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PubMed1981

Biochemical mechanism of infarct size reduction by pyruvate.

We have explored the biochemical mechanism of the infarct size reduction found after intracoronary pyruvate infusion. Using the double infarct model, we simultaneously produced in nine dogs a control- and a therapy-infarct and compared the infarct sizes in each dog after 90 min of occlusion and 90 min of reflow. Intracoronary pyruvate reached the therapy infarct only by way of collaterals but had no access to the control infarct. Tissue levels of reduced nicotinamide dinucleotide (NADH) were measured in control-normal-, therapy-normal-, control-ischaemic-and pyruvate-treated ischaemic areas. In all nine dogs we found a significant reduction in infarct size and NADH levels in the pyruvate-treated areas. Therapy-normal NADH levels fell to 30+/-10% (mean+/-SD) of control-normal levels and therapy-ischaemic NADH levels to 26+/-17% of control-ischaemic levels. We assumed that the infused pyruvate was converted to lactate and at the same time NAD was generated from NADH. Thereby the blockage of glyceraldehyde-3-phosphate-dehydrogenase (GAPDH) by high NADH/NAD-ratios in ischaemic myocardium should be moderated, and ATP production by anaerobic glycolysis stimulated. These small amounts of ATP may be sufficient to guarantee membrane integrity over 90 min of ischaemia and so diminish its harmful effects on the myocardium.

Adenosine Triphosphate↗
PubMed1993

The effects of exogenous lactate and pyruvate on the recovery of coronary flow in the rat heart after ischaemia.

OBJECTIVE: The effect of exogenous lactate and pyruvate on the recovery of coronary flow (total, regional) after ischaemia as a function of the duration of ischaemia was evaluated. METHODS: Isolated, ejecting rat hearts were subjected to ischaemia for 15, 30, or 45 minutes. Glucose (11 mM) was present as the basal substrate in the perfusion medium and lactate (5 mM) or pyruvate (5 mM) was added as the cosubstrate. Flow variables were measured by the timed collection of coronary effluents and by the radioactive microsphere technique. RESULTS: In the lactate perfused hearts, reactive hyperaemia was present after 15 minutes but absent after 30 and 45 minutes of ischaemia. Total coronary flow was significantly reduced after 45 minutes of ischaemia. Transmural flow was impaired after 15, 30, and 45 minutes of ischaemia in the lactate perfused hearts, -that is, flow in the inner layers of the left ventricle was transiently reduced after 15 minutes and remained continuously depressed after 30 and 45 minutes of ischaemia. The pyruvate perfused hearts showed reactive hyperaemia after 15 and 30 minutes of ischaemia. After 45 minutes total coronary flow was reduced below the value before ischaemia, and in particular, the inner layers of the left ventricle were severely deprived of flow as in lactate perfused hearts. When neither lactate nor pyruvate was added to the perfusion medium (containing glucose), impairment of coronary flow in the inner layers of the left ventricle was only transiently obvious after 30 and 45 minutes of ischaemia. Impaired perfusion of the inner layers during reperfusion resulted in delayed washout of lactate dehydrogenase. CONCLUSIONS: Exogenous substrates modify the recovery of flow after ischaemia. In the presence of exogenous lactate, severe disturbances of flow are already obvious after 30 minutes of ischaemia in the inner layers of the left ventricle. Exogenous pyruvate delays impairment of flow in the inner layers compared with exogenous lactate.

Animals↗
PubMed1994

Effects of lactate and pyruvate on glucose deprivation in rat hippocampal slices.

Rat hippocampal slices were used to evaluate the effects of glucose deprivation and the ability of lactate or pyruvate to preserve histological integrity and synaptic function. Dark cell changes were observed during 180 min incubations in glucose-free solutions. These changes were blocked by substituting 10 mM lactate or pyruvate for glucose during the incubation. Excitatory postsynaptic potentials disappeared during 60 min of glucose deprivation but were restored by subsequent introduction of glucose, lactate or pyruvate. Incubation of slices with iodoacetate revealed a distinct pattern of damage that was blocked completely by pyruvate and partially by lactate. These results indicate that exogenous pyruvate and lactate can serve as energy substrates in the hippocampus when glucose is unavailable or glycolytic metabolism is impaired.

