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PubMed1991

[Study of the pyruvate dehydrogenase complex by circular dichroism].

A comparative study of the pyruvate dehydrogenase complex and its pyruvate dehydrogenase component was carried out by using the circular dichroism method. It was found that the spectral properties of the pyruvate dehydrogenase complex are determined by those of its first component: i) the spectrum of the thiamine pyrophosphate-free pyruvate dehydrogenase complex displayed the main characteristics of the pyruvate dehydrogenase component; ii) the appearance of the charge transfer complex band during thiamine pyrophosphate saturation was revealed for the both proteins; iii) in both cases the charge transfer complex band disappeared after the interaction of the holoform with pyruvate and reappeared after the addition of dithiothreitol used as a deacetylating reagent. Coenzyme A in the same reaction selectively deacetylated the pyruvate dehydrogenase complex (but not its pyruvate dehydrogenase component). The spectral dynamics of pyruvate dehydrogenase reflects the functional changes in the enzyme active centers during the catalytic act. The similarity of the spectral behaviour of pyruvate dehydrogenase within the complex structure and in the isolated state provides support for the earlier proposed mechanism of the pyruvate dehydrogenase action and ensures a methodological basis for its direct investigation within the complex structure.

Acetylation↗
PubMed1976

Hepatic pyruvate kinase. Regulation by glucagon, cyclic adenosine 3'-5'-monophosphate, and insulin in the perfused rat liver.

A reversible interconversion of two kinetically distinct forms of hepatic pyruvate kinase regulated by glucagon and insulin is demonstrated in the perfused rat liver. The regulation does not involve the total enzyme content of the liver, but rather results in a modulation of the substrate dependence. The forms of pyruvate kinase in liver homogenates are distinguished by measurements of the ratio of the enzyme activity at a subsaturating concentration of P-enolpyruvate (1.3 mM) to the activity at a saturating concentration of this substrate (6.6 mM). A low ratio form of pyruvate kinase (ratio between 0.1 and 0.2) is obtained from livers perfused with 10(-7) M glucagon or 0.1 mM adenosine 3':5'-monophosphate (cyclic AMP). A high ratio form of the enzyme is obtained from livers perfused with no hormone (ratio = 0.35 to 0.45). The regulation of pyruvate kinase by glucagon and cyclic AMP occurs within 2 min following the hormone addition to the liver. Insulin (22 milliunits/ml) counteracts the inhibition of pyruvate kinase caused by 5 X 10(-11) M glucagon, but has only a slight influence on the enzyme properties in the absence of the hyperglycemic hormone. The low ratio form of pyruvate kinase obtained from livers perfused with glucagon or cyclic AMP is unstable in liver extracts and will revert to a high ratio form within 10 min at 37 degrees or within a few hours at 0 degrees. Pyruvate kinase is quantitatively precipitated from liver supernatants with 2.5 M ammonium sulfate. This precipitation stabilizes the enzyme and preserves the kinetically distinguishable forms. The kinetic properties of the two forms of rat hepatic pyruvate kinase are examined using ammonium sulfate precipitates from the perfused rat liver. At pH 7.5 the high ratio form of the enzyme has [S]0.5 = 1.6 +/- 0.2 mM P-enolpyruvate (n = 8). The low ratio form of enzyme from livers perfused with glucagon or cyclic AMP has [S]0.5 = 2.5 +/- 0.4 mM P-enolpyruvate (n = 8). The modification of pyruvate kinase induced by glucagon does not alter the dependence of the enzyme activity on ADP (Km is approximately 0.5 mM ADP for both forms of the enzyme). Both forms are allosterically modulated by fructose 1,6-bisphosphate, L-alanine, and ATP. The changes in the kinetic properties of hepatic pyruvate kinase which follow treating the perfused rat liver with glucagon or cyclic AMP are consistent with the changes observed in the enzyme properties upon phosphorylation in vitro by a clyclic AMP-stimulated protein kinase (Ljungström, O., Hjelmquist, G. and Engström, L. (1974) Biochim. Biophys. Acta 358, 289--298). However, other factors also influence the enzyme activity in a similar manner and it remains to be demonstrated that the regulation of hepatic pyruvate kinase by glucagon and cyclic AMP in vivo involes a phosphorylation.

