (to 13.3 +/- 3.2 nmol/mg from control value of 5.7 +/- 1.9 nmol/mg), and ATP and glycogen remained significantly lowered. Creatine phosphate or energy charge did not change significantly during the experiment. The finding of deteriorated myocardial mechanical function and a shift in energy metabolism shows that the heart could be an important target during hypothermia and rewarming in vivo, thus contributing to the development of a posthypothermic circulatory collapse.
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PMID:Experimental hypothermia and rewarming: changes in mechanical function and metabolism of rat hearts. 884 17

Exposure of cultured cerebellar granule cells to 100 microM glutamate plus glycine in the absence of Mg2+ causes calcium loading of the in situ mitochondria and is excitotoxic, as demonstrated by a collapse of the cellular ATP/ADP ratio, cytoplasmic Ca2+ deregulation (the failure of the cell to maintain a stable cytoplasmic free Ca2+ concentration), and extensive cell death. Glutamate-evoked Ca2+ deregulation is exacerbated by the mitochondrial respiratory chain inhibitor rotenone. Cells maintained by glycolytic ATP, i.e., in the presence of the mitochondrial ATP synthase inhibitor oligomycin, remain viable for several hours but are still susceptible to glutamate; thus, disruption of mitochondrial ATP synthesis is not a necessary step in glutamate excitotoxicity. In contrast, the combination of rotenone (or antimycin A) plus oligomycin, which collapses the mitochondrial membrane potential, therefore preventing mitochondrial Ca2+ transport, allows glutamate-exposed cells to maintain a high ATP/ADP ratio while accumulating little 45Ca2+ and maintaining a low bulk cytoplasmic free Ca2+ concentration determined by fura-2. It is concluded that mitochondrial Ca2+ accumulation is a necessary intermediate in glutamate excitotoxicity, whereas the decreased Ca2+ flux into cells with depolarized mitochondria may reflect a feedback inhibition of the NMDA receptor mediated by localized Ca2+ accumulation in a microdomain accessible to the mitochondria.
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PMID:Mitochondria, calcium regulation, and acute glutamate excitotoxicity in cultured cerebellar granule cells. 893 59

To test the role of inorganic phosphate (Pi) in downregulation of myocardial contractile force at the onset of ischemia, Pi of rat hearts was determined with 31P nuclear magnetic resonance spectroscopy. Forty cycles of brief hypoperfusion (30% of baseline flow for 33 s) were used to achieve a time resolution of 0.512 s for comparing dynamic changes in Pi and contractile force. Initial control values of left ventricular developed pressure (LVP), heart rate, and oxygen consumption were 136 +/- 11 mmHg, 236 +/- 4 beats/min, and 95 +/- 3 microl O2 x min(-1) x g(-1); these values were unchanged at the end of the experiment. During the first 10 s of hypoperfusion, Pi increased at a rate (percentage of the total observed change) faster than the decrease in LVP; Pi and LVP then changed at the same rate during the remainder of the hypoperfusion. ADP did not change in advance of LVP. Intracellular pH did not change. The results indicate that Pi plays an important role in initiating the downregulation of myocardial contractile force at the onset of ischemia. Perfusion pressure also declined faster than LVP at the onset of ischemia, indicating potential importance of vascular collapse in contractile downregulation during early ischemia.
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PMID:Correlation between myocardial contractile force and cytosolic inorganic phosphate during early ischemia. 908 9

The membrane permeability transition (MPT) induced by Ca2+ and Pi or Asi was studied in rat kidney mitochondria. Membrane potential, Ca2+ transport and swelling were used to monitor the MPT. Asi promoted a faster and more extensive collapse of membrane potential, Ca2+ release and swelling than Pi. The MPT induced by Pi was fully blocked by Mg(2+)+ADP, spermine+ADP, Mg(2+)+ cyclosporin A (CSA), and ADP+CSA. In contrast, the MPT induced by Asi was only prevented, although not completely, by CSA+Mg2+ or ADP+CSA. Asi, but not Pi, was able to cause collapse of membrane potential in the presence of Sr2+. Carboxyatractyloside (CAT) produced collapse of membrane potential at a lower concentration in the presence of Asi+Ca(2+)+ADP than with Pi+Ca(2+)+ADP. The addition of Pi+Ca2+ to [14C]-ADP loaded mitochondria brought about a greater ADP release than Asi+Ca2+. The ADP release was CAT-sensitive with Pi but it was only partially blocked by Asi. The diminution of external pH did not inhibit the MPT induced by Pi or Asi. The results of this study suggest that the adenine nucleotide translocase does not have an essential role in the MPT induced by Asi+Ca2+.
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PMID:The mitochondrial membrane permeability transition induced by inorganic phosphate or inorganic arsenate. A comparative study. 918 17

