Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hydrogen peroxide (H2O2) may incite cardiac ischemia-reperfusion injury. We evaluate herein the influence of H2O2-induced oxidative stress on heart muscle hexose metabolism in cultured neonatal rat cardiomyocytes, which have a substrate preference for carbohydrate. Cardiomyocyte exposure to 50 microM-1.0 mM bolus H2O2 transiently activated the pentose phosphate cycle and thereafter inhibited cellular glucose oxidation and glycolysis. These metabolic derangements were nonperoxidative in nature (as assessed in alpha-tocopherol-loaded cells) and occurred without acute change in cardiomyocyte hexose transport or glucose/glycogen reserves. Glycolytic inhibition was supported by the rapid, specific inactivation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). The degree of GAPDH inhibition correlated directly with the magnitude of the oxidative insult and was independent of both metal-catalyzed H2O2 reduction to free radicals and lipid peroxidation. Severe GAPDH inhibition was required for a rate-limiting effect on glycolytic flux. Cardiomyocyte pyruvate dehydrogenase was also inhibited by H2O2 overload, but to a lesser degree than GAPDH such that entry of hexose-derived acetyl units into the tricarboxylic acid cycle was not as restrictive as GAPDH inactivation to glycolytic ATP production. An increase in phosphofructokinase activity accompanied GAPDH inactivation, leading to the production and accumulation of glycolytic sugar phosphates at the expense of ATP equivalents. Cardiomyocyte treatment with iodoacetate or 2-deoxyglucose indicated that GAPDH inactivation/glycolytic blockade could account for approximately 50% of the maximal ATP loss following H2O2 overload. Partial restoration of GAPDH activity after a brief H2O2 "pulse" afforded some ATP recovery. These data establish that specific aspects of heart muscle hexose catabolism are H2O2-sensitive injury targets. The biochemical pathology of H2O2 overload on cardiomyocyte carbohydrate metabolism has implications for post-ischemic cardiac bioenergetics and function.
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PMID:Hydroperoxide-induced oxidative stress impairs heart muscle cell carbohydrate metabolism. 830 15

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

We investigated metabolic factors related to the recovery of myocardial function during ischemia and after reperfusion using dichloroacetic acid (DCA) in canine models with repeated 10-min regional ischemia and reperfusion. Administration of 100 mg/kg DCA, which activates pyruvate dehydrogenase, improved regional wall motion significantly as compared with the nontreated controls (p < 0.05). The mechanism was studied by determining changes in myocardial levels of pH, glucose, lactate, and nonesterified fatty acids (NEFA). Glucose extraction was increased significantly during ischemia and reperfusion by the pretreatment of DCA (p < 0.01). the calculated contribution of glucose to myocardial oxidative metabolism during ischemia and reperfusion was greater than that of NEFA and lactate in case of DCA treatment. The uptake of [99mTc]pyrophosphate (PYP), which reflects myocardial injury, was also significantly suppressed by DCA (p < 0.01). pH was not affected by an infusion of DCA. These findings suggest that the activation of glucose metabolism by DCA, which is impaired and reduced during ischemia and reperfusion, may be responsible for the improved myocardial function after reperfusion.
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PMID:Improvement of myocardial ischemic dysfunction with dichloroacetic acid: experimental study by repeated ischemia in dogs. 860 39

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

This study was undertaken to determine the effect of dichloroacetate (DCA) on myocardial functional and metabolic recovery following global ischemia. Isolated rabbit hearts were subjected to 120 min of mildly hypothermic (34 degrees C), cardioplegic arrest with multidose, modified St. Thomas' cardioplegia. Hearts were reperfused with either physiologic salt solution (PSS) as controls, (CON, n = 10) or PSS containing DCA (DCA, n = 6) at a concentration of 1 mM. Functional and metabolic indices were determined at baseline and at 15, 30, and 45 min of reperfusion. In four DCA and four CON hearts, myocardial biopsies were taken at baseline, end-ischemia, 15 and 45 min for nucleotide levels. Functional recovery was significantly better in hearts reperfused with DCA as demonstrated by recovery of baseline developed pressure (DCA = 69 +/- 5%, CON = 45 +/- 9%) and dP/dt (DCA = 64% +/- 10% versus CON = 48% +/- 10%). Coronary blood flow was not different between groups either at baseline or during reperfusion, but myocardial oxygen consumption (MVO2) was increased in the DCA versus CON hearts (79% +/- 20% of baseline vs 50% +/- 18%). Recovery of myocardial adenylate energy status was improved in the DCA versus CON hearts (ATP recovered to 45% +/- 20% versus 8% +/- 6% of baseline). Coronary sinus lactate concentration was decreased in DCA perfused hearts at 45 min of reperfusion. Percent of baseline NADH values was similar at 15 min of reperfusion, but at 45 min, DCA hearts showed a decrease in NADH levels, while CON hearts showed an increase (DCA = 48%; CON = 121%). The enhanced myocardial function and improved metabolic status noted with DCA may result from increased oxidative phosphorylation due to altered pyruvate dehydrogenase (PDH) activity.
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PMID:Dichloroacetate enhanced myocardial functional recovery post-ischemia : ATP and NADH recovery. 866 Dec 1