Adenosine Triphosphate↗
PubMed1985

Transcriptional and post-transcriptional regulation of L-type pyruvate kinase in diabetic rat liver by insulin and dietary fructose.

Regulation of the expression of the hepatic L-type pyruvate kinase gene by insulin and dietary fructose was studied in diabetic rats. Insulin increased the levels of putative nuclear RNA precursor species of this enzyme in parallel with that of total cellular pyruvate kinase L mRNA. These changes occurred more slowly than those induced by dietary fructose. Insulin caused a 3-fold increase in transcription of the pyruvate kinase L gene after 6 h and a 6-fold increase after 16 h. The increase caused by insulin was inhibited by glucagon, but not by adrenalectomy. Cycloheximide inhibited the induction caused by insulin, suggesting that insulin may stimulate transcription of the pyruvate kinase L gene by stimulating synthesis of some unknown protein. On the other hand, feeding fructose had no effect on transcription of the pyruvate kinase L gene. We previously showed that increases in the levels of putative nuclear RNA precursor species of the pyruvate kinase L after fructose feeding preceded changes in the levels of cytosolic pyruvate kinase L mRNA (Inoue, H., Noguchi, T., and Tanaka, T. (1984) J. Biochem. (Tokyo) 96, 1457-1462). Thus, dietary fructose may increase the levels of pyruvate kinase L mRNA by stabilizing nuclear RNA species. Glucagon inhibited the increase in pyruvate kinase L mRNA caused by dietary fructose. However, plasma levels of glucagon and thyroid hormones were not decreased in diabetic rats after fructose feeding. In addition, treatment with triiodo-L-thyronine caused no change in the pyruvate kinase L mRNA level. Furthermore, adrenalectomy did not impair enzyme induction by fructose in diabetic rats. Thus, the effect of fructose on pyruvate kinase L seems to be directly on the liver.

Adrenalectomy↗
PubMed1987

Hemopoietic progenitor cells are sensitive to the cytostatic effect of pyruvate.

The addition of certain oxidizable substrates (such as pyruvate and oxalacetate) produced a marked diminution of the number of colonies formed in vitro by mouse bone marrow cells (BMC) stimulated by spleen cell-conditioned medium (SCM). Pyruvate apparently exerted an all-or-none inhibition on colony forming cells (CFCs), affecting neither the size nor morphology of detectable colonies, which were essentially composed of immature cells, neutrophils, and monocytes-macrophages. Pyruvate furthermore reduced BMC proliferation in SCM-stimulated liquid cultures, apparently without modifying the cell population's morphological profile. The effects of pyruvate on hemopoietic progenitor cells were further studied by replating aliquots of BMC liquid cultures with or without pyruvate into agar medium devoid of this substrate. Pyruvate did not interfere with the increase in CFC number observed in the controls during the first few days of incubation, indicating that CFC generation is not inhibited by this substrate. However, the plating efficiency of CFCs recovered from liquid cultures with or without pyruvate was strongly inhibited when these cells were seeded into pyruvate-containing agar plates, thus supporting the theory that CFCs generated in vitro in both conditions have the same sensitivity to pyruvate as those originally present in bone marrow. On the whole, our results indicated that the pyruvate cytostatic effect is a metabolic feature distinguishing CFCs from their progenitors. These differences are discussed in the light of the explanation advanced for the pyruvate cytostatic effect in other cell systems.

Animals↗
PubMed1986

Regulation of muscle pyruvate metabolism during exercise.

