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

Transient cerebral ischemia in normoglycemic animals is followed by a decrease in glucose utilization, reflecting a postischemic cerebral metabolic depression and a reduction in the activity of the pyruvate dehydrogenase complex (PDHC). Preischemic hyperglycemia, which aggravates ischemic brain damage and invariably causes seizure, is known to further reduce cerebral metabolic rate. To investigate whether these effects are accompanied by changes in PDHC activity, the postischemic cerebral cortical activity of this enzyme was investigated in rats with preischemic hyperglycemia (plasma glucose 20-25 mM). The results were compared with those obtained in normoglycemic animals (plasma glucose 5-10 mM). The activated portion of PDHC and total PDHC activity were measured in neocortical samples as the rate of decarboxylation of [14C]pyruvate in crude brain mitochondrial homogenates after 5 min, 15 min, 1 h, 6 h, and 18 h of recirculation following 15 min of incomplete cerebral ischemia. In normoglycemic animals the fraction of activated PDHC, which rises abruptly during ischemia, was reduced to 19-25% during recirculation compared with 30% in sham-operated controls. In hyperglycemic rats the fraction of activated PDHC was higher during the first 15 min of recirculation. However, after 1 and 6 h of recirculation, the fraction was reduced to values similar to those measured in normoglycemic animals. Fifteen of 26 rats experienced early (1-4 h post ischemia) seizures in the recovery period. The PDHC activity appeared unchanged prior to these early postischemic seizures. We conclude that the accentuated depression of postischemic metabolic rate observed in hyperglycemic animals is not coupled to a corresponding postischemic depression of PDHC.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Preischemic hyperglycemia and postischemic alteration of rat brain pyruvate dehydrogenase activity. 234 83

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 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 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

Calcium homeostasis and mitochondrial oxidative metabolism interact closely in brain and both processes are impaired during hypoxia. Since the regulation of the pyruvate dehydrogenase complex (PDHC) may link these two processes, the relation of cytosolic free calcium ([Ca2+]i) to the activation state of PDHC (PDHa) was assessed in isolated nerve terminals (i.e. synaptosomes) under conditions that alter [Ca2+]i. K+ depolarization elevated [Ca2+]i and PDHa and both responses required external calcium. Treatment with KCN, an in vitro model of hypoxia decreased ATP and elevated [Ca2+]i and PDHa. Furthermore, in the presence of KCN, PDHa became more sensitive to K+ depolarization as indicated by larger changes in PDHa than in [Ca2+]i. The calcium ionophore Br-A23187 elevated [Ca2+]i, but did not affect PDHa. K+ depolarization elevated [Ca2+]i and PDHa even if [Ca2+]i was elevated by prior addition of ionophore or KCN. Previous in vivo studies by others show that PDHa is altered during and after ischemia. The current in vitro results suggest that hypoxia, only one component of ischemia, is sufficient to increase PDHa. These data also further support the notion that PDHa is regulated by [Ca2+]i as well as by other factors such as ATP. Our results are consistent with the concept that PDHa in nerve endings may be affected by [Ca2+]i and that these two processes are clearly linked.
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PMID:The role of cytosolic free calcium in the regulation of pyruvate dehydrogenase in synaptosomes. 813 69

Previous studies showed that in rats exposed to 30 min of forebrain ischemia, there were reductions in pyruvate-supported respiration within the first 3 h of recirculation in mitochondria isolated from the dorsolateral striatum (a region in which the majority of neurons are susceptible to ischemia) but not the ischemia-resistant paramedian neocortex. The present study demonstrates that the changes in mitochondrial respiration apparently result from a loss of activity of the pyruvate dehydrogenase complex (PDHC). In mitochondria from the dorsolateral striatum, incubated in the presence of pyruvate and ADP (state 3 conditions) and treated to preserve the phosphorylation state of PDHC, there was no significant change from preischemic activity after 30 min of ischemia or 1 h of recirculation. However, a significant reduction (to 71% of control value) was observed at 3 h of recirculation, and the activity decreased further at 6 and 24 h (to 64 and 43% of control values, respectively). Total PDHC activity in the isolated mitochondria was similarly reduced at 3 h (68% of control values) and 6 h (73% of control values), indicating that the alteration was due to loss or inactivation of the PDHC rather than changes in phosphorylation of the complex. No significant changes were observed in the activity of two other mitochondrial markers, rotenone-sensitive NADH-cytochrome c oxidoreductase and alpha-ketoglutarate dehydrogenase. None of the activities of these three enzymes in mitochondria from the paramedian neocortex was significantly affected by ischemia or recirculation. These results (together with previous observations) indicate an early and specific change affecting the PDHC in cells of the dorsolateral striatum.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Selective reductions in the activity of the pyruvate dehydrogenase complex in mitochondria isolated from brain subregions following forebrain ischemia in rats. 841 13

