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)

Brain ischemia reperfusion causes increased formation of reactive oxygen species (ROS). Activity of the mitochondrial enzyme pyruvate dehydrogenase (PDH) has been shown to undergo a significant decrease following reperfusion of the ischemic tissue. We have examined the effect of a superoxide radical-generating system (xanthine oxidase/hypoxanthine, XO/HX) on the activity of this enzyme. Incubation of PDH in the presence of XO/HX resulted in its inactivation. The degree of the inactivation was dependent on the amount of XO present, which correlated linearly with the concentration of superoxide radical generated by this system. The activity of lactate dehydrogenase, an enzyme resistant to inactivation by ischemia reperfusion, was not affected by this system. Superoxide dismutase partially prevented and catalase exerted a nearly complete protective effect against the inactivation of PDH. Deferoxamine was partially protective. The sulfhydryl protective reagents, dithiothreitol and glutathione, prevented the inactivation of PDH, even though to varying degrees, which implicates sulfhydryl oxidation. A hydroxyl radical-generating system (hydrogen peroxide irradiated with ultraviolet radiation) effectively inactivated PDH. These results demonstrate that PDH is susceptible to damage and inactivation by ROS and point to the involvement of Fenton chemistry and hydroxyl radicals formed through it in PDH inactivation by XO/HX. A similar mechanism may be responsible for the PDH inactivation during ischemia/reperfusion.
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PMID:Reactive oxygen species-mediated inactivation of pyruvate dehydrogenase. 895 77

The objective of this study was to determine if the pretreatment with a sublethal ischemic insult, which has been shown to protect against delayed neuronal death, effects the recovery of energy metabolites or alters the activity of pyruvate dehydrogenase (PDH) following transient cerebral ischemia. Gerbils were pretreated with a sublethal ischemic insult, 2 min of bilateral common carotid artery occlusion, and 24 h later given a 5-min lethal ischemic insult. Animals were reperfused for 0, 10, or 60 min, or 1, 3 or 7 days. Brain metabolites, ATP, PCr, and lactate, and PDH activity were measured in the cortex and the hippocampal CA1 region. The pretreatment had no effect on ATP and PCr depletion or on lactate accumulation after the 5-min insult, nor on their recovery up to 1 day reperfusion, although there was a difference in the lactate levels of the non-pretreated and the pretreated gerbils after 10 min reperfusion. The pretreatment also had no effect on PDH activity during ischemia and reperfusion in either region. However, at 3 days reperfusion the non-pretreated animals exhibited a secondary decrease in ATP levels in the hippocampus. At 7 days reperfusion, ATP levels in the hippocampus of both the pretreated animals and the non-pretreated animals were significantly decreased compared to controls. Additionally, the level of ATP in the non-pretreated group was significantly lower than that in the pretreated group. The pretreatment with a sublethal ischemic insult did not effect the initial recovery of metabolites or the activity of PDH following transient cerebral ischemia. However, it protected against the secondary decrease of ATP levels in the hippocampus. Thus, the induction of ischemic tolerance is not caused by a reduction in metabolic impairment during the secondary insult.
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PMID:Ischemic tolerance phenomenon from an approach of energy metabolism and the mitochondrial enzyme activity of pyruvate dehydrogenase in gerbils. 903 91

The aim of this study was to investigate the possible beneficial effect on perfused mouse liver of alanine as an exogenous substrate for gluconeogenesis. Livers from fed and fasted animals were perfused with oxygenated Krebs' Henseleit buffer for 30 min, then stored at 4 degrees C in University of Wisconsin solution for 48 h. Then reperfusion at 37 degrees C was performed according to two protocols. In the first one, reperfusion with alanine-free Krebs' Henseleit buffer was used for 1 h. 8 mM (3-(13)C) alanine was then added and perfusion was prolonged for a second hour. In the second one, the first hour of perfusion was omitted and the organs were reperfused directly for an hour in the presence of 8 mM (3-(13)C)alanine. 31P NMR was used to measure the NTP recovery of the livers. At the end of the reperfusions, 13C and 1H NMR spectra of perfusates and of glutamine extracted from these perfusates by HPLC were recorded. These data were analysed according to a model of liver metabolism assuming that the only substrate of the liver was (3-(13)C)alanine and endogenous substrates were metabolizable only through pyruvate. It was found that in the absence of initial alanine at reperfusion, livers from fasted mice recovered less NTP than those of fed ones (40 +/- 4% vs 60 +/- 5%, p <0.01), but not if this substrate is present at the beginning of reperfusion (61 +/- 5% vs 60 +/- 5%). This was confirmed by the amount of labelled metabolites produced. However, the dilution of 13C labelled metabolites by unlabelled ones did not indicate a larger concentration of endogenous substrates in livers from fed mice. The conclusion reached was that the lower pyruvate dehydrogenase activity of livers from fasted mice relatively to that from fed mice could be compensated for by the greater pyruvate concentration provided by alanine for the initial production of NTP after cold ischemia and warm reperfusion.
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PMID:Beneficial effect of alanine on metabolic recovery of fasted livers submitted to cold ischemia. 907 3