Pyruvate dehydrogenase and phosphoenolpyruvate carboxykinase are important enzymes in the regulation of muscle pyruvate metabolism and their in vitro measured activities have been studied in muscle from rested and exercised rats. In addition, the muscle concentration of metabolic intermediates associated with pyruvate metabolism has been measured after exercise. Phosphoenolpyruvate concentration was decreased to less than half the value found in rested muscle but pyruvate concentration did not change. This suggests an increase in the in vivo rate of conversion of phosphoenolpyruvate to pyruvate. Concentrations of malate and aspartate increased two- to threefold which suggests that oxaloacetate concentration was also increased. An increase in oxaloacetate availability would increase acetyl CoA metabolism and therefore would increase pyruvate dehydrogenase activity in vivo. The basal activity of pyruvate dehydrogenase measured in vitro increased approximately twofold after 2 hr of exercise and returned to control values 5 min after the cessation of exercise. Total pyruvate dehydrogenase activity (activated to the maximal extent) was not changed by exercise. Muscle PEPCK activity was also increased during exercise suggesting an increased rate of conversion of oxaloacetate to pyruvate to provide net oxidation of oxaloacetate and other citric acid cycle intermediates. Results of this study demonstrate that the rates of formation and metabolism of pyruvate are increased during exercise.

Animals↗
PubMed1993

The effect of treatment of the rat with bacterial endotoxin on gluconeogenesis and pyruvate metabolism in subsequently isolated hepatocytes.

The effect of treatment of rats with bacterial endotoxin on gluconeogenesis and the flux through pyruvate kinase, phosphoenolpyruvate carboxykinase (PEPCK), pyruvate carboxylase and pyruvate dehydrogenase (PDH) was measured in isolated hepatocytes, prepared from animals starved for 18 h, incubated in the presence of 1 mM pyruvate. The lipopolysaccharide reduced gluconeogenesis by 50% and lowered the flux through pyruvate kinase, PEPCK and pyruvate carboxylase by comparable amounts. There was no effect of endotoxaemia on PDH flux, indicating that the lowered rate of gluconeogenesis is not the result of a redistribution of pyruvate metabolism between oxidation and carboxylation. The results confirm that a stimulation of pyruvate kinase activity following treatment with lipopolysaccharide is not involved in the inhibition of gluconeogenesis, but that the effect resides at the level of phosphoenolpyruvate formation. The most favoured mechanism for the inhibition of glucose synthesis is via an inhibition of PEPCK and subsequent feedback inhibition of pyruvate carboxylase, although a secondary effect at the level of the mitochondria and pyruvate carboxylase cannot be excluded.

Animals↗
PubMed1991

Isotopic evaluation of the metabolism of pyruvate and related substrates in normal adult volunteers and severely burned children: effect of dichloroacetate and glucose infusion.

In this study we have assessed the hypothesis that there is a postreceptor defect in glucose metabolism that makes the severely burned patient unable to oxidize glucose efficiently as an energy source. The intracellular pyruvate pool was labeled by the infusion of 3-13C-lactate, and expired CO2 production and isotopic enrichment of both pyruvate and CO2 were determined to calculate the rate of pyruvate production and oxidation. 6,6-d2-Glucose and 15N-alanine were infused simultaneously to relate pyruvate kinetics and oxidation to glucose and alanine kinetics. Five normal volunteers and 10 severely burned patients (mean of 80% +/- 5% body surface burned) were studied in the basal state and during continuous (unlabeled) glucose infusion. Also, the effect of dichloroacetate, which normally stimulates pyruvate dehydrogenase activity, was assessed in both volunteers and patients. The burned patients had many of the classic metabolic responses to severe injury, including significant increases in resting energy expenditure, glucose production, and alanine release from protein breakdown. However, rather than being inhibited, the rate of pyruvate oxidation was increased approximately 300% in burned patients. Although the patients had an elevated mean concentration of lactate, stemming from increased lactate production, no deficit in pyruvate dehydrogenase activity was evident. Rather, the high rate of lactate production was apparently a consequence of the high rate of glycolysis. On the other hand, the direct pathway for synthesis of glycogen from infused glucose appeared to be impaired in burned patients. In both volunteers and patients, dichloroacetate stimulated the percent of pyruvate directed to oxidation, thereby reducing the conversion of pyruvate to other fates, including lactate. However, because there was no deficit in pyruvate dehydrogenase activity in the patients compared with normal volunteers before dichloroacetate treatment, no unique effect of dichloroacetate on glucose or protein kinetics was observed in burned patients. From these results we conclude that if there is a postreceptor defect in glucose metabolism in burned patients, it involves the pathway of direct glycogen synthesis and not the pathway of oxidation.

