UMLS:C0022116 - FACTA Search

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

Pyruvate dehydrogenase complex (PDHC) is a major enzyme of glucose metabolism. Dichloroacetate (DCA) is a noncompetitive inhibitor of PDHC kinase, an enzyme that inactivates PDHC. We examined the effects of DCA on extracellular lactate and pyruvate concentration changes and spinal somatosensory evoked potentials (SSEP) in ischemic rabbit spinal cords. In the first group of 26 animals, the aorta was occluded until postsynaptic SSEP waves were completely suppressed for 10 min, a period of ischemia that causes neurologic deficits in 50% of untreated animals. DCA (25 mg/kg) was given to 13 of these animals before ischemia. In the second group of 24 animals, the aorta was occluded until the postsynaptic SSEP waves were absent for 20 min, a period of ischemia that produces paraplegia in 100% of untreated animals. DCA (25 mg/kg) was given to 16 of these animals just before the aortic occlusion was released. After occlusion, extracellular spinal lactate concentrations increased abruptly while pyruvate concentrations fell. Both lactate and pyruvate concentrations reached a plateau during the ischemic period but increased when the aortic balloon was deflated. DCA-treated animals had lower lactate and pyruvate peak concentrations during reperfusion, as well as more rapid and greater recovery of SSEP at 2 h after reperfusion. DCA did not alter spinal metabolism during the ischemia but appeared to produce a more rapid shift to glucose metabolism on reperfusion. Thus, DCA treatment resulted in better electrophysiological recovery after both moderate and severe ischemia, either by reducing lactic acidosis or by increasing the recovery rate of aerobic energy production.
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PMID:Reduction in spinal cord postischemic lactic acidosis and functional improvement with dichloroacetate. 234 14

Bioenergetic and hemodynamic consequences of cellular redox manipulations by 0.2-20 mM pyruvate were compared with those due to adrenergic stress (0.7-1.1 microM norepinephrine) using isolated working guinea-pig hearts under the conditions of normoxia, low-flow ischemia, and reperfusion. 5 mM glucose (+ 5 U/l insulin) + 5 mM lactate were the basal energy-yielding substrates. To stabilize left ventricular enddiastolic pressure, ventricular filling pressure was held at 12 cmH2O under all conditions; this preload control minimized Frank-Starling effects on ventricular inotropism. Global low-flow ischemia was induced by reducing aortic pressure to levels (20-10 cmH2O) below the coronary autoregulatory reserve. Reactants of the creatine kinase, including H+ and other key metabolites, were measured by enzymatic, HPLC, and polarographic techniques. In normoxic hearts, norepinephrine stimulations of inotropism, heart rate x pressure product, and oxygen consumption (MVO2) were associated with a fall in the cytosolic phosphorylation potential [( ATP]/[( ADP].[Pi]] as judged by the creatine kinase equilibrium. In contrast, infusion of excess pyruvate (5 mM) markedly increased [ATP]/[( ADP].[Pi]) and ventricular work output, while intracellular phosphate decreased; MVO2 remained constant under the same conditions. During reperfusion following ischemia, pyruvate effected striking and concentration-dependent increases in MVO2, phosphorylation potential, and inotropism. Pyruvate dehydrogenase flux was augmented during reperfusion hyperemia followed by near-complete recoveries of [ATP]/([ADP].[Pi]), contractile force, heart rate x pressure product, and MVO2 in the presence of 5-10 mM pyruvate. Pyruvate also attenuated ischemic adenylate degradation. Omission of glucose from the perfusion medium rendered pyruvate ineffective in postischemic hearts. Similarly, excess lactate (5-15 mM) or acetate (5 mM) failed to reenergize reperfused hearts and severe depressions of MVO2 and inotropism developed despite the presence of glucose. Apparently, subcellular redox manipulations by pyruvate dissociated stimulated mitochondrial respiration and increased inotropism from low cytosolic phosphorylation potentials. This was evidence against the extramitochondrial [ADP].[Pi]/[ATP] ratio being the primary factor in the control of mitochondrial respiration. The mechanism of pyruvate enhancement of inotropism during normoxia and reperfusion is probably multifactorial. Thermodynamic effects on subcellular [NADH]/[NAD+] ratios are coupled with a rise in the cytosolic [ATP]/[( ADP].[Pi]) ratio at constant (normoxia) or increased (reperfusion) MVO2.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Pyruvate-enhanced phosphorylation potential and inotropism in normoxic and postischemic isolated working heart. Near-complete prevention of reperfusion contractile failure. 270 62

