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PubMed1983

Storage of red cell concentrates in CPD-A2 for 42 and 49 days.

CPD-A2 is a modified CPD blood preservative with adenine, containing 1 1/2 times as much glucose as CPD. Units (450 ml) of blood from 21 normal donors were collected in CPD-A2 in plastic bags and held at room temperature for 8 hr. An 80% red cell concentrate was prepared and this was stored for 42 or 49 days at 4 degrees C, with the containers in either a standing or lying position. Measurements of glucose consumption, red cell ATP, and 2,3-DPG and of plasma hemoglobin, pH, Na+, and K+ were performed on all samples. The size of the "fragile tail" of osmotically fragile red cells was estimated in 12 samples. The poststorage 24 hr viability of their own stored 51Cr-tagged red cells was documented in 19 of the volunteers. At least 4 months after the original donation, a second unit of blood was collected from eight of the donors to make possible intradonor comparison of the biochemical effects of storage position. After 42 days but not after 49 days of storage, red cells in concentrates stored in the lying position had consumed more glucose and had a higher poststorage pH than did cells stored in the standing position. The poststorage 24 hr viability of red cells stored for 42 days averaged 83.6%, with all units exceeding 70% viability. At 49 days the average viability was 69.1%. Although the average viability of cells stored in the lying position for 42 days was higher than that of concentrates stored standing, the difference was not statistically significant at the 5% level. The plasma hemoglobin level showed a weak correlation with viability of stored cells. Red cell ATP levels were correlated with viability only at 42 days' and not at 49 days' storage. Concentrates of red cell collected in CPD-A2 manifested fully satisfactory viability for 42 days. At 49 days storage the results of viability studies were borderline. High plasma hemoglobin values are observed at both 42 and 49 days' storage and may limit the usefulness of red cell concentrates stored for prolonged periods of time.

2,3-Diphosphoglycerate↗
PubMed1990

Impaired mitochondrial respiration and stimulated glycolysis by m-iodobenzylguanidine (MIBG).

m-Iodobenzylguanidine (MIBG) is a functional analogue of the neurotransmitter norepinephrine. Radio-iodinated 131I-MIBG is used clinically as a tumor-targeted radiopharmaceutical agent in the diagnosis and treatment of adrenergic tumors. Native MIBG has previously been demonstrated to be cytotoxic in cultured cells and to produce anti-tumor responses in animals when non-toxic schedules are used. In this study the effect of MIBG was investigated on isolated rat liver mitochondria and on various tumor cell lines (human neuroblastoma SK-N-SH, mouse neuroblastoma N1E115 and mouse lymphosarcoma S49). Results revealed that MIBG inhibits respiration of isolated liver mitochondria at complex I of the respiratory chain, without affecting F1 ATP-ase. In cell lines, impairment of the mitochondrial respiration was evident from reduced oxygen consumption and decreased intracellular ATP levels. In response to this effect, the glycolytic flux was stimulated as shown by increased glucose consumption and lactic acid production. Cytotoxicity of MIBG was proportional to drug-induced alterations in glucose metabolism.

3-Iodobenzylguanidine↗
PubMed1989

Mitochondrial function in carbon tetrachloride-induced cirrhosis in the rat. Qualitative and quantitative defects.

Mitochondrial function is impaired in patients and experimental animals with liver cirrhosis. The relationship between mitochondrial impairment and severity of cirrhosis is unknown, however. We therefore characterized the severity of cirrhosis in rats with phenobarbital/CCl4-induced cirrhosis by the aminopyrine breath test, a microsomal function test reflecting hepatocellular mass. Mitochondrial function was evaluated by measuring oxygen consumption, enzyme activities and ATP production in mitochondria isolated from cirrhotic (N = 8) and control livers (N = 4). Oxygen consumption and mitochondrial enzyme activities calculated per liver were significantly reduced in the presence of cirrhosis. This decrease corresponded to the loss of hepatocytes calculated from the reduction in aminopyrine breath test. The effect of atractylate, oligomycin and dinitrophenol on state 3 respiration was equal between the two groups. The respiratory control ratio was significantly reduced in mitochondria from cirrhotic livers with beta-hydroxybutyrate (4.01 +/- 0.94 vs 5.45 +/- 0.40), but not with succinate as substrate. The rate of ATP production was significantly decreased in mitochondria from cirrhotic rats for both substrates. In contrast, the static head (state 4) phosphate potential was fully developed after 10 min and was equal between the two groups. We conclude that cirrhosis of the liver leads to a loss of hepatocytes which is paralleled by reduced oxygen uptake and reduced mitochondrial enzyme activities.

Adenosine Triphosphate↗
PubMed2003

Correlation between adenosine triphosphate content and apoptosis in liver of rats treated with alcohol.