Animals↗
PubMed2006

Phosphoenolpyruvate synthetase and pyruvate, phosphate dikinase of Thermoproteus tenax: key pieces in the puzzle of archaeal carbohydrate metabolism.

The interconversion of phosphoenolpyruvate and pyruvate represents an important control point of the Embden-Meyerhof-Parnas (EMP) pathway in Bacteria and Eucarya, but little is known about this site of regulation in Archaea. Here we report on the coexistence of phosphoenolpyruvate synthetase (PEPS) and the first described archaeal pyruvate, phosphate dikinase (PPDK), which, besides pyruvate kinase (PK), are involved in the catalysis of this reaction in the hyperthermophilic crenarchaeote Thermoproteus tenax. The genes encoding T. tenax PEPS and PPDK were cloned and expressed in Escherichia coli, and the enzymic and regulatory properties of the recombinant gene products were analysed. Whereas PEPS catalyses the unidirectional conversion of pyruvate to phosphoenolpyruvate, PPDK shows a bidirectional activity with a preference for the catabolic reaction. In contrast to PK of T. tenax, which is regulated on transcript level but exhibits only limited regulatory potential on protein level, PEPS and PPDK activities are modulated by adenosine phosphates and intermediates of the carbohydrate metabolism. Additionally, expression of PEPS is regulated on transcript level in response to the offered carbon source as revealed by Northern blot analyses. The combined action of the differently regulated enzymes PEPS, PPDK and PK represents a novel way of controlling the interconversion of phosphoenolpyruvate and pyruvate in the reversible EMP pathway, allowing short-term and long-term adaptation to different trophic conditions. Comparative genomic analyses indicate the coexistence of PEPS, PPDK and PK in other Archaea as well, suggesting a similar regulation of the carbohydrate metabolism in these organisms.

Amino Acid Sequence↗
PubMed1975

Effect of glutamate on the control of fatty-acid synthesis in white adipose tissue of the rat. Inhibition of pyruvate dehydrogenase.

Glutamate (5mM) inhibited glucose conversion to fatty acids by approximately one-third in adipocytes from fed rats. This inhibition was significantly less in the pressence of pyruvate or 2-oxoglutarate. After incubation of adipose tissue from fed rats with glucose and insulin, pyruvate dehydrogenase activity was 180 plus or minus 17 mU/g wet weight. Addition of glutamine to the incubation medium decreased this activity significantly (118 plus or minus 14 mU/g wet weight). This inhibition by glutamate was also diminished when 2-oxoglutarate or pyruvate were present. Glutamate added to homohentates of adipose tissue had no effect on the activation of pyruvate dehydrogenase by Mg-2+. However, glutamate inhibited the active form of the enzyme and enhanced the rate of inactivation of the enzyme complex by ATP and Mg-2+. Aminooxyacetate, a transaminase inhibitor, did not reverse the effects of glutamate on pyruvate dehydrogenase nor fatty acid synthesis.

Adipose Tissue↗
PubMed1980

Pyruvate carboxylase and propionyl-CoA carboxylase as anaplerotic enzymes in skeletal muscle mitochondria.

Oxygen uptake in skeletal muscle mitochondria respiring on pyruvate or on acetylcarnitine plus propionylcarnitine is stimulated 3--4-fold by bicarbonate. The stimulation is highly dependent on ATP. The respiration rate obtained amounts to 1/4-1/3 of the rate obtained with pyruvate-malate in the presence of ADP. With decreasing ATP/ADP ratios in the medium, a decreasing stimulation by bicarbonate is obtained. Similar results were obtained with heart mitochondria. With ATP added, a pyruvate-dependent build up of citric acid cycle intermediates takes place in incubations with skeletal muscle mitochondria amounting to about 0.5 nmol x min-1 x mg protein-1. In 14CO2-fixation experiments, the activity of pyruvate carboxylase (EC 6.4.2.1) amounts to about 3 nmol x min-1 x mg protein-1 under similar conditions. With propionylcarnitine plus acetylcarnitine a similar stimulation of respiration and fixation of bicarbonate is observed. In this case the respiration and the propionyl-CoA carboxylase (EC 6.4.1.3) is less inhibited by ADP. The results are discussed in relation to the regulation of the level of citric acid cycle intermediates in muscle tissues. It is concluded that pyruvate carboxylase is an important anaplerotic enzyme in skeletal muscle mitochondria.