Absorption↗
PubMedDate not supplied

Tyrphostin 47 nonenzymatically decarboxylates [1-14C]-pyruvate.

Tyrphostins inhibit tyrosine kinases and have little effect on the activity of serine/threonine kinases. Pyruvate dehydrogenase kinase inactivates pyruvate dehydrogenase by phosphorylating serine residues within the multienzyme complex. This serine/theronine kinase represents a new family of protein kinases, and one (tyrphostin 47) of two tyrphostins tested appeared to activate the pyruvate dehydrogenase kinase as determined by [1-14C]-lactate oxidation to 14CO2. Experiments designed to determine if the tyrphostins altered pyruvate dehydrogenase activity in mitochondria prepared from rat epididymal adipocytes using [1-14C]-pyruvate as the substrate demonstrated a dose dependent increase in enzyme activity in the presence of tyrphostin 47, but not in tyrphostin 23. This apparent stimulation of pyruvate dehydrogenase activity was attributed to tyrphostin 47's ability to nonenzymatically decarboxylate [1-14C]-pyruvate, the substrate for the pyruvate dehydrogenase assay. Neither tyrphostin directly altered pyruvate dehydrogenase kinase activity. Therefore, assays utilizing [1-14C]-pyruvate and tyrphostin 47 are subject to analytical interference.

Adipocytes↗
PubMed1994

Alteration of pyruvate metabolism in African trypanosomes during differentiation from bloodstream into insect forms.

In the presence of glucose and ample oxygen, insect form African trypanosomes release pyruvate more than 100-fold more slowly than do bloodstream forms. This rate decrease could not be accounted for simply by an increased mitochondrial pyruvate oxidation rate as inhibiting mitochondrial respiration increases pyruvate efflux to rates only 2-3% of that observed for bloodstream form trypanosomes. Alternatively, decreased pyruvate efflux from insect form trypanosomes could not be accounted for by decreased pyruvate transporter activity, which, surprisingly, was nearly as high in insect form trypanosomes as reported by us earlier for bloodstream forms (J.P. Barnard, B. Reynafarje, and P.L. Pedersen (1993) J. Biol. Chem. 268, 3654-3661). Rather, the low pyruvate efflux rate appears to be due primarily to reduced levels of the enzyme pyruvate kinase, which, in contrast to conclusions of an earlier study, is readily detected in insect form trypanosomes in the absence of added activators at an activity level about 4% of that found in bloodstream forms. Insect form pyruvate kinase seems to be located in the cytosol and exhibits kinetic profiles and constants nearly identical to those reported by us earlier for the bloodstream form enzyme (J.P. Barnard, and P.L. Pedersen (1988) Mol. Biochem. Parasitol. 31, 141-148). It is suggested that the reduced levels of pyruvate kinase, and hence the reduced pyruvate efflux rates, in insect form trypanosomes result from down regulation of the gene encoding the cytosolic enzyme.

Animals↗
PubMed1976

Regulation of the pyruvate dehydrogenase activity in the isolated perfused heart of guinea-pigs.

The activity and the interconversion of the between the pyruvate after pyruvate should read: utilization in the perfused hearts and the pyruvate dehydrogenease complex has been measured in the isolated perfused working hearts of guinea-pigs. 1. The pyruvate dehydrogenase complex is transferred into the active form by high work, in anoxia, with 2,4-dinitrophenol and by perfusion without substrate. The rate of interconversion is faster in the perfused heart than in the homogenate. 2. The active form of the pyruvate dehydrogenase complex limits the pyruvate oxidation. There is a close correlation between the pyruvate utilization in the perfused hearts and the pyruvate dehydrogenase of the active form in the homogenates of the same hearts. 3. The "adenylate energy charge" of the cells is considered as the main regulating factor of the interconversion of the pyruvate dehydrogenase complex as seen in experiments with anoxia, dinitrophenol and high work. The inactivation of the pyruvate dehydrogenase complex by acetyl CoA can be overcome by decreasing ATP/ADP ratios.

