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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies indicated a role for ischemia in the metabolic changes induced by cholestasis. Liver pyruvate kinase is a key enzyme for the concurrent control of glycolysis and gluconeogenesis. In this experiment the control of pyruvate kinase activity was investigated in cholestatic rats. Pyruvate kinase kinetics changed from a sigmoidal type in sham-operated rats to a hyperbolic type in obstructed rats. The change in the enzymatic kinetics paralleled the reduction in the portal blood flow, which reached 50% of the control value 7 days after obstruction. Dibutyryl cyclic AMP (5 mumol/kg body wt) plus theophylline 0.1 mmol/L failed to inactivate the enzyme when injected into the portal veins of rats whose livers were obstructed 7 days before. Both the kinetics changes and the lack of phosphorylation control are compatible with ischemia.
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PMID:Lack of control of liver gluconeogenesis in cholestatic rats with reduced portal blood flow. 132 7

The effects of insulin in vitro on perfused liver from streptozotocin-diabetic rats and their untreated littermates during gluconeogenesis from either [3-13C]alanine + ethanol or [2-13C]pyruvate + NH4Cl + ethanol were studied by 13C NMR. A 13C NMR determination of the rate of pyruvate kinase flux under steady-state conditions of active gluconeogenesis was developed; this assay includes a check on the reuse of recycled pyruvate. The preparations studied provided gradations of pyruvate kinase flux within the confines of the assay's requirement of active gluconeogenesis. By this determination, the rate of pyruvate kinase flux was 0.74 +/- 0.04 of the gluconeogenic rate in liver from 24-h-fasted controls; in liver from 12-h-fasted controls, relative pyruvate kinase flux increased to 1.0 +/- 0.2. In diabetic liver, this flux was undetectable by our NMR method. Insulin's hepatic influence in vitro was greatest in the streptozotocin model of type 1 diabetes: upon treatment of diabetic liver with 7 nM insulin in vitro, a partial reversal of many of the differences noted between diabetic and control liver was demonstrated by 13C NMR. A major effect of insulin in vitro upon diabetic liver was the induction of a large increase in the rate of pyruvate kinase flux, bringing relative and absolute fluxes up to the levels measured in 24-h-fasted controls. By way of comparison, the effects of ischemia on diabetic liver were studied by 13C NMR to test whether changes in allosteric effectors under these conditions could also increase pyruvate kinase flux. A large increase in this activity was demonstrated in ischemic diabetic liver.
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PMID:Effects of insulin on perfused liver from streptozotocin-diabetic and untreated rats: 13C NMR assay of pyruvate kinase flux. 303 Apr 12

RheothRx Injection, an aqueous solution of a nonionic block copolymer (poloxamer 188) formulated for intravenous administration, was investigated as an inhibitor of red blood cell (RBC)-induced platelet aggregation at plasma concentrations of 0.05-5mgmL-1. Platelet aggregation was determined by measuring the fall in single platelet counts after mechanical agitation of 2mL aliquots of citrated whole blood in a 37 degrees C shaking waterbath. Inhibition of RBC-induced platelet aggregation of > 95% was observed for poloxamer 188 at a concentration of 1mgmL-1, and 41% inhibition was observed at 0.05mgmL-1. Poloxamer 188 was observed to be a more effective inhibitor of RBC-induced platelet aggregation than 2-chloradenosine (2-ClAd) or phosphoenolpyruvate/pyruvate kinase (PEP/PK). Studies using platelet rich plasma (PRP) showed that platelet aggregation could not be induced by shaking in the absence of RBC, though aggregation was induced by the addition of exogenous adenosine diphosphate (ADP). Poloxamer 188 did not inhibit ADP-induced platelet aggregation. We propose that poloxamer 188 protects RBC from mechanical trauma by non-specific adsorption of copolymer to the RBC surface (via the hydrophobic polyoxypropylene moiety), and that this effect prevents mechanical damage and hence leakage of ADP from RBC. RheothRx Injection has been shown to have value in the treatment of acute ischemic disorders such as myocardial infarction. The observation of significant inhibition of RBC-induced platelet aggregation at clinically relevant concentrations suggests that RheothRx Injection may have antithrombotic properties in vivo, and may therefore have potential not only in acute ischemia but also to prevent thrombosis within vascular prostheses or to prevent rethrombosis after angioplasty or endarterectomy.
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PMID:Inhibition of red blood cell-induced platelet aggregation in whole blood by a nonionic surfactant, poloxamer 188 (RheothRx injection). 750 70

The current study was undertaken so that the effects of both ischemia and ischemia + hypothermia could be examined in mammalian liver. Particular reference was made to the function of glycolysis, which is the only mechanism for energy production under these conditions. The response of adenylate pools reflected the energy imbalance created during warm ischemia within minutes of organ isolation. ATP levels and energy charge values for control (freshly isolated) livers were 1.20 +/- 0.07 and 0.49 +/- 0.02 mumol/g. Within 5 min of warm ischemia, ATP levels had dropped well below control values and by 30 min warm ischemia, ATP, AMP, and E.C. values were 0.21, 2.01, and 0.17 mumol/g, respectively. Cold ischemic livers (flushed with Marshall's citrate solution and stored on ice) exhibited similar, but more protracted, patterns of adenylate depletion (ATP and ADP) and accumulation (AMP). In both warm and cold ischemic livers, levels of fructose-6-phosphate (F6P) and fructose-1,6-bisphosphate (F1,6P2) indicated a marked activation of glycolysis at the phosphofructokinase (PFK) locus after a certain time of ischemia. Although the activations occurred at different times (30 min and 10 h for warm and cold ischemic livers, respectively), the patterns of change in levels of glycolytic metabolites associated with the PFK-catalyzed reaction were similar; levels of F6P dropped and F1,6P2 increased. Changes in metabolite levels (phosphoenol pyruvate and pyruvate) associated with another key suspect regulatory enzyme, pyruvate kinase, indicated no role in regulatory control of glycolysis during warm or cold ischemia. The activation of PFK at 30 min and 10 h of warm and cold ischemia, respectively, may reflect the accumulating effects of loss of intracellular homeostasis, which leads to impending irreversible damage.
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PMID:Glycolysis and energy metabolism in rat liver during warm and cold ischemia: evidence of an activation of the regulatory enzyme phosphofructokinase. 798 53

Rapid depression of Ca(2+)-uptake by sarcoplasmic reticulum (SR) vesicles and inhibition of the activity of creatine kinase (CK) and pyruvate kinase (PK) was observed during incubation of enzymes with micromolar concentrations of iron in the presence of adenine nucleotides. This effect of iron was dependent on the redox state of the iron as determined by the redox state of the environment. Redox conditions that generated an Fe2+/Fe3+ ratio close to 1 were most effective in depressing Ca(2+)-uptake by SR vesicles. Redox conditions that decreased the Fe2+/Fe3+ ratio by oxidizing iron were most effective in depressing CK activity while redox conditions that significantly increased the Fe2+/Fe3+ ratio by reducing iron were most effective in depressing PK activity. All iron sensitive enzymes possessed N-etylmaleimide (NEM) sensitive sulphydryl groups that are essential for their activity. The sensitivity to inhibition by NEM increased in the order: PK < Ca(2+)-uptake < CK. Iron initiated depression of CK and PK activities were reversible with dithiothreitol (DTT). This indicated that modification of SH groups was an important step in the mechanism by which iron depressed enzyme activity. Iron initiated depression of Ca(2+)-uptake and of the activity of CK and PK was prevented by not allowing the critical Fe2+/Fe3+ ratio to be reached and by binding of iron with desferroxamine and EDTA. These results, together with data from the literature, led us to suggest that changes in the redox state of cellular micro-environments, inevitably taking place during ischemia and reperfusion, may increase the availability of "low molecular weight iron" and, through changes in the redox state of this iron, selectively initiate reversible depression of several enzymes which contain SH groups essential for their activity.
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PMID:Iron effects on myocardial enzymes depend on redox state. 800 76

The current study was undertaken to investigate energy metabolism during hypoxia in the cold in livers from euthermic and hibernating Columbian ground squirrels. We hypothesized that the hibernating Columbian ground squirrel would be able to maintain liver energetics for a considerably longer time than euthermic animals. Particular reference was made to the function of glycolysis, which is the only mechanism for energy production under hypothermic ischemia. The transition from aerobic to anaerobic metabolism was apparent in both euthermic and hibernating animals as lactate levels rose within 1-3 h; total lactate accumulation was 2.5 micromol/g in both groups. In euthermic squirrels, liver ATP and ADP decreased considerably over the first 3-h storage; values dropped by 55% and 34%, respectively. Conversely, as the drain on high energy phosphate pools progressed, there was an increase in low energy adenylate, AMP. Between 10 and 24 h of storage, increases in AMP accounted for approximately 25-30% of total ATP + ADP decrease. The remainder of the drop in adenylates was accounted for by considerable decreases in total adenylate (TA) contents; by 24 h TA contents had decreased by 2.0 micromol/g. Livers from hibernating squirrels exhibited similar patterns of adenylate change and were not significantly higher than their euthermic counterparts. With respect to regulatory control of glycolysis, livers from euthermic squirrels exhibited no regulatory control at phosphofructokinase (PFK) or pyruvate kinase (PK). Livers from hibernating animals, however, showed an activation at PFK by 10 h of cold storage; levels of hexose phosphates, glucose-6-phosphate + fructose 6-phosphate (G6P + F6P), dropped and fructose 1, 6-biphosphate (F1,6P2), increased. Changes in metabolite levels (phosphoenolpyruvate and pyruvate) associated with another key suspect regulatory enzyme, PK, indicated no role in regulatory control of glycolysis during the 24-h period. The apparent increase in PFK responsiveness to declining energy stores may be a futile activation since there was no accompanying increase in anaerobic end product, lactate, and no maintenance of energetics.
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PMID:Metabolic effects of cold storage on livers from euthermic and hibernating Columbian ground squirrels. 881 83

Using an isolated ferret heart preparation (Langendorff perfusion, perfusion pressure 90 mmHg), energy metabolism has been characterized in right and left ventricles from control and hypertrophied hearts. Hypertrophy was induced by pulmonary artery clipping for 30-45 days (right ventricle wall weight/body weight ratio increased by 70%). Myocardial contents of high energy phosphate compounds, glycogen and lactate, and the activities of some enzymes were biochemically measured in perfused hearts and also after ischemic arrest (30 min global ischemia). In hypertrophied right ventricles, PCr (-46%), Cr (-34%) levels, creatine kinase activity (-18%) were significantly decreased compared with control. ATP and Pi levels were not affected by hypertrophy. The adenylate energy charges were similar (0.85-0.86) in both types of heart. The activities of hexokinase (+26%), aldolase (+212%), pyruvate kinase (+14%) and glucose 6-phosphate dehydrogenase (+107%) were increased by hypertrophy. The LDH isozyme pattern was significantly changed such that LDH3 was decreased by 11%, and LDH4 and LDH5 were increased by a factor 1.4 and 2.9 respectively in hypertrophy. After 30 min of global ischemia, PCr level was decreased by 89 and 79% in control and hypertrophied ventricles respectively. ATP level was depressed by 41 in control and only by 21% in hypertrophied muscles. Altogether, the present data suggested that, in the adult ferret heart, the capacity for the ATP synthesis could be maintained during hypertrophy by the enhancement of the glycolytic pathway. The smaller decline of ATP after ischemia in hypertrophied tissue could be explained by a lower consumption of ATP in the hypertrophied compared to the control heart during the earliest period of ischemia.
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PMID:Energy metabolism in normal and hypertrophied right ventricle of the ferret heart. 923 44

Reactive oxygen species have been suggested to play an important role in damage to cardiac tissue following ischemia and reperfusion. Oxygen radicals may also contribute to the cardiotoxicity of the anthracycline antibiotics, such as doxorubicin. We tested whether a selective inhibition of muscle gene expression, previously observed in cardiocytes treated with doxorubicin, might be reflective of a more generalized response evoked by oxidative stress in cardiac tissue. Cardiocytes in culture were exposed to hydrogen peroxide or glucose oxidase, and the effects on muscle gene expression were measured. Exposure to these agents led to a reduction in the levels of mRNA for the muscle-specific genes cardiac alpha-actin, troponin I, myosin light chain 2 (slow), and M isoform of creatine kinase, without affecting levels of the non-muscle genes pyruvate kinase and beta-actin. The magnitude of this effect was similar to that observed with doxorubicin. Although the hydrogen peroxide scavenging enzyme catalase and the intracellular radical scavengers N-acetylcysteine and 1,3-dimethyl-2-thiourea were without effect on doxorubicin-dependent reduction in gene expression, they inhibited the reduction in muscle gene expression mediated by hydrogen peroxide. These observations suggest that oxygen free radicals modulate muscle gene expression in cardiocytes by a pathway distinct from that utilized by doxorubicin.
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PMID:Selective inhibition of muscle gene expression by oxidative stress in cardiac cells. 968 91

In this work, it is shown that the Ca2+-transport ATPase found in the microsomal fraction of the cerebellum can use both glucose 6-phosphate/hexokinase and fructose 1,6-bisphosphate/phosphofructokinase as ATP-regenerating systems. The vesicles derived from the cerebellum were able to accumulate Ca2+ in a medium containing ADP when either glucose 6-phosphate and hexokinase or fructose 1,6-bisphosphate and phosphofructokinase were added to the medium. There was no Ca2+ uptake if one of these components was omitted from the medium. The transport of Ca2+ was associated with the cleavage of sugar phosphate. The maximal amount of Ca2+ accumulated by the vesicles with the fructose 1,6-bisphosphate system was larger than that measured either with glucose 6-phosphate or with a low ATP concentration and phosphoenolpyruvate/pyruvate kinase. The Ca2+ uptake supported by glucose 6-phosphate was inhibited by glucose, but not by fructose 6-phosphate. In contrast, the Ca2+ uptake supported by fructose 1,6-bisphosphate was inhibited by fructose 6-phosphate, but not by glucose. Thapsigargin, a specific SERCA inhibitor, impaired the transport of Ca2+ sustained by either glucose 6-phosphate or fructose 1,6-bisphosphate. It is proposed that the use of glucose 6-phosphate and fructose 1,6-bisphosphate as an ATP-regenerating system by the cerebellum Ca2+-ATPase may represent a salvage route used at early stages of ischemia; this could be used to energize the Ca2+ transport, avoiding the deleterious effects derived from the cellular acidosis promoted by lactic acid.
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PMID:Glucose 6-phosphate and fructose 1,6-bisphosphate can be used as ATP-regenerating systems by cerebellum Ca2+-transport ATPase. 988 57

The purpose of this report was to describe mRNA abundance for the glycolytic enzymes glyceraldehyde-3-phosphate dehydrogenase (GAPDH), pyruvate kinase, and pyruvate dehydrogenase in ischemic and adjacent aerobic myocardium. Mechanical, metabolic, and mRNA data were acquired in a pig model of regulated coronary flow using extracorporeal perfusion. Trials of coronary hypoperfusion included sustained and intermittent exposures of acute ischemia with or without reperfusion. These were compared with a chronic 4-day model of partial coronary stenosis. In ischemic tissues, levels of mRNA, normalized by mRNA for beta-actin, were increased over control values for GAPDH (range 2.7- to 4.6-fold), pyruvate kinase (2.9-fold), and pyruvate dehydrogenase (2.1-fold). It is of interest that increases in mRNA levels over control values were also observed in adjacent aerobic heart muscle from intervention hearts, including 3.6- to 4.5-fold elevations in message for GAPDH and a 2.1-fold increase in signal for pyruvate dehydrogenase. Augmentation in mRNA abundance occurred in as short a time as 40 min of ischemia and was maintained for as long as 4 days in partial coronary stenosis. Whether the former time was of an interval sufficient to affect protein production is problematic, but the latter time was ample to influence enzyme concentration, which may in turn have regulated glycolysis in this condition.
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PMID:Alteration of gene expression for glycolytic enzymes in aerobic and ischemic myocardium. 1051 79


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