Acetylcarnitine↗
PubMed1985

Component X. An immunologically distinct polypeptide associated with mammalian pyruvate dehydrogenase multi-enzyme complex.

The mammalian pyruvate dehydrogenase multi-enzyme complex contains a tightly-associated 50 000-Mr polypeptide of unknown function (component X) in addition to its three constituent enzymes, pyruvate dehydrogenase (E1), lipoate acetyltransferase (E2) and lipoamide dehydrogenase (E3) which are jointly responsible for production of CoASAc and NADH. The presence of component X is apparent on sodium dodecyl sulphate/polyacrylamide gel analysis of the complex, performed in Tris-glycine buffers although it co-migrates with the E3 subunit on standard phosphate gels run under denaturing conditions. Refined immunological techniques, employing subunit-specific antisera to individual components of the pyruvate dehydrogenase complex, have demonstrated that protein X is not a proteolytic fragment of E2 (or E3) as suggested previously. In addition, anti-X serum elicits no cross-reaction with either subunit of the intrinsic kinase of the pyruvate dehydrogenase complex. Immune-blotting analysis of SDS extracts of bovine, rat and pig cell lines and derived subcellular fractions have indicated that protein X is a normal cellular component with a specific mitochondrial location. It remains tightly-associated with the 'core' enzyme, E2, on dissociation of the complex at pH 9.5 or by treatment with 0.25 M MgCl2. This polypeptide is not released to any significant extent from E2 by p-hydroxymercuriphenyl sulphonate, a reagent which promotes dissociation of the specific kinase of the complex from the 'core' enzyme. Incubation of the complex with [2-14C]pyruvate in the absence of CoASH promotes the incorporation of radio-label, probably in the form of acetyl groups, into both E2 and component X.

Animals↗
PubMed1989

Thermodynamic nonideality in enzyme catalysis. Effect of albumin on the reduction of pyruvate by lactate dehydrogenase.

The enhanced catalytic reduction of pyruvate by rabbit muscle lactate dehydrogenase that results from the addition of serum albumin [Nichol, L. W., Sculley, M. J., Ward, L. D. & Winzor, D. J. (1983) Arch. Biochem. Biophys. 222, 574-581] is shown to emanate solely from an increase in maximal velocity, there being no discernible effect of this inert space-filling macromolecular solute on the Michaelis constant for either pyruvate or NADH. As part of the search for a mechanistic explanation of this kinetic phenomenon, the space-filling effects of albumin have been used to eliminate the possibility that the increase in sedimentation coefficient of lactate dehydrogenase effected by inclusion of oxamate with enzyme-NADH complex reflects preferential binding of this pyruvate analog to a more compact isomeric state of the binary complex. The enzyme kinetic results are therefore considered in terms of a reaction scheme entailing gross conformational changes during the formation of ternary enzyme-NADH-pyruvate complex and its isomerization to an activated transition state. The experimentally observed insensitivity of the Michaelis constant for pyruvate to albumin concentration is in keeping with theoretical prediction, but incorporation of the measured extent of maximal velocity enhancement into the kinetic model leads to a predicted volume for the fully saturated transition-state complex that is far too small to be experimentally feasible. A more complex mechanistic model involving additional isomerizations of enzyme-substrate species is thus required to achieve quantitative description of the albumin effect solely in terms of thermodynamic nonideality.