Acetates↗
PubMed2003

Impaired mitochondrial pyruvate importation in a patient and a fetus at risk.

The patient was the first child of healthy consanguineous parents. She presented at birth with hypotonia, mild facial dysmorphism, periventricular cysts, marked metabolic acidosis, hyperlactacidemia with normal lactate/pyruvate molar ratios, normoglycemia, and normal ammonia. Hyperlactacidemia was severe (5-14 mmol/l) and not corrected with bicarbonate, thiamine (10 mg/d), 2-chloropropionate (100 mg/kg/d) and a ketogenic diet. Pyruvate dehydrogenase (PDHC) activity was normal in lymphocytes and fibroblasts. Functional assays were performed in digitonin-permeabilized fibroblasts to measure oxidation rates from radiolabeled pyruvate and malate. The production of [14C]acetylcarnitine or [14C]citric cycle intermediates derived from [2-14C]pyruvate as well as the release of 14CO(2) from [1-14C]pyruvate was severely impaired, whereas decarboxylation of [U-14C]malate was normal. With increasing concentrations of [1-14C]pyruvate, the patient's fibroblasts behave like control fibroblasts incubated in the presence of alpha-cyano-4-hydroxycinnamate, a specific inhibitor of mitochondrial pyruvate uptake: a progressive increase in 14CO(2) production was observed, likely due to passive diffusion of [1-14C]pyruvate through the mitochondrial membranes. Our results are consistent with a defect of mitochondrial pyruvate transport in the patient. Mutational analysis was precluded as the cDNA sequence of the pyruvate carrier has not been identified as yet in any organism. An affected fetus was recognized in a subsequent dichorionic twin pregnancy using the coupled assay measuring [2-14C]pyruvate oxidation rates on digitonin-permeabilized trophoblasts. After selective feticide, the pregnancy was uncomplicated with delivery at 37w of a healthy female, who is currently 2-month old.

Algeria↗
PubMed1994

Effect of pyruvate on oxidant injury to isolated and cellular DNA.

Drawing upon the capacity of pyruvate to detoxify H2O2, we demonstrate that pyruvate (i) protects against H2O2-dependent, hydroxyl radical-mediated degradation of isolated DNA; (ii) reduces the amount of 8-hydroxy-2-deoxyguanosine detected following oxidative injury to isolated DNA and (iii) diminishes the amounts of detectable hydroxyl radical generated by a H2O2-dependent system. Compared to mannitol, pyruvate protects weakly against oxidative degradation of DNA induced by a H2O2-independent, hydroxyl radical-generating system. The protective effects of pyruvate against H2O2-instigated DNA damage were also evinced in cells in culture exposed to H2O2. In contrast to its protective effects against H2O2-dependent injury to DNA, pyruvate failed to offer convincing protection to another intracellular, H2O2-vulnerable target, glyceraldehyde-3-phosphate dehydrogenase. The protection conferred by pyruvate to intracellular H2O2-vulnerable targets is thus influenced by the nature of the target exposed to H2O2. Pyruvate was markedly protective in a model of cytotoxicity induced by the concomitant depletion of cellular glutathione and inhibition of catalase activity; pyruvate can thus function as an intracellular antioxidant and in this latter model, no evidence of DNA damage was observed. Pyruvate, in contrast to catalase, is a potent protector against cytotoxicity induced by organic peroxides, a finding that cannot be explained by the scavenging of organic peroxides, differences in glutathione content or attenuation in oxidative injury to DNA. We conclude that while DNA damage is a key pathogenetic event in oxidative stress induced by H2O2, such nuclear changes may not universally subserve a critical role in models of H2O2-dependent cell death. We also conclude that the antioxidant capabilities of pyruvate extend beyond scavenging of H2O2 to include potent protection against cytotoxicity induced by organic peroxides.

Animals↗
PubMed1985

Influence of insulin and glucose on pyruvate catabolism in perfused rat hindlimbs.