The activity of pyruvate dehydrogenase complex (PDC) was studied in the human quadriceps femoris muscle during isometric contraction induced by intermittent electrical stimulation at 20 Hz. Muscle biopsy samples were obtained at rest and after 10, 20, and 46 contractions. The active form of PDC (PDCa) increased from a mean value of 26% of the total PDC at rest to mean values of 46, 78, and 80%, respectively. Muscle biopsy samples were also obtained at rest, after 46 contractions with limb blood flow intact or occluded, and after 2 min of oxidative recovery. In another experiment, muscle biopsy samples were obtained at rest, after 10 min of resting ischemia, and after 46 contractions with limb blood flow occluded. The transformation of PDC to PDCa was nearly complete, regardless of whether the blood flow was intact or occluded. However, the accumulation of acetyl groups observed during stimulation with intact blood flow was abolished when the blood flow was occluded. The absence of NADH oxidation during anoxia had no effect on the contraction-induced transformation of PDC to PDCa, but it inhibited the flux through the enzyme reaction.
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PMID:PDC activity and acetyl group accumulation in skeletal muscle during isometric contraction. 851 86

Skeletal muscle contractile function is impaired during acute ischemia such as that experienced by peripheral vascular disease patients. We therefore, examined the effects of dichloroacetate, which can alter resting metabolism, on canine gracilis muscle contractile function during constant flow ischemia. Pretreatment with dichloroacetate increased resting pyruvate dehydrogenase complex activity and resting acetylcarnitine concentration by approximately 4- and approximately 10-fold, respectively. After 20-min contraction the control group had demonstrated an approximately 40% reduction in isomeric tension whereas the dichloroacetate group had fatigued by approximately 25% (P < 0.05). Dichloroacetate resulted in less lactate accumulation (10.3 +/- 3.0 vs 58.9 +/- 10.5 mmol.kg-1 dry muscle [dm], P < 0.05) and phosphocreatine hydrolysis (15.6 +/- 6.3 vs 33.8 +/- 9.0 mmol.kg-1 dm, P < 0.05) during contraction. Acetylcarnitine concentration fell during contraction by 5.4 +/- 1.8 mmol.kg-1 dm in the dichloroacetate group but increased by 10.0 +/- 1.9 mmol.kg-1 dm in the control group. In conclusion, dichloroacetate enhanced contractile function during ischemia, independently of blood flow, such that it appears oxidative ATP regeneration is limited by pyruvate dehydrogenase complex activity and acetyl group availability.
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PMID:Increased acetyl group availability enhances contractile function of canine skeletal muscle during ischemia. 860 48

Dichloroacetate (DCA) activates the pyruvate dehydrogenase complex (PDHC), and improves the recovery of cerebral pH, lactate, ATP, and PCr following reperfusion in animal models of forebrain ischemia. In order to determine whether this results in neuroprotection, rats were administered NaDCA (100 mg/kg or 10mg/kg i.v.) 10 min before 12 min of normothermic forebrain ischemia (bilateral carotid artery occlusion plus systemic hypotension, 45 mmHg). Neuronal injury assessed histopathologically 7 days post-ischemia was significantly reduced in the CA1 region of the hippocampus, the dorsal lateral striatum, and the neocortex, in rats treated with 100 mg/kg NaDCA, but not in rats treated with 10 mg/kg NaDCA.
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PMID:Protective effect of dichloroacetate in a rat model of forebrain ischemia. 873 Nov 65


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