BACKGROUND: Chronic alcohol consumption depresses adenosine triphosphate (ATP) synthesis and induces mitochondrial DNA (Mt-DNA) deletion. ATP content in cells may play a critical role in inducing cell death, apoptosis, or necrosis. However, it is unknown which type of cell death occurs in alcoholic liver disease. In this study, the deletions of hepatic Mt-DNA, hepatic ATP content, and the number of single-stranded DNA (ss-DNA) of hepatocytes in rats treated with ethanol were determined to elucidate the relationship among Mt-DNA deletion, ATP synthesis, and/or hepatic apoptosis. METHODS: Sixteen male Wistar rats were fed with a liquid diet containing 36% ethanol (E group) or liquid diet without ethanol (C group) for 5 weeks. Hepatic ATP content was measured and the deletions of Mt-DNA encoding complexes I, IV, and V were determined in fresh liver tissue, and ss-DNA was stained in paraffin sections. RESULTS: Fatty change was observed in the E group, but not in the C group. Hepatic ATP content in the E group was 0.44 micromol/g of liver, which was significantly lower than that in the C group (0.84 micromol/g of liver). However, no deletion of Mt-DNA encoding complexes I, IV, and V was detected in either the E or the C group. ss-DNA staining was clearly observed in the nuclei of hepatocytes in both groups. The number of ss-DNA-positive hepatocytes in the E group was 5.6 +/- 1.8/10,000 hepatocytes, which was significantly less than that in the C group: 20.6 +/- 4.8/10,000 hepatocytes. There was a positive correlation between hepatic ATP contents and the number of ss-DNA-positive cells. CONCLUSIONS: The results suggest that mitochondrial function, at least in part ATP synthesis, was depressed before the damage of Mt-DNA by chronic ethanol consumption. Chronic ethanol consumption may not be responsible for the apoptosis of hepatocytes.

Adenosine Triphosphate↗
PubMed1990

Intracellular glutathione in the protection from anoxic injury in renal proximal tubules.

Previous results (Weinberg, J. M., J. A. David, M. Abarzua, and T. Rajan. 1987. J. Clin. Invest. 80:1446-1454) have shown that GSH and glycine (GLY) are cytoprotective during anoxia when added extracellularly. The present studies investigate the role that intracellular GSH plays in this cytoprotection. Proximal renal tubules in suspension prepared with either high (11 +/- 1 nmol/mg protein) or low (6 +/- 1 nmol/mg protein) GSH contents were subjected to 40 min of anoxia and 40 min of reoxygenation. Low GSH tubules were protected from plasma membrane damage during anoxia by exogenous addition of 1 mM GSH or GLY, reducing lactate dehydrogenase (LDH) release from 42 +/- 7 to 14 +/- 1 and 10 +/- 1%, respectively. High GSH tubules were equally protected from anoxic damage without exogenous additions. Since the high GSH content approximates the in vivo values, it may be concluded that GSH may be cytoprotective during anoxia in vivo. However, it is not the intracellular GSH itself that is cytoprotective; rather, this protection resides in the ability to produce GLY, which appears to be the cytoprotective agent. Alanine was also shown to have similar cytoprotective properties, although higher concentrations were required. Sulfhydryl reducing agents such as cysteine and dithiothreitol offered less, but significant protection from anoxic damage. Protection by GSH, GLY, or alanine was not associated with higher ATP levels during anoxia. Tubules that were protected from membrane damage during anoxia recovered oxygen consumption and K and ATP contents significantly better during reoxygenation than unprotected tubules.

Adenosine Triphosphate↗
PubMed1990

Control of respiration and oxidative phosphorylation in isolated rat liver cells.

NAD(P)H fluorescence, mitochondrial membrane potential and respiration rate were measured and manipulated in isolated liver cells from fed and starved rats in order to characterize control of mitochondrial respiration and phosphorylation. Increased mitochondrial NADH supply stimulated respiration and this accounted for most of the stimulation of respiration by vasopressin and extracellular ATP. From the response of respiration to NADH it was estimated that the control coefficient over respiration of the processes that supply mitochondrial NADH was about 0.15-0.3 in cells from fed rats. Inhibition of the ATP synthase with oligomycin increased the mitochondrial membrane potential and decreased respiration in cells from fed rats, while the uncoupler carbonyl cyanide p-trifluoromethoxyphenylhydrazone had the opposite effect. There was a unique relationship between respiration and membrane potential irrespective of the ATP content of the cells indicating that phosphorylation potential controls respiration solely via phosphorylation (rather than by controlling NADH supply). From the response of respiration to the mitochondrial membrane potential (delta psi M) it was estimated that the control coefficients over respiration rate in cells from fed rats were: 0.29 by the processes that generate delta psi M, 0.49 by the process of ATP synthesis, transport and consumption, and 0.22 by the processes that cycle protons across the inner mitochondrial membrane other than via ATP synthesis (e.g. the passive proton leak). Control coefficients over the rate of mitochondrial ATP synthesis were 0.23, 0.84 and -0.07, respectively, by the same processes. The control distribution in cells from starved rats was similar.

Animals↗
PubMed1993

Kinetic analysis of cellular nucleotides correlated to growth and tPA production in perfusion cultures of human fibroblast cells.

A maximum cell density of 8 x 10(6) viable human fibroblast cells/ml was obtained on microcarriers at a perfusion rate of 0.6 mL/min-a rate which maintained a quasi-steady state. The maximum tPA production was approximately 1.2 micrograms/ml and obtained when the cell density was relatively constant during the later periods of cultivation. Specific UTP and tPA production rates had a correlation factor of 0.85, and cell growth to oxygen consumption had an 0.92 correlation factor. ATP generation was strongly correlated to glutamine consumption, with a lower correlation to oxygen utilization.

Adenosine Triphosphate↗
PubMed1996

Cellular ATP release by the cystic fibrosis transmembrane conductance regulator.

Recent studies from our laboratory indicate that members of