Kinetics↗
PubMed1993

Supersensitivity to beta-adrenoceptor stimulation evoked in cultured neonatal rat heart myocytes by L(+)-lactate and pyruvate.

1. Cells from the ventricles of newborn rats were cultured for 8 days in flasks attached to a rocker apparatus to ensure an adequate oxygen supply. 2. The rocked cultures, which had previously been found to be low in lactate and subsensitive to the positive chronotropic action of the beta-adrenergic agonist isoprenaline (ISO; EC50 of (+/-)-ISO around 7 x 10(-7) M), became resensitized and even highly supersensitive to the catecholamine upon treatment with 3 mM L(+)-lactate or 1 mM pyruvate. 3. The resulting concentration-response curves were anomalous in that they extended over 8 log units, with a threshold at about 10(-13) M, but with little or no change in the height and the position of the maximum (at 10(-5) M). The EC50 values and 95% confidence intervals were 2.4 (1.9-3.0) and 5.4 (4.9-6.0) x 10(-11) M, respectively, for the lactate- and pyruvate-induced components of the chronotropic response to (+/-)-ISO. 4. The supersensitive portion of the ISO concentration-response curve was abolished by (-)-propranolol (10(-6) M), indicating that it was due to beta-adrenoceptor stimulation. 5. The cultured heart cells had to be incubated with L(+)-lactate or pyruvate for a minimum of 45 min before an increase in sensitivity to ISO became apparent. This latency was not due to a requirement for protein synthesis. 6. The adenosine-3',5'-monophosphate (cAMP) response to ISO was not noticeably altered by lactate, but (+/-)-ISO, which at 10(-8) M had no effect on the activation state of cAMP-dependent protein kinase (PKA), caused a significant increase in the activity of the enzyme following a 2-h exposure of the cells to 3 mM L(+)-lactate. 7. alpha-cyanocinnamate, an inhibitor of transmembrane transport of lactate and pyruvate, severely inhibited the utilization of L-[U-14C] lactate by the cultured cells at a concentration (5 microM) that eliminated the lactate-evoked potentiation of the chronotropic action of ISO without significantly affecting its unpotentiated action. 8. The beat-accelerating action of the phosphodiesterase inhibitor 3-isobutyl-l-methylxanthine (IBMX) and the lipophilic N6,2'-O-dibutyryl derivative of cAMP (dbcAMP), both of which are capable of elevating myocardial cAMP levels, was not potentiated by 1 mM pyruvate. 9. The question is raised, whether accumulation of lactate, a biochemical hallmark of anaerobiosis, might be a factor in some of the catecholamine-triggered events occurring in acute myocardial ischaemia and infarction.

1-Methyl-3-isobutylxanthine↗
PubMed1982

Pathophysiology of metabolic acidosis: effect of low pH on the hepatic uptake of lactate, pyruvate and alanine.

The uptake of lactate, pyruvate and alanine in perfused rat liver was investigated under normal perfusion conditions (pH 7.4, PCO2 40 mmHg) and under conditions mimicking partially compensated metabolic acidosis (pH 6.9, PCO2 20 mmHg). At 1 mM lactate as well as 10 mM lactate in the medium a lowering of pH from 7.4 to 6.9 did not affect the lactate plus pyruvate uptake. A significant effect of the low pH was seen on pyruvate uptake which at 1 mM lactate was increased from 0.027 +/- 0.008(4) mumol/min per g liver at normal pH to 0.084 +/- 0.013(4) at low pH. At 10 mM lactate the liver produced pyruvate, but the production was significantly reduced by a lowering of the pH, being 0.45 +/- 0.13(8) mumol/min per g liver at pH 7.4 and 0.22 +/- 0.06(4) at pH 6.9. THe counterbalancing changes in lactate metabolism were too small to attain statistical significance. The stimulation of gluconeogenesis by an increase in FFA from 0 to 1 mM in the medium was unaffected by pH. Alanine uptake was decreased from 0.48 +/- 0.05(6) to 0.39 +/- 0.07(3) by lowering the pH from 7.4 to 6.9. We conclude that metabolic acidosis does not in itself inhibit the capacity of the perfused rat liver to remove lactate and pyruvate from the blood. If the same is true in man, no beneficial effect of bicarbonate treatment on lactate clearance in patients with lactic acidosis should be expected.