The purpose of this study was to determine if nicardipine, a calcium ion channel blocker, affects pyruvate dehydrogenase (PDH) activity and improves energy metabolism during cerebral ischemia and reperfusion. Cerebral ischemia was induced, using the bilateral carotid artery occlusion method, for 60 min followed by reperfusion up to 120 min in gerbils. Nicardipine (1 mg/kg) or saline (vehicle-treated) was given to gerbils 30 min prior to the occlusion of the common carotid arteries. PDH activity and metabolites (ATP, PCr, and lactate) were measured in cortex prior to ischemia, immediately following ischemia, and after each reperfusion period. After 60 min ischemia, PDH activity increased in both groups, and was significantly higher in the nicardipine-treated group. After 20 min reperfusion, PDH activity in the nicardipine-treated group recovered to control levels, whereas, the PDH activity in the vehicle-treated group remained elevated, and was higher than the nicardipine-treated animals. At 60 and 120 min reperfusion, the activities in the vehicle-treated group were significantly below control levels, there were no differences, however, between the two groups. ATP and PCr concentrations were markedly depleted immediately after ischemia in both groups. ATP levels at 20 min reperfusion and PCr levels at 60 min reperfusion were significantly higher in the nicardipine-treated group. Lactate concentrations in both groups increased 7-8 fold, similarly, immediately after ischemia. During reperfusion, the lactate remained elevated in both groups, though the levels in the nicardipine-treated group were lower than those in the vehicle-treated group, but not significantly. Nicardipine treatment normalized PDH activity quickly and improved energy metabolism after reperfusion.
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PMID:Effect of nicardipine, a Ca2+ channel blocker, on pyruvate dehydrogenase activity and energy metabolites during cerebral ischemia and reperfusion in gerbil brain. 950 35

The effects of dichloroacetate (DCA) on fatty acid oxidation and flux through pyruvate dehydrogenase (PDH) were studied in ischemic, reperfused myocardium supplied with glucose, long-chain fatty acids, lactate, pyruvate, and acetoacetate. The oxidation rates of all substrates were determined by combined 13C nuclear magnetic resonance (NMR) spectroscopy and oxygen-consumption measurements, and PDH flux was assessed by lactate plus pyruvate oxidation. In nonischemic control hearts, DCA increased PDH flux more than eightfold (from 0.68 +/- 0.28 to 5.81 +/- 1.16 micromol/min/g dry weight; n = 8 each group; p < 0.05) and significantly inhibited the oxidation of acetoacetate and fatty acids. DCA also improved mechanical recovery after 30 min of ischemia plus 30 min of reperfusion but did not significantly increase PDH flux measured at the end of the reperfusion period (1.35 +/- 0.42 micromol/min/g dry weight) compared with untreated ischemic hearts (0.87 +/- 0.28 micromol/min/g dry weight; n = 8 each group; p = NS). Although DCA had a modest effect on functional recovery in the reperfused myocardium, this beneficial effect was not associated with either marked stimulation of PDH flux or inhibition of fatty acid oxidation.
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PMID:Effects of dichloroacetate on mechanical recovery and oxidation of physiologic substrates after ischemia and reperfusion in the isolated heart. 951 76