Ischemic dysfunction, including contracture, has been attributed to lack of ATP, although previous work has not been consistent with this concept. We describe here a model of no flow ischemic arrest, characterized by depressed levels of mechanical function upon reperfusion and high energy phosphate stores within normal limits. The decreased mechanical function bears an inverse relationship to myocardial lactate levels after twenty-minutes of reperfusion in the absence or presence of dichloroacetic acid (DCA). Post-ischemic non-DCA treated hearts attained peak work of only 25% of that of controls, while those treated with DCA following ischemia performed almost as well as controls. ATP and CP levels remained high in both DCA treated and non-DCA treated hearts. Lactate levels were high in hearts immediately following ischemia, but were reduced to control levels in post-ischemic hearts perfused with DCA within twenty minutes, whereas those not treated with DCA had lactate levels two to three times that of controls within the same time period. Pyruvate dehydrogenase (PDH) activity was reduced in non-DCA treated post ischemic hearts after twenty minutes reperfusion but was elevated above controls in hearts reperfused with DCA. The data indicates that DCA increases mechanical performance of the isolated post-ischemic rat heart and the proposed mechanism for this increase is the oxidative removal of lactate resulting from an increase in PDH activity.
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PMID:The effect of dichloroacetate on the isolated no flow arrested rat heart. 274 13

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 metabolic effects of partial ischemia on canine skeletal muscle were examined during 20 min of isometric contraction. A reduction in blood flow of approximately 75% resulted in an approximate 40% reduction in contractile function. Muscle lactate accumulation and phosphocreatine (PCr) hydrolysis were greater during ischemia, indicating a greater reliance on anaerobic ATP regeneration. Pyruvate dehydrogenase transformation to its active form (PDCa) during contraction was not affected by ischemia, such that PDCa did not appear to be a determinant of skeletal muscle fatigue. Acetylcarnitine concentration was greater during ischemic contraction and inversely correlated with PCr concentration (r = -0.79, P<0.01). Furthermore, acetylcarnitine accumulation and PCr degradation correlated with the degree of skeletal muscle fatigue (r = 0.56, P<0.05 and r = 0.70, P<0.01, respectively). Thus the greater the acetyl group oxidation, the lesser the contribution from anaerobic ATP provision and, subsequently, the smaller the degree of muscle fatigue observed. The metabolic characteristics of this model of ischemic muscle contraction are indistinguishable from the normal metabolic responses observed with increasing contractile intensity.
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PMID:Metabolic responses of canine gracilis muscle during contraction with partial ischemia. 863 84

