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

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 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

The effects of myocardial ischemia and reperfusion on pyruvate dehydrogenase (PDH) activity were studied in isolated rat hearts. PDH remained largely (80%) in the active form during 10 min of whole heart ischemia in hearts receiving 11 mM glucose as substrate. With reperfusion, PDH was converted to the inactive form (45% by 2 min) and then returned slowly to control levels. Addition of pyruvate (10 mM) to the glucose containing perfusate during reperfusion prevent the reperfusion inactivation of PDH (96% active). The maintenance of a high percent of PDH in the active form during ischemia occurred in spite of high mitochondrial ratios of NADH/NAD and acetyl CoA/CoA and was related to a very low mitochondrial ATP/ADP ratio. The low ATP and high ADP would restrict PDH kinase phosphorylation and inactivation of PDH during ischemia. Reperfusion resulted in a rapid increase in mitochondrial ATP/ADP ratio and the increased availability of ATP as substrate for the kinase coupled with continued high levels of NADH and acetyl CoA which stimulate kinase activity may have accounted for the early inactivation of PDH with reperfusion. Addition of pyruvate to the perfusate probably inhibited the PDH kinase and prevent the reperfusion inactivation of PDH.
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PMID:Effects of ischemia and reperfusion on pyruvate dehydrogenase activity in isolated rat hearts. 687 85

Trimetazidine (TMZ) is an anti-ischemic compound whose precise mode of action is unknown, although several studies have suggested a metabolic effect, and there have been reports of protection of mitochondria against oxidative stress damage. Using a Langendorff rat heart model, we examined the effects of TMZ on the mitochondrial damage following 30 minutes of ischemia and 5 minutes of reperfusion. Mitochondrial respiration with succinate, glutamate-malate and ascorbate-N,N,N',N'-tetramethylphenylenediamine (TMPD) as substrates was significantly decreased following ischemia-reperfusion. Preperfusion with 10(-5) M TMZ had no effect on these rates in normoxic or ischemic hearts. However, 10(-3) M TMZ significantly decreased the glutamate-malate rate in mitochondria from normoxic hearts, and this rate was not further decreased following ischemia-reperfusion, and 10(-3) M TMZ also partially protected ascorbate-TMPD activity. The effect on glutamate-malate was probably due to an inhibition of complex I by TMZ, which specifically inhibited reduced nicotinamide-adenine-dinucleotide-cytochrome c reductase and complex I in lysed mitochondria. We also studied the effects of TMZ on the activity of pyruvate dehydrogenase (PDH) in normoxic and ischemic hearts perfused with 0.5 mM palmitate, which caused the enzyme to be almost completely inactivated. After short periods of ischemia (10-20 minutes) the PDH inactivation by palmitate was progressively lost. Preperfusion with 10(-5) M TMZ had a tendency to decrease lactate dehydrogenase release, accompanied by a maintenance of the inhibition of PDH by palmitate. This may allow the heart to oxidize fatty acids preferentially during reperfusion, hence removing possible toxic acyl esters.
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PMID:Trimetazidine effects on the damage to mitochondrial functions caused by ischemia and reperfusion. 764 24

Dichloroacetate facilitated a reduction in brain lactate following ischemia in the gerbil. This treatment also improved high-energy metabolite and pyruvate dehydrogenase enzyme recovery. The purpose of this study was to determine the effect of dichloroacetate on ischemia-induced neuronal damage in the hippocampus of the gerbil. In adult male gerbils, carotid arteries were clamped bilaterally for 5 min. After ischemia, each gerbil was graded neurologically and received an ip injection of dichloroacetate (75 or 225 mg/kg) or an equal volume (5 mL/kg) of sodium acetate (66 mg/kg). On the following morning, gerbils received a second injection, and 3 d later were anesthetized and perfused intracardially. Brains were processed, and stained sections were analyzed for neuronal damage. Gerbils treated with 225 mg/kg dichloroacetate exhibited significantly less damage than the untreated group (p = 0.05, Dunn's test). Gerbils with a normal neurologic score evidenced no neuronal damage. Abnormal neurologic scores immediately after ischemia did not correlate with degree of neuronal damage observed 4 d later. These results indicate that neuronal damage is less in gerbils treated after ischemia with an appropriate dose of dichloroacetate. The lack of any histological evidence for an adverse effect of dichloroacetate in the controls supports the safety of this drug in this protocol. Normal neurologic scores immediately after ischemia can be used to identify gerbils mimicking ischemia in this model.
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PMID:Dichloroacetate attenuates neuronal damage in a gerbil model of brain ischemia. 771 Sep 22

Increased carbohydrate utilization may protect the heart during ischemia and reperfusion. Dichloroacetate (DCA) stimulates pyruvate dehydrogenase, which is the rate-limiting step in oxidation of lactate and pyruvate. The purpose of this study was to determine if the myocardial metabolic changes induced by intracoronary DCA during myocardial ischemia were accompanied by improvement in systolic function. A perfusion circuit was created from the carotid to left anterior descending coronary artery (LAD) in 11 anesthetized Yorkshire swine. Data were obtained under strict hemodynamic control at baseline, after 15 min of moderate (30%) LAD flow reduction, and after an additional 15 min of ischemia with either intracoronary DCA (3 mM, n = 6) or saline (n = 5) infusion. DCA decreased lactate release and increased lactate uptake during ischemia as measured by glucose and lactate carbon-labeled tracers. Despite these metabolic changes, no improvement in systolic shortening, microsphere blood flow, or oxygen consumption occurred. Thus, although DCA stimulated carbohydrate metabolism during myocardial ischemia, it did not directly improve systolic function.
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PMID:Dichloroacetate stimulates carbohydrate metabolism but does not improve systolic function in ischemic pig heart. 786 15


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