The liver is the major site for lactate clearance, and liver disease exacerbates lactic acidosis during orthotopic liver transplantation (OLT). This study assessed pyruvate dehydrogenase (PDH) activity in control, cirrhotic, and graft liver to test the hypotheses that 1) liver disease decreases hepatic PDH activity, 2) graft PDH activity is inhibited due to protracted ischemia, and 3) dichloroacetate (DCA) reverses functional PDH inhibition in cirrhotic and graft liver. After having given their informed consent, 43 patients received either DCA (80 mg/kg) or aqueous 5% glucose during OLT. Six patients without apparent liver dysfunction that were undergoing subtotal hepatic resection served as controls. Liver biopsy PDH activity was assayed by measuring [14C]citrate synthesis from [14C]oxaloacetate and PDH-derived acetyl-CoA. PDH in the active form (PDHa) in cirrhotic and control liver was 5.6 +/- 1.3 (SE) and 57 +/- 10 nmol.g wet wt-1.min-1, respectively (P < 0.001). Total PDH activity (PDHt) was 21.5 +/- 3.6 and 264 +/- 27 nmol.g wet wt-1.min-1, respectively (P < 0.001). DCA increased PDHa in cirrhotic liver to 22.3 +/- 4.1 nmol.g wet wt-1.min-1 (P < 0.05 vs. no DCA) without altering PDHt. Graft liver PDHa was 166 +/- 19 nmol.g wet wt-1.min-1, which was not altered by DCA. We conclude that decreased hepatic PDH activity secondary to decreased content may underlie lactic acidosis during OLT, which can be partially compensated by DCA administration. There is no apparent inhibition of graft liver PDH activity after reperfusion.
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PMID:Hepatic pyruvate dehydrogenase activity in humans: effect of cirrhosis, transplantation, and dichloroacetate. 953 Jan 59

The effects of hyperglycemia on brain pyruvate dehydrogenase (PDH) and metabolites (ATP, PCr, and lactate) were investigated at 20 min ischemia, 0, 20, and 60 min, and 4 h reperfusion. During reperfusion, PDH activities were suppressed corresponding to the poor recovery of ATP and PCr concentrations and the increase in lactate concentration in the hyperglycemic group, suggesting that preischemic hyperglycemia may impair metabolism by suppressing PDH activity.
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PMID:Effect of hyperglycemia on pyruvate dehydrogenase activity and energy metabolites during ischemia and reperfusion in gerbil brain. 955 66

The objective of this study was to determine whether the duration of an ischemic insult effects the activity of the mitochondrial enzyme pyruvate dehydrogenase (PDH) in relation to the recovery of metabolites and regional cerebral blood flow (rCBF) immediately after ischemia and during reperfusion in gerbil cortex. Cerebral ischemia was induced, using the bilateral carotid artery occlusion method, for 20 or 60 min, followed by reperfusion up to 120 min. Immediately after ischemia PDH activity increased threefold regardless of ischemic duration. In the 60-min ischemic group, PDH remained activated, the recovery of high energy phosphates and the clearance of lactate were poor, and the rCBF was 48% of controls after 20-min reperfusion, decreasing gradually to 26% at 120-min reperfusion. In the 20-min ischemic group, PDH activity normalized quickly, the restoration of energy phosphates was good, there was a quick reduction in lactate within the first 60 min of reperfusion, and the rCBF was 65% of control at 20-min reperfusion, and remained over 48% of control throughout reperfusion. Recovery of metabolism after reperfusion did not parallel the changes in rCBF in either group, most noticeably in the 60-min ischemic group. The slow normalization of PDH activity reflected the poor recovery of metabolites in the 60-min ischemic group, indicating that PDH activity is important in the resynthesis of energy metabolites during reperfusion. In conclusion, prolonging the ischemic insult effected PDH activity during reperfusion, impaired recovery of energy metabolites, and worsened the recovery of rCBF.
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PMID:The effect of duration of cerebral ischemia on brain pyruvate dehydrogenase activity, energy metabolites, and blood flow during reperfusion in gerbil brain. 959 22