Acidosis↗
PubMed1997

Regulation of pyruvate carboxylase in Rhizobium etli.

Pyruvate carboxylase (PYC) is a biotin-dependent enzyme catalyzing the anaplerotic conversion of pyruvate to oxaloacetate in Rhizobium etli strain CE3. A pyc::Tn5 mutant had severely reduced growth, or failed to grow on sugars, three-carbon organic acids or glycerol, consistent with these substrates being metabolized via pyruvate. Transconjugants expressing a pyc::beta-glucuronidase gene fusion had slightly increased apparent pyc transcription during growth on pyruvate as compared to succinate, similar to the modest carbon source dependent changes in PYC activity reported previously. Biotin supplementation of cultures growing on pyruvate dramatically increased PYC activity but not apparent pyc transcription. Bacteroids isolated from bean nodules did not contain detectable PYC activity while apparent pyc transcription occurred at a moderate level.

Bacterial Proteins↗
PubMed2006

Antiparasitic drug nitazoxanide inhibits the pyruvate oxidoreductases of Helicobacter pylori, selected anaerobic bacteria and parasites, and Campylobacter jejuni.

Nitazoxanide (NTZ) exhibits broad-spectrum activity against anaerobic bacteria and parasites and the ulcer-causing pathogen Helicobacter pylori. Here we show that NTZ is a noncompetitive inhibitor (K(i), 2 to 10 microM) of the pyruvate:ferredoxin/flavodoxin oxidoreductases (PFORs) of Trichomonas vaginalis, Entamoeba histolytica, Giardia intestinalis, Clostridium difficile, Clostridium perfringens, H. pylori, and Campylobacter jejuni and is weakly active against the pyruvate dehydrogenase of Escherichia coli. To further mechanistic studies, the PFOR operon of H. pylori was cloned and overexpressed in E. coli, and the multisubunit complex was purified by ion-exchange chromatography. Pyruvate-dependent PFOR activity with NTZ, as measured by a decrease in absorbance at 418 nm (spectral shift from 418 to 351 nm), unlike the reduction of viologen dyes, did not result in the accumulation of products (acetyl coenzyme A and CO(2)) and pyruvate was not consumed in the reaction. NTZ did not displace the thiamine pyrophosphate (TPP) cofactor of PFOR, and the 351-nm absorbing form of NTZ was inactive. Optical scans and (1)H nuclear magnetic resonance analyses determined that the spectral shift (A(418) to A(351)) of NTZ was due to protonation of the anion (NTZ(-)) of the 2-amino group of the thiazole ring which could be generated with the pure compound under acidic solutions (pK(a) = 6.18). We propose that NTZ(-) intercepts PFOR at an early step in the formation of the lactyl-TPP transition intermediate, resulting in the reversal of pyruvate binding prior to decarboxylation and in coordination with proton transfer to NTZ. Thus, NTZ might be the first example of an antimicrobial that targets the "activated cofactor" of an enzymatic reaction rather than its substrate or catalytic sites, a novel mechanism that may escape mutation-based drug resistance.

Acetyl Coenzyme A↗
PubMed2001

Efficient homolactic fermentation by Kluyveromyces lactis strains defective in pyruvate utilization and transformed with the heterologous LDH gene.