The effects of insulin and glucose on the oxidative decarboxylation of pyruvate in isolated rat hindlimbs was studied in non-recirculating perfusion with [1-14C]pyruvate. Insulin increased the calculated pyruvate decarboxylation rate in a concentration-dependent manner. At supramaximal insulin concentrations, the calculated pyruvate decarboxylation rate was increased by about 40% in perfusions with 0.15-1.5 mM-pyruvate. Glucose up to 20 mM had no effect. In the presence of insulin and low physiological pyruvate concentrations (0.15 mM), glucose increased the calculated pyruvate oxidation. This effect was abolished by high concentrations of pyruvate (1 mM). The data provide evidence that in resting perfused rat skeletal muscle insulin primarily increased the activity of the pyruvate dehydrogenase complex. The effect of glucose was due to increased intracellular pyruvate supply.

Animals↗
PubMed1987

Characterization of the specific pyruvate transport system in Escherichia coli K-12.

A mutant of Escherichia coli K-12 lacking pyruvate dehydrogenase and phosphoenolpyruvate synthase was used to study the transport of pyruvate by whole cells. Uptake of pyruvate was maximal in mid-log phase cells, with a Michaelis constant for transport of 20 microM. Pretreatment of the cells with respiratory chain poisons or uncouplers, except for arsenate, inhibited transport up to 95%. Lactate and alanine were competitive inhibitors, but at nonphysiological concentrations. The synthetic analogs 3-bromopyruvate and pyruvic acid methyl ester inhibited competitively. The uptake of pyruvate was also characterized in membrane vesicles from wild-type E. coli K-12. Transport required an artificial electron donor system, phenazine methosulfate and sodium ascorbate. Pyruvate was concentrated in vesicles 7- to 10-fold over the external concentration, with a Michaelis constant of 15 microM. Energy poisons, except arsenate, inhibited the transport of pyruvate. Synthetic analogs such as 3-bromopyruvate were competitive inhibitors of transport. Lactate initially appeared to be a competitive inhibitor of pyruvate transport in vesicles, but this was a result of oxidation of lactate to pyruvate. The results indicate that uptake of pyruvate in E. coli is via a specific active transport system.

Alanine↗
PubMed1962

Pyruvate oxidation by Pasteurella tularensis strains of graded virulence.

Weinstein, I. (U.S. Army Chemical Corps, Fort Detrick, Frederick, Md.), M. L. Guss, and R. A. Altenbern. Pyruvate oxidation by Pasteurella tularensis strains of graded virulence. J. Bacteriol. 83:1010-1016. 1962.-The rate of oxidation of sodium pyruvate by Pasteurella tularensis was shown to be correlated with the virulence of the strain studied. No qualitative differences in cofactor requirements for or products of pyruvate oxidation were found among strains of graded virulence. The rate of pyruvate oxidation was directly related to strain virulence, whereas the endogenous respiration rate was inversely correlated with virulence. For all tested strains possessing some degree of virulence, maximal rates of pyruvate oxidation were obtained with small concentrations of pyruvate (10 to 20 mumoles), above which the oxidation rate was depressed. Small concentrations of glutamate or other dicarboxylic acids effected nonadditive stimulation (sparking) of the pyruvate oxidation rate only at pyruvate concentrations above optimal (greater than 20 mumoles). The avirulent strain 38A was unique, being characterized by a low endogenous respiration rate, a maximal rate of pyruvate oxidation at all concentrations above 20 mumoles, and the absence of glutamate sparking. Studies of cell-free extracts indicated that the differences in pyruvate oxidation among the strains may be attributed in part to variation in the properties of enzymes of the tricarboxylic acid cycle.

Citric Acid Cycle↗
PubMed1994

Measurement of pyruvate and lactate kinetics across the hindlimb and gut of anesthetized dogs.