The purposes of this study were to: (1) assess myocardial pyruvate dehydrogenase (PDH) activity and substrate exchange under well-perfused and ischemic conditions; (2) determine the metabolic effects of an intra-coronary infusion of the PDH activator, dichloroacetate (DCA); and (3) measure the effects of ischemia and DCA on malonyl CoA levels. Experiments were performed in anesthetised open-chest swine under non-ischemic conditions, followed by 40 min with a 60% reduction in left anterior descending coronary artery (LAD) blood flow. Myocardial needle biopsies for measurement of PDH activity were taken after an intracoronary infusion of either saline or DCA (1 mM in LAD blood) under aerobic conditions, and after 37 min of ischemia. Pyruvate dehydrogenase activity was measured with and without maximal activation by swine PDH phosphatase. Malonyl CoA and acetyl CoA were measured after 40 min of LAD ischemia in myocardium from the ischemic DCA- or saline-treated LAD bed, and the non-ischemic untreated left circumflex coronary artery (CFX) perfusion bed. Net glucose, lactate and free fatty acid (FFA) uptakes were measured across the LAD perfusion bed throughout the study. Dichloroacetate treatment increased the amount of active dephosphorylated PDH to 88% of the total activity under aerobic conditions, compared to 55% with saline (P < 0.01). Ischemia did not significantly change PDH activation state in either group. Acetyl CoA and malonyl CoA contents were significantly elevated in ischemic DCA-treated myocardium compared to saline-treated ischemic myocardium. Dichloroacetate treatment significantly lowered rates of myocardial FFA uptake under both aerobic and ischemic conditions, but did not effect glucose uptake or lactate exchange. Free fatty acid uptake was negatively correlated to malonyl CoA levels (r = -0.68) during ischemia. It is proposed that the inhibition of FFA uptake observed with DCA in ischemic myocardium is due to malonyl CoA inhibition of carnitine palmitoyl transferase I.
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PMID:Pyruvate dehydrogenase activity and malonyl CoA levels in normal and ischemic swine myocardium: effects of dichloroacetate. 876 30

Pyruvate dehydrogenase (PDH) is one of the mitochondrial enzymes which regulate the glucose metabolism. The purpose of this study is to determine the effect of the duration of cerebral ischemia on PDH activity and the metabolites. Cerebral ischemia was produced by bilateral common carotid artery occlusion in Mongolian Gerbils. 20-minute (1) and 60-minute ischemic groups (2) were made. PDH activity and energy metabolites (ATP, PCr, lactate) were measured in the caudate nucleus and cortex at each time period. 1) 20 min ischemic group: PDH activity significantly increased after 20-min ischemia in both the caudate nucleus and cortex, and decreased to levels less than that of the control after 20 min reperfusion. At 60 and 120 min reperfusion, PHD activity returned to the control levels. ATP and PCr concentrations were significantly depleted after the ischemic insult, returning to 60-80% of the control level after reperfusion. Lactate concentrations increased significantly after ischemia, and were reduced by reperfusion. 2) 60 min ischemic group: PDH activity significantly increased after 60 min ischemia, and decreased but remained higher than the control level after 20 min reperfusion. At 60 and 120 min reperfusion, PDH activity gradually decreased towards control levels. ATP and PCr concentrations were depleted after ischemia, and were gradually restored after 20 min reperfusion, recovering to 50% after 60 min reperfusion. Lactate concentrations increased after the ischemic insult, and became more elevated after reperfusion. These findings indicate that there is a significant difference in the PDH activity and metabolism depending on the duration of ischemia. The data suggest that impaired metabolism and persistent elevation of PDH activity may be caused by damage to the mitochondria allowing the influx of Ca2+ during prolonged ischemia.
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PMID:[Effect of duration of cerebral ischemia on pyruvate dehydrogenase activity (PDH) and metabolites in the gerbil brain]. 893 13

Pyruvate dehydrogenase is one of the mitochondrial enzymes considered important in the regulation of oxidative metabolism. To further understand the relationship between its activity and ischemic brain damage we conducted three experiments. We studied the effects of (1) duration of cerebral ischemia, (2) the Ca2+ channel blocker, nicardipine, and (3) the immunosuppressant, FK506, on PDH activity and energy metabolites during ischemia and reperfusion. In the first study we also measured regional cerebral blood flow (rCBF). (1) Increasing the duration of the ischemic insult delayed the deactivation of PDH, slowed the resynthesis of high energy phosphates and the clearance of lactate, and impaired recovery of rCBF. Additionally, (2) nicardipine normalized PDH activities and improved the impaired metabolism after reperfusion, and (3) FK506 did not effect PDH activity, but significantly improved the impaired metabolism during the early phase of reperfusion. From these studies we conclude that PDH plays a role in the recovery of metabolism during reperfusion, and both nicardipine and FK506 improve metabolism during the early phase of reperfusion.
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PMID:[Studies on brain pyruvate dehydrogenase (PDH) activity and energy metabolites during ischemia and reperfusion]. 1079 Nov 3