A high yield of lactic acid per gram of glucose consumed and the absence of additional metabolites in the fermentation broth are two important goals of lactic acid production by microrganisms. Both purposes have been previously approached by using a Kluyveromyces lactis yeast strain lacking the single pyruvate decarboxylase gene (KlPDC1) and transformed with the heterologous lactate dehydrogenase gene (LDH). The LDH gene was placed under the control the KlPDC1 promoter, which has allowed very high levels of lactate dehydrogenase (LDH) activity, due to the absence of autoregulation by KlPdc1p. The maximal yield obtained was 0.58 g g(-1), suggesting that a large fraction of the glucose consumed was not converted into pyruvate. In a different attempt to redirect pyruvate flux toward homolactic fermentation, we used K. lactis LDH transformant strains deleted of the pyruvate dehydrogenase (PDH) E1alpha subunit gene. A great process improvement was obtained by the use of producing strains lacking both PDH and pyruvate decarboxylase activities, which showed yield levels of as high as 0.85 g g(-1) (maximum theoretical yield, 1 g g(-1)), and with high LDH activity.

Culture Media↗
PubMed1970

Characterization and properties of the pyruvate phosphorylation system of Acetobacter xylinum.

The enzyme responsible for the direct phosphorylation of pyruvate during gluconeogenesis in Acetobacter xylinum has been purified 46-fold from ultrasonic extracts and freed from interfering enzyme activities. The enzyme was shown to catalyze the reversible Mg(2+) ion-dependent conversion of equimolar amounts of pyruvate, adenosine triphosphate (ATP), and orthophosphate (P(i)) into phosphoenolpyruvate (PEP), adenosine monophosphate (AMP), and pyrophosphate (PP). The optimal pH for PEP synthesis was pH 8.2; for the reversal it was pH 6.5. The ratio between the initial rates of the reaction in the forward and reverse directions was 5.1 at pH 8.2 and 0.45 at pH 6.5. The apparent K(m) values of the components of the system in the forward reaction were: pyruvate, 0.2 mm; ATP, 0.4 mm; P(i), 0.8 mm; Mg(2+), 2.2 mm; and for the reverse reaction: PEP, 0.1 mm; AMP, 1.6 mum; PP, 0.067 mm; Mg(2+), 0.87 mm. PEP formation was inhibited by AMP and PP. The inhibition by AMP was competitive with regard to ATP (K(i) = 0.2 mm). The reverse reaction was inhibited competitively by ATP and noncompetitively by pyruvate. The enzyme was strongly inhibited by p-hydroxymercuribenzoate. The inhibition was reversed by dithiothreitol and glutathione. The properties of the enzyme are discussed in relation to the regulation of the opposing enzymatic activities involved in the interconversion of PEP and pyruvate in A. xylinum.

Adenosine Triphosphate↗
PubMed1978

Reduction of nicotinamide adenine dinucleotide by pyruvate:lipoate oxidoreductase in anaerobic, dark-grown Rhodospirillum rubrum mutant C.

Cell extracts from fermentatively grown Rhodospirillum rubrum reduced about 80 nmol of nicotinamide adenine dinucleotide (NAD) per mg of protein per min under anaerobic conditions with sodium pyruvate. The reaction was specific for pyruvate and NAD; NAD phosphate was not reduced. Results indicated that pyruvate-linked NAD reduction occurred via pyruvate:lipoate oxidoreductase. The reaction required catalytic amounts of both coenzyme A and thiamine pyrophosphate. Addition of sodium arsenite inhibited enzyme activity by 90%. Pyruvate:lipoate oxidoreductase was the only system detected in anaerobic, dark-grown R. rubrum cell extracts which operated to produce reduced NAD. The low activity of the enzyme system suggested that it was not quantitatively important in ATP formation.

Anaerobiosis↗
PubMed1991

Pyruvate carboxylation prevents the decline in contractile function of rat hearts oxidizing acetoacetate.