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

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

The mammalian heart is normally well oxygenated and anaerobic glycolysis is extremely rare except for the production of extra ATP during extreme exercise like a marathon race. Anaerobic glycolysis plays a role when there is a serious impairment in coronary blood flow such as during heart attack and open heart surgery. The control of glycolysis in ischemic myocardial tissue appears to be extremely complex. During aerobic glycolysis, phosphofructokinase is the most important regulatory enzyme that controls the energy requirements of the cell. Under anaerobic conditions, however, glyceraldehyde-3-phosphate dehydrogenase becomes the key enzyme because it responds promptly to any changes in the essential supply of co-factors for oxidation. The conversion of pyruvate to acetyl CoA (aerobic metabolism) involves a series of chain reactions primarily catalyzed by pyruvate dehydrogenase complex which is situated at the cross roads between both aerobic and anaerobic glycolysis. It is important to remember that substrate utilization is carefully controlled by substrate availability. During aerobic metabolism, control mechanisms using fatty acids, lactate and glucose as energy substrates regulate the rate of ATP production according to energy demand. This precise mechanism is upset during ischemia and post-ischemic reperfusion for reasons discussed in this review. The demand for ATP can no longer be met by its supply because of severely reduced anaerobic glycolysis and significantly inhibited beta-oxidation of fatty acids. The impairment of bioenergetics is discussed in the context of several diseases such as cardiomyopathy, heart failure, diabetes, arrhythmias, cardiac surgery, heart-lung transplantation, and also in aging and oxidative stress. The regulation of energy metabolism in preconditioned heart is also discussed. Finally, methods used to preserve energy in ischemic myocardium are summarized and quantitation of the high-energy phosphates is discussed. This review challenges scientists to discover drugs which will stimulate energy supply during myocardial ischemia.
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PMID:Bioenergetics, ischemic contracture and reperfusion injury. 880 94

The heart is known for its ability to produce energy from fatty acids (FA) because of its important beta-oxidation equipment, but it can also derive energy from several other substrates including glucose, pyruvate, and lactate. The cardiac ATP store is limited and can assure only a few seconds of beating. For this reason the cardiac muscle can adapt quickly to the energy demand and may shift from a 100% FA-derived energy production (after a lipid-rich food intake) or any balanced situation (e.g., diabetes, fasting, exercise). These situations are not similar for the heart in terms of oxygen requirement because ATP production from glucose is less oxygen-consuming than from FA. The regulation pathways for these shifts, which occur in physiologic as well as pathologic conditions (ischemia-reperfusion), are not yet known, although both insulin and pyruvate dehydrogenase activation are clearly involved. It becomes of strategic importance to clarify the pathways that control these shifts to influence the oxygen requirement of the heart. Excess FA oxidation is closely related to myocardial contraction disorders characterized by increased oxygen consumption for cardiac work. Such an increased oxygen cost of cardiac contraction was observed in stunned myocardium when the contribution of FA oxidation to oxygen consumption was increased. In rats, an increase in n-3 polyunsaturated FA in heart phospholipids achieved by a fish-oil diet improved the recovery of pump activity during postischemic reperfusion. This was associated with a moderation of the ischemia-induced decrease in mitochondrial palmitoylcarnitine oxidation. In isolated mitochondria at calcium concentrations close to that reported in ischemic cardiomyocytes, a futile cycle of oxygen wastage was reported, associated with energy wasting (constant AMP production). This occurs with palmitoylcarnitine as substrate but not with pyruvate or citrate. The energy wasting can be abolished by CoA-SH and other compounds, but not the oxygen wasting. Again, the calcium-induced decrease in mitochondrial ADP/O ratio was reduced by increasing the n-3 polyunsaturated FA in the mitochondrial phospholipids. These data suggest that in addition to the amount of circulating lipids, the quality of FA intake may contribute to heart energy regulation through the phospholipid composition. On the other hand, other intervention strategies can be considered. Several studies have focused on palmitoylcarnitine transferase I to achieve a reduction in beta-oxidation. In a different context, trimetazidine was suggested to exert its anti-ischemic effect on the heart by interfering with the metabolic shift, either at the pyruvate dehydrogenase level or by reducing the beta-oxidation. Further studies will be required to elucidate the complex system of heart energy regulation and the mechanism of action of potentially efficient molecules.
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PMID:Fatty acid oxidation in the heart. 889 66


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