Clinical studies have demonstrated improved myocardial recovery after severe ischemia in response to acute triiodothyronine (T3) treatment. We determined whether T3 improves the recovery of ischemic hearts by improving energy substrate metabolism. Isolated working rat hearts were perfused with 5.5 mM glucose and 1.2 mM palmitate and were subjected to 30 min of no-flow ischemia. Glycolysis, glucose oxidation, and palmitate oxidation were measured during aerobic reperfusion by adding [5-3H]glucose, [U-14C]glucose, or [9,10-3H]palmitate to the perfusate, respectively. During reperfusion, cardiac work in untreated hearts recovered to a lesser extent than myocardial O2 consumption (MVO2), resulting in a decreased recovery of cardiac efficiency, which recovered to only 25% of preischemic values. Treatment of hearts with T3 (10 nM) before ischemia increased glucose oxidation during reperfusion, which was associated with a significant increase in pyruvate dehydrogenase (PDH) activity, the rate-limiting enzyme for glucose oxidation. In contrast, T3 had no effect on MVO2, glycolysis, or palmitate oxidation. This resulted in a significant decrease in H+ production from glycolysis uncoupled from glucose oxidation (2.7 +/- 0.3 and 1.9 +/- 0.3 micromol . g dry wt-1 . min-1 in control and T3-treated hearts, respectively, P < 0.05), as well as a 3.2-fold improvement in cardiac work and a 2.3-fold increase in cardiac efficiency compared with untreated postischemic hearts (P < 0.05). These data suggest that T3 can exert acute effects that improve the coupling of glycolysis to glucose oxidation, thereby decreasing H+ production and increasing cardiac efficiency as well as contractile function during reperfusion of the postischemic heart.
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PMID:Acute effects of triiodothyronine on glucose and fatty acid metabolism during reperfusion of ischemic rat hearts. 972 4

Aberrations in cell Ca2+ homeostasis have been known to parallel both changes in membrane lipid composition and aging. Previous work has shown that the lowered efficiency of work performance, which occurs in isolated hearts from rats fed a diet rich in n-6 polyunsaturated fatty acids (PUFA), relative to those fed n-3 PUFA, could be raised by mitochondrial (Mito) Ca2+ transport inhibition. We tested whether, after Ca2+-dependent stress, the Ca2+-dependent activation of pyruvate dehydrogenase (PDHA/PDHTotal) and Mito Ca2+ cycling could be manipulated by varying the ratio of n-3 to n-6 PUFA in Mito membranes in young (6 mo) and aged (24 mo) isolated rat hearts treated to n-3 or n-6 PUFA-rich diet. Inotropic stimulation by 1 microM norepinephrine (NE) of 24-mo n-6 PUFA-rich hearts elevated total Mito Ca2+ content 38% more than in 6-mo hearts (P < 0. 05). However, both the NE-induced rise in Mito Ca2+ and the difference in response between 6- and 24-mo hearts were partially abolished by n-3 PUFA treatment. NE increased the fractional activation of PDH by 44% above control levels in the 6-mo group compared with 49% in the 24-mo group after n-6 PUFA diet. However, NE stimulation of PDHA was attenuated by n-3 PUFA diet, attaining values only 29 and 23% above control levels in 6- and 24-mo mitochondria, respectively (P < 0.05). Global ischemia and reperfusion (I/R) in n-6 PUFA hearts gave rise to higher levels of total Mito Ca2+ concentration (P < 0.0001) and PDHA (P < 0.0001) compared with n-3 PUFA. Ruthenium red (3.4 microM) abolished the effects of I/R in all groups. With aging, heart Mito membrane phosphatidylcholine was increased after n-6 PUFA-rich diet (by approximately 15%, P < 0.05), whereas cardiolipin and n-3 PUFA content were diminished by 31% (P < 0.05) and 73% (P < 0.05), respectively. These effects were prevented by n-3 PUFA-rich diet. The present study, by directly manipulating the cardiac Mito membrane n-3-to-n-6 PUFA ratio, shows that the activation of Ca2+-dependent PDH can be augmented when the n-3-to-n-6 PUFA ratio is low (n-6 PUFA-rich diet; 24-mo hearts) or attenuated when this ratio is relatively high (n-3 PUFA-rich diet). We propose that one of the consequences of dietary-induced manipulation of membrane phospholipids and PUFAs may be the altered flux of Ca2+ across the Mito membrane and thus altered intramitochondrial Ca2+-dependent processes.
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PMID:PUFA and aging modulate cardiac mitochondrial membrane lipid composition and Ca2+ activation of PDH. 988 28


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