We have developed a new model to quantify regional pyruvate and lactate transmembrane transport, shunting, exchange, production, and oxidation in vivo. The method is based on the systemic continuous infusion of pyruvate or lactate stable isotopic carbon tracers and the measurement of pyruvate and lactate enrichment and concentration in the artery and vein of that region (e.g., leg or gut), the pyruvate and lactate enrichment of intracellular free water in the tissue as measured by biopsy, and the rate of blood flow through the tissue. The purpose of the experiment was to measure the pyruvate and lactate kinetics in leg muscle and gut in anesthetized dogs (n = 6). The transmembrane transport and degree of shunting of pyruvate and lactate were comparable in muscle and gut. When modified for substrate inflow, interconversion between pyruvate and lactate took place at a rate twice as fast in muscle as in the gut, and production and oxidation of pyruvate was approximately 50% greater in muscle than in the gut. Thus our new model enables quantitation of many aspects of lactate and pyruvate kinetics. We conclude that in anesthetized animals the muscle is the tissue most responsible for whole body peripheral pyruvate and lactate kinetics.

Anesthesia↗
PubMed1995

Lactate and pyruvate isotopic enrichments in plasma and tissues of postabsorptive and starved rats.

It has been proposed that plasma pyruvate isotopic enrichment (IE) during infusion of labeled lactate could be used to estimate the intracellular IE of lactate and pyruvate and thus to calculate their turnover rate. We determined the relations of plasma and tissue IE of lactate and pyruvate in anesthetized rats infused with [3-13C]lactate in an artery and sampled from a vein (A-V mode) or infused in a vein and sampled from an artery (V-A mode). In both groups of rats, the ratio of tissue to plasma lactate IE was < 1 with large differences between tissues: the highest ratio was observed in heart and the lowest in soleus. With the exception of liver, this ratio was higher in the A-V than in the V-A mode. Pyruvate IE was lower than lactate IE in tissues, with a few exceptions, and in plasma. This ratio of pyruvate to lactate IE was approximately 0.70 in plasma in A-V and V-A modes. Moreover pyruvate IE was also always higher in plasma than in tissues. This seemingly surprising result could be explained by the production of labeled pyruvate from labeled lactate inside the circulation by erythrocytes, because we observed a rapid isotopic equilibrium between lactate and pyruvate in blood "in vitro." Apparent lactate turnover was higher in the A-V than in the V-A mode when it was calculated using lactate as well as pyruvate IE. Therefore plasma pyruvate IE cannot be used in rats to estimate tissue IE and did not reconcile turnover rates measured using the A-V or V-A mode.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Pyruvate and lactate metabolism in the in vivo dog heart.

Pyruvate increases the phosphorylation potential in perfused heart to a greater extent than the closely correlated substrate L-lactate. Therefore, metabolism of these compounds was studied in the myocardium of intact dogs. Phosphocreatine/ATP was increased 23% at 5.3 mM plasma pyruvate but was not significantly increased by lactate except at the highest concentration (17.5 mM in blood). Calculated [ADP] fell during pyruvate infusion from 51.5 +/- 2.0 to 38.6 +/- 3.3 microM but did not change significantly during lactate infusion. Intracellular free [Mg2+] fell from 705 +/- 53 to 498 +/- 30 microM at the highest pyruvate infusion and from 692 +/- 112 to 417 +/- 19 microM with lactate infusion. Extraction of both substrates was linear at low concentrations, reaching 0.56 mumol lactate.min-1.g wet wt-1 at 17.5 mM blood lactate and 0.58 mumol pyruvate.min-1.g wet wt-1 at 5.3 mM plasma pyruvate. Therefore, lactate uptake was almost five times lower than pyruvate uptake at similar concentrations. Elevated pyruvate (> 3 mM) resulted in almost complete inhibition of net lactate uptake. Infused [3-13C]lactate or -pyruvate gave rise to labeled glutamate and alanine in vivo, but labeled lactate was not visible when [3-13C]pyruvate was the substrate. The 13C enrichment of myocardial lactate was similar to alanine and acetyl CoA with infused [3-13C]lactate but was only one-half that of alanine and acetyl CoA when [3-13C]-pyruvate was the substrate, indicating a possible inhibition of lactate dehydrogenase.

Animals↗