Acetoacetate, when present as the only fuel for respiration in rat hearts, causes an impairment in contractile function that is reversible with the addition of substrates that can contribute to anaplerosis. To determine the importance of pyruvate carboxylation via NADP(+)-dependent malic enzyme on metabolism and function in hearts oxidizing acetoacetate, isolated working rat hearts were perfused with [1-14C]pyruvate and acetoacetate. While the cardiac power output after 60 min of perfusion in hearts utilizing acetoacetate alone had fallen to 44% of the initial value, the addition of pyruvate resulted in a stable performance with no fall in the work output. When hydroxymalonate, an inhibitor of NADP(+)-dependent malic enzyme and malate dehydrogenase, was added to the two substrates, function at 60 min was similar to the value for hearts oxidizing acetoacetate alone. Measurements of the specific activities of malate, aspartate, and citrate confirm inhibition of both pyruvate carboxylation and malate oxidation. The findings are consistent with a mechanism in which the enrichment of malate by pyruvate improves function by increasing the production of reducing equivalents by the malate dehydrogenase and the isocitrate dehydrogenase reactions increase flux through the span of the tricarboxylic acid cycle from malate to 2-oxoglutarate. The present study demonstrates the physiological importance of anaplerotic pathways in maintaining contractile function in the heart.

Acetoacetates↗
PubMed1999

Cytosolic redox state mediates postischemic response to pyruvate dehydrogenase stimulation.

Augmented pyruvate oxidation via pharmacological stimulation of pyruvate dehydrogenase (PDH) during reperfusion has been related to improved recovery of postischemic hearts independent of glycolytic activity. This study examined recovery of postischemic rabbit hearts during activation of PDH with dichloroacetate (DCA) in the presence of lactate, as a source of pyruvate, to determine the response to substrate-dependent changes in cytosolic redox state. After 10 min of ischemia, isolated hearts were reperfused with either 2.5 mM or 0. 5 mM pyruvate (Pyr) or 2.5 mM lactate (Lac), with or without 5 mM DCA. (13)C-enriched substrates allowed NMR assessment of metabolic perturbations. During normal perfusion, Pyr and Lac supported similar mechanical work. Increasing Pyr oxidation restored postischemic rate-pressure product to 82 +/- 4 and 88 +/- 6% of preischemic values during reperfusion with 2.5 and 0.5 mM Pyr, respectively, vs. 61 +/- 6 and 45 +/- 14% for untreated 2.5 and 0.5 mM Pyr, respectively (P < 0.05). In contrast, increasing Lac oxidation did not benefit recovery of RPP in untreated (44 +/- 7%) vs. DCA-treated 36 +/- 4% hearts. Thus the benefit of PDH activation for contractile recovery of postischemic hearts is mediated by the source of pyruvate, which also influences cytosolic redox state.

Animals↗
PubMed1993

Effects of insulin, glucose analogues, and pyruvate on vascular responses to anoxia in isolated ferret lungs.

In isolated ferret lungs, the vasopressor response to anoxia is characterized by an intense initial vasoconstriction, followed by marked vasodilation. This hypoxic pulmonary vasodilation (HPVD) is inhibited by perfusate glucose concentration > or = 15 mM. To determine whether this inhibition of HPVD was mediated by an effect of glucose transport or a product of glucose metabolism beyond pyruvate, we studied the effects of 5 mM glucose + insulin, transportable but nonmetabolizable analogues of glucose, and pyruvate on the pulmonary vascular response to anoxia. Isolated ferret lungs were ventilated with 28% O2 at constant flow. Perfusate glucose concentration was allowed to fall spontaneously. Thirty-minute anoxic exposures were performed at 60, 120, and 180 min of perfusion. Before the third anoxic exposure 15 mM glucose, 15 mM sucrose, 5 mM glucose (with 10 mM sucrose) + 10 mU/ml insulin, 15 mM 3-O-methylglucose (3-O-MG), or 15 mM alpha-methylglucose (alpha-MG) was added to the perfusate and vasomotor responses recorded. In another series of experiments, 15 mM pyruvate was added to the preparation at the beginning of perfusion. Peak vasoconstrictor responses were not different among groups. HPVD was greater in sucrose, insulin, 3-O-MG, alpha-MG, and pyruvate lungs than in high glucose lungs. These results suggest that glucose transport or a product of glucose metabolism beyond pyruvate was not responsible for inhibiting HPVD. We speculate that hyperglycemia inhibits HPVD by increasing production of ATP from the glycolytic pathway and that this ATP inhibits ATP-dependent K+ channels.

Animals↗