Widespread hemorrhagic manifestations commonly occur in patients with severe heat stroke. The pathogenesis of hemostatic disorders in these patients is not fully understood, although it is believed to be multifactorial in origin. The present investigation was designed to study the changes in blood platelets caused by heat stress in an experimental model of five merino sheep. The experiments were performed in two groups of five merino sheep each. In one group the sheep were subjected to a combination of heat (elevated environmental temperature) and exertional stress, and allowed to proceed throughout the experiment until a state of near collapse was reached (Task A). In the other group (Task B) the animals were heated in the same manner as those in Task A and also subjected to exertional heat; however, when the temperature reached 43.6 +/- 0.2 degrees C, the critical core temperature (CCT), they were subjected to evaporative cooling in a climatic chamber. Serial changes in the platelet counts and platelet functions were measured throughout the duration of the experiments. At the core temperature (CT) of 42.1 degrees C and above there was a significant impairment of adhesion of platelets to glass beads. During the early phases of elevation of CT, platelets showed hyperaggregation in the presence of different agonists (such as, collagen, ADP, ristocetin); this was followed by hypoaggregation when the CCT was raised above 43.6 +/- 0.2 degrees C. However, these impairments of platelet functions occurring at elevated CT and CCT were found to reverse to normal within 24 hours after the animals were cooled to 39 degrees C. It was also found that the hyperaggregation of platelets to different agonists induced by raised CT could be partially prevented by prior in vitro treatment of platelets with apyrase, a known enzyme destroying of ADP. The results of these experiments indicate that heat stress induced by exposing merino sheep to elevated controlled temperature directly activates the platelets. This may be an important contributing factor in causing altered hemostasis in heat stroke activated directly by heat. This mechanism may be operating in altered hemostasis in heat stroke.
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PMID:Pathophysiology of bleeding in heat stress: an experimental study in sheep. 921 37

Diminished availability of oxygen at the cellular level might account for organ dysfunction in sepsis. Although the classical forms of tissue hypoxia due to hypoxemia, anemia, or inadequate perfusion all might be important under some conditions, it seems increasingly likely that a fourth mechanism, namely cytopathic hypoxia, might play a role as well. The term cytopathic hypoxia is used to denote diminished production of adenosine triphosphate (ATP) despite normal (or even supranormal) PO2 values in the vicinity of mitochondria within cells. At least in theory, cytopathic hypoxia could be a consequence of several different (but mutually compatible) pathogenic mechanisms, including diminished delivery of a key substrate (e.g., pyruvate) into the mitochondrial tricarboxylic acid (TCA) cycle, inhibition of key mitochondrial enzymes involved in either the TCA cycle or the electron transport chain, activation of the enzyme, poly-(ADP)-ribosylpolymerase (PARP), or collapse of the protonic gradient across the inner mitochondrial membrane leading to uncoupling of oxidation (of NADH and FADH) from phosphorylation of ADP to form ATP. Tantalizing, but limited, data support the view that cytopathic hypoxia occurs in both animals and patients with sepsis or endotoxemia.
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PMID:Cytopathic hypoxia in sepsis. 924 46