Pyruvate dehydrogenase complex (PDC) plays an important role in energy homeostasis in the heart by catalyzing the oxidative decarboxylation of pyruvate derived primarily from glucose and lactate. Because various pathophysiological states can markedly alter cardiac glucose metabolism and PDC has been shown to be altered in response to chronic ischemia, cardiac physiology of a mouse model with knockout of the alpha-subunit of the pyruvate dehydrogenase component of PDC in heart/skeletal muscle (H/SM-PDCKO) was investigated. H/SM-PDCKO mice did not show embryonic lethality and grew normally during the preweaning period. Heart and skeletal muscle of homozygous male mice had very low PDC activity (approximately 5% of wild-type), and PDC activity in these tissues from heterozygous females was approximately 50%. Male mice did not survive for >7 days after weaning on a rodent chow diet. However, they survived on a high-fat diet and developed left ventricular hypertrophy and reduced left ventricular systolic function compared with wild-type male mice. The changes in the heterozygote female mice were of lesser severity. The deficiency of PDC in H/SM-PDCKO male mice greatly compromises the ability of the heart to oxidize glucose for the generation of energy (and hence cardiac function) and results in cardiac pathological changes. This mouse model demonstrates the importance of glucose oxidation in cardiac energetics and function under basal conditions.
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PMID:Tissue-specific pyruvate dehydrogenase complex deficiency causes cardiac hypertrophy and sudden death of weaned male mice. 1864 Dec 70

In failing hearts, coronary flow is normal, but the coronary flow reserve (CFR) is reduced, so demand-induced ischemia (DII) may occur in response to greater demand for O(2). The objectives of this study were: (i) to verify that dobutamine stimulation produces DII in isolated rat hearts having, like failing hearts, increased left ventricular end-diastolic pressure (LVEDP) and hence reduced CFR and (ii) to study the effects of stimulation of glucose oxidation and of inhibition of fatty acid oxidation in this new model of DII. Isolated rat hearts perfused with 11 mM glucose and 0.6 mM palmitate (or no palmitate) were studied. Stepwise increments in the volume of a balloon placed in LV resulted in reciprocal impairment of CFR, supporting the role of the extravascular compressive forces in determining CFR. CFR was 1.82+/-0.1 and 1.32+/-0.1 (p<0.05) in the hearts with LVEDP set to 5 mmHg (controls) and 40 mmHg (expanded), respectively. In controls, dobutamine increased coronary flow, myocardial oxygen consumption (MVO(2)), LVDP, mechanical efficiency, and the rates of palmitate and glucose oxidation, however, the effluent lactate concentration remained unchanged. In the expanded hearts vs. controls, dobutamine-induced increases in coronary flow and MVO(2) were reduced by approximately 50%, the increases in LVDP, efficiency, and rates of glucose and fatty acid oxidation were completely prevented, and lactate production greatly increased with dobutamine, indicating DII. Pyruvate dehydrogenase activator, dichloroacetate (DCA 1 mM) and a putative inhibitor of fatty acid beta-oxidation, trimetazidine (5 microM), both increased the rate of glucose oxidation and attenuated myocardial lactate production during DII, however they did not improve myocardial function during DII. Likewise, palmitate-free perfusion had no beneficial effect during DII although it attenuated lactate production. In the hearts subjected to palmitate-free perfusion plus DCA, lactate overproduction during DII was completely abolished, however, the deterioration of LVDP and mechanical efficiency was only partially prevented. Thus, greater demand for O(2) induces DII in the expanded hearts with reduced CFR. Lactate overproduction secondary to an imbalance between glycolysis and glucose oxidation is not a primary factor adversely affecting cardiac mechanical function during DII. Interventions shifting this balance toward glucose oxidation are not beneficial in the setting of DII in our model although they are known to effectively mitigate contractile dysfunction in the post-ischemic myocardium.
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PMID:Demand-induced ischemia in volume expanded isolated rat heart; the effect of dichloroacetate and trimetazidine. 2043 15

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