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

The effects of levocarnitine chloride [LC-80, (-)-(R)-(3-carboxy-2-hydroxypropyl)-trimethylammonium chloride] on the oxidation of [U-14C]palmitate, [U-14C]glucose and [2-3H]glucose under hypoxic conditions in homogenates from the rat heart were investigated. LC-80 at concentrations of 0.5 and 1.0 mM caused significant and concentration-dependent increases in the depressed 14CO2 production from [U-14C]palmitate or [U-14C]-glucose oxidation under hypoxia up to 50 min after the addition of LC-80. In contrast, a marked increase in 3H2O production from [2-3H]glucose oxidation under hypoxia was observed, and LC-80 at concentrations of 0.5 and 1.0 mM caused further significant and concentration-dependent enhancement of 3H2O production up to 50 min after the addition of LC-80. Moreover, LC-80 at a concentrations of 1.0 mM significantly restored the marked depression of pyruvate dehydrogenase complex activity and mitochondrial respiratory function under hypoxia. These results suggested that LC-80 has an improving effect on myocardial metabolism under ischemia by enhancing fatty acid and glucose metabolisms.
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PMID:[Effects of levocarnitine chloride, a new mitochondrial function reactivating agent, on fatty acid and glucose oxidation under hypoxic condition in homogenates from rat heart]. 237 95

The effect of cerebral ischemia on the activity of pyruvate dehydrogenase (PDH) enzyme complex (PDHC) was investigated in homogenates of frozen rat cerebral cortex following 15 min of bilateral common carotid occlusion ischemia and following 15 min, 60 min, and 6 h of recirculation after 15 min of ischemia. In frozen cortical tissue from the same animals, the levels of labile phosphate compounds, glucose, glycogen, lactate, and pyruvate was determined. In cortex from control animals, the rate of [1(-14)C]pyruvate decarboxylation was 9.6 +/- 0.5 nmol CO2/(min-mg protein) or 40% of the total PDHC activity. This fraction increased to 89% at the end of 15 min of ischemia. At 15 min of recirculation following 15 min of ischemia, the PDHC activity decreased to 50% of control levels and was depressed for up to 6 h post ischemia. This decrease in activity was not due to a decrease in total PDHC activity. Apart from a reduction in ATP levels, the acute changes in the levels of energy metabolites were essentially normalized at 6 h of recovery. Dichloroacetate (DCA), an inhibitor of PDH kinase, given to rats at 250 mg/kg i.p. four times over 2 h, significantly decreased blood glucose levels from 7.4 +/- 0.6 to 5.1 +/- 0.3 mmol/L and fully activated PDHC. In animals in which the plasma glucose level was maintained at control levels of 8.3 +/- 0.5 mumol/g by intravenous infusion of glucose, the active portion of PDHC increased to 95 +/- 4%. In contrast, the depressed PDHC activity at 15 min following ischemia was not affected by the DCA treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pyruvate dehydrogenase activity in the rat cerebral cortex following cerebral ischemia. 271 7

The objective of this study was to determine whether administration of dichloroacetate (DCA), an activator of pyruvate dehydrogenase (PDH), improves recovery of energy metabolites following transient cerebral ischemia. Gerbils were pretreated with DCA, and cerebral ischemia was produced using bilateral carotid artery occlusion for 20 min, followed by reperfusion up to 4 h. DCA had no effect on the accumulation of lactic acid and the decrease in ATP and phosphocreatine (PCr) during the 20-min insult, nor on the recovery of these metabolites measured at 20 and 60 min reperfusion. However, at 4 h reperfusion, levels of ATP and PCr were significantly higher in DCA-treated animals than in controls, as PCr exhibited a secondary decrease in caudate nucleus of control animals. PDH was markedly inhibited at 20 min reperfusion in both groups, but was reactivated to a greater extent in DCA-treated animals at 60 min and 4 h reperfusion. These results demonstrate that DCA had no effect on the initial recovery of metabolites following transient ischemia. However, later in reperfusion, DCA enhanced the postischemic reactivation of PDH and prevented the secondary failure of energy metabolism in caudate nucleus. Thus, inhibition of PDH may limit the recovery of energy metabolism following cerebral ischemia.
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PMID:Effect of dichloroacetate on regional energy metabolites and pyruvate dehydrogenase activity during ischemia and reperfusion in gerbil brain. 272 37

Activity of cytoplasmic inhibitor of Ca2+ transport in rat heart mitochondria was studied after total ischemia and incubation of heart homogenates with cAMP. Distinct inactivation of the inhibitor occurred under these conditions. The decrease of the inhibitor activity in ischemic myocardium appears to serve as a compensatory mechanism: 1. pyruvate dehydrogenase and the enzymes of tricarboxylic acid cycle were activated due to increase in Ca2+ concentration in mitochondria, 2. as a result of Ca2+ accumulation in mitochondria the elevated concentration of Ca2+ was decreased in myoplasm, which developed after impairment of plasmatic membranes and of sarcoplasmic reticulum membranes.
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PMID:[Effect of total ischemia and 3',5'-cAMP on the activity of the thermostable cytoplasmic inhibitor of Ca2+ ion transport in rat heart mitochondria]. 298 45

Elevated cerebral lactate levels following cerebral ischemia have been associated with brain cell damage and death. We previously found that pre- or postischemia treatment with dichloroacetate (DCA), presumably by its activation of brain pyruvate dehydrogenase, effectively lowers cerebral lactate levels in rats subjected to 30 minutes of partial global ischemia (PGI) followed by 30 minutes of recirculation. The goal of the present study was to determine the effects of preischemia DCA treatment on cortical lactate levels during the ischemia period or during early recirculation. Rats (four in each group) received preischemia treatment with DCA and were then subjected to 0, 10, or 30 minutes of PGI or 30 minutes of PGI followed by 15 minutes of recirculation. Cortical lactate levels in pretreated animals were not significantly different from lactate levels of untreated rats at any time during PGI, but were significantly lower than levels in untreated rats at 15 minutes of recirculation (P less than .05, ANOVA). These results suggest that preischemia treatment with DCA does not limit the accumulation of cortical lactate during PGI but may promote its clearance during recirculation following PGI. If reperfusion events influence the degree of brain cell injury, DCA may enhance cell recovery by lower cortical lactate levels in the reperfusion period.
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PMID:Brain lactate during partial global ischemia and reperfusion: effect of pretreatment with dichloroacetate in a rat model. 359 91

The effects of sodium dichloroacetate (DCA) on the activity of the pyruvate dehydrogenase complex (PDH) and the mechanical function of the isolated ischemic rat heart were investigated. Ischemia was induced by restriction of coronary flow. Perfusion with DCA caused a decrease in the tension developed (DT) and the maximal rate of tension development (+ dT/dt max), and an increase in the resting tension (RT) at low flow rates (0.6 and 0.15 ml/min). However, it did not affect the DT or +dT/dt max of normoxic hearts (3 ml/min) or hearts at zero flow rate. DCA increased PDH activity in hearts at all flow rates. It was concluded that this effect of DCA was associated with a decrease in lactate production, rather than an increase in the lactate/pyruvate ratio.
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PMID:Effects of dichloroacetate on the mechanical function of the isolated ischemic heart. 368 88

Dichloroacetate (DCA) is known to prevent the phosphorylation of the pyruvate dehydrogenase complex (PDHC) by blocking the action of PDH kinase. This action allows the active PDHC to exert its effect on the metabolism of glucose, lactate and alanine to acetyl CoA. DCA has been shown to reduce serum lactate levels in humans and animals in such conditions as diabetes, phenformin-induced hepatic failure, exercise, and endotoxin-induced shock. Lactic acidosis in the brain has often been postulated as a cause of neuronal damage following ischemia and hypoxia. Therefore, we examined the effect of intravenously administered DCA (100 mg/kg) in rats that were rendered hyperglycemic by intravenous glucose (2 g/kg), and then made to undergo 15 minutes of incomplete cerebral ischemia by bilateral carotid ligation and systemic hypotension (mean arterial pressure of 50 mm Hg). DCA significantly reduced serum lactate levels pre-ischemia, but had no effect on serum lactate levels after ischemia induction. Brain levels of lactate, ATP and PCr after 15 minutes of incomplete ischemia were unaffected by DCA. We conclude that in this in-vivo model the control of PDHC activity in the brain may be different than that in the periphery, and that DCA was not effective in reducing brain tissue lactate levels.
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PMID:The effect of dichloroacetate on brain lactate levels following incomplete ischemia in the hyperglycemic rat. 371 55

The effect of ischemia on the concentration of active pyruvate dehydrogenase (PDH) complex has been investigated in glucose-perfused hearts of normal rats fed a normal diet or a high-fat diet or starved for 48 hr and in hearts from alloxan-diabetic rats. Global ischemia induced by low flow (approximately equal to 1 ml/min) lowered the concentration of active complex under most conditions employed. Parallel studies of the effect of anoxia and of potassium arrest of the heart indicated that the effect of low-flow ischemia may result from decreased mechanical activity of the heart as a consequence of tissue hypoxia; the enzymatic mechanism may be activation of PDH kinase by increased reduction of mitochondrial NAD. In hearts of normal rats fed a normal diet, global ischemia induced by zero flow increased the concentration of active complex. Evidence is given that this may result from a combination of anoxia and acidosis. In aerobic perfusions, concentrations of active complex were ranked in the order: normal diet greater than high-fat diet greater than 48-hr starved greater than alloxan-diabetic. This order was maintained when the concentration of active complex was lowered by global ischemia induced by zero flow.
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PMID:Regulation of pyruvate dehydrogenase complex activity during myocardial ischemia. 399 45

We studied the effects of different metabolic interventions, which stimulate oxidative myocardial carbohydrate metabolism, on ischemic stress during repeated coronary occlusions of three minutes in open-chest dog hearts. Increase of glucose concentration in plasma and decrease of peripheral lipolysis by glucose-insulin-potassium (n = 6) had no substantial beneficial effects on myocardial damage indicated by hemodynamic, electrocardiographic, and metabolic parameters. Infusion of lactate and pyruvate (10 mM, n = 6) was detrimental. Only activation of pyruvate dehydrogenase by dichloroacetate (n = 6) without influence on plasma osmolality reduced epicardial ST-segment elevations (-42%) and myocardial release of potassium (-36%), phosphate (-58%), and lactate (-39%). Elevations of plasma osmolalities by 10 and 20 mOsm with the metabolically inert mannitol increased ECG changes, functional loss and release of potassium, phosphate, and lactate during ischemia in our model. It is suggested, that the oxygen-saving potency of metabolic interventions can exert univocal beneficial effects in experimental and in clinical conditions only when systemic hyperosmolality and hypervolemia are avoided.
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PMID:Different effects of interventions suppressing free fatty acid metabolism on myocardial ischemia. 643 Jun 18

The effect of flow-induced ischemia on the rate of pyruvate decarboxylation and the activation state of the pyruvate dehydrogenase multienzyme complex was investigated in the isolated, perfused rat heart. Pyruvate dehydrogenase activity in the heart decreased significantly during flow-induced ischemia and was a function of changes in the activation state (i.e., active/total activity) of the enzyme complex. In the absence of pyruvate, the activation state of pyruvate dehydrogenase decreased from nearly 100% active at the normal flow rate (10 ml/min) to 20% active as the flow was reduced to 0.5 ml/min. At high pyruvate levels (5 mM), the activation state increased from nearly 70% active at control flow rates to 100% active during ischemia. At an intermediate pyruvate concentration (0.5 mM), the enzyme complex was maintained at a relatively low activation state (30-35% active) throughout the range of flow rates tested. Ischemia caused elevated perfusate lactate concentrations only when the flow rates were less than 5.0 ml/min. The activation state of the pyruvate dehydrogenase complex in hearts perfused with glucose was also decreased during ischemia.
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PMID:Regulation of pyruvate dehydrogenase complex in ischemic rat heart. 674 52


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