The mitochondrial permeability transition was investigated under both oxidative and nonoxidative conditions. It was observed that dithiothreitol (DTT) was able to inhibit the permeability transition only when an oxidant, t-butylhydroperoxide, was used. Although cyclosporin A (CsA) showed also a partial protective effect under these conditions, it progressively lost its ability as the oxidant concentration was increased. Indeed, CsA and ADP were very effective under nonoxidative conditions where Ca2+ and Pi were used to induce the permeability transition, and no effect of DTT was observed. These results suggest that the Ca(2+)-dependent permeability transition pore opening is not directly dependent of dithiol oxidation. It was also shown here that CsA, independent of the presence of ADP, was able to restore the mitochondrial membrane electrical potential (delta psi) after the Ca(2+)-induced collapse. Moreover, carboxyatractyloside (CAT) did not prevent the effect of CsA, even when previously added, although it completely abolished the protective effect of ADP, indicating the participation of the ADP/ATP carrier on this process. The data with submitochondrial particles, besides providing further support to the existence of two distinct binding sites for Ca2+ in the mitochondrial inner membrane, with opposite effects on the pore opening probability, demonstrated, for the first time, that very low Ca2+ concentrations induced the permeability transition pore (PTP) opening in submitochondrial particles, an event fully prevented by CsA. The existence of such CsA-sensitive Ca(2+)-induced pore in submitochondrial particles also suggests that matrix cyclophilin is probably not the mediator of this process.
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PMID:The permeability transition pore opening in intact mitochondria and submitochondrial particles. 941 11

The magnitude and space-temporal profile of the intracellular Ca2+ transients are determined both by the mechanism that decrease and increase calcium levels in the cytoplasm. By the use of cocktails with different content of specific inhibitors of the extrusion and sequester mechanisms, the ability of mitochondrial Ca2+ transport to limit the elevation in free cytosolic Ca2+ concentration, following an imposed Ca2+ load was reexamined, indicating variable data with respect to various cells. In chromaffin cells, inhibition of mitochondrial Ca2+ accumulation with protonophore, dramatically modifies the shape of the [Ca2+]c response, indicating that mitochondrial Ca2+ uptake is an important mechanism for clearance of large Ca2+ loads. By contrast, using digital imaging in the presence of specific mitochondria inhibitors to investigate the [Ca2+]c responses of cerebellar granule cells in which ATP generation has been totally separated from mitochondrial Ca2+ transport, indicates surprising results: it was confirmed that mitochondria in these cells accumulate Ca2+ entering the cell in response to plasma membrane depolarization, but specific abolition of mitochondrial Ca2+ accumulation without ATP depletion significantly decreases the bulk cytoplasmic Ca2+ transients generated by elevated KCl levels, whereas the response in greatly increased when protonophore are present and ATP/ADP ratios are allowed to collapse. The results suggest that nonmitochondrial ATP-dependent transport pathways are primarily responsible for removing excess Ca2+ from the cytoplasm. Far from restricting the elevation in [Ca2+]c in response to a Ca2+ load, functional mitochondria may enhance the elevation in the bulk cytoplasm. The existent conflict of data, suggests the need for a new reevaluation of the role of mitochondria in Ca2+ clearance, and the possibility that mitochondria contribute to, rather than protect against, excitoxicity has to be investigated.
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PMID:[The role of the mitochondria in the clearance of cytosolic calcium]. 945 35

Thromboxane A2 (TXA2) is a labile metabolite of arachidonic acid that has potent biological effects. Its actions are mediated by G protein-coupled thromboxane-prostanoid (TP) receptors. TP receptors have been implicated in the pathogenesis of cardiovascular diseases. To investigate the physiological functions of TP receptors, we generated TP receptor-deficient mice by gene targeting. Tp-/- animals reproduce and survive in expected numbers, and their major organ systems are normal. Thromboxane agonist binding cannot be detected in tissues from Tp-/- mice. Bleeding times are prolonged in Tp-/- mice and their platelets do not aggregate after exposure to TXA2 agonists. Aggregation responses after collagen stimulation are also delayed, although ADP-stimulated aggregation is normal. Infusion of the TP receptor agonist U-46619 causes transient increases in blood pressure followed by cardiovascular collapse in wild-type mice, but U-46619 caused no hemodynamic effect in Tp-/- mice. Tp-/- mice are also resistant to arachidonic acid-induced shock, although arachidonic acid signifi-cantly reduced blood pressure in Tp-/- mice. In summary, Tp-/- mice have a mild bleeding disorder and altered vascular responses to TXA2 and arachidonic acid. Our studies suggest that most of the recognized functions of TXA2 are mediated by the single known Tp gene locus.
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PMID:Coagulation defects and altered hemodynamic responses in mice lacking receptors for thromboxane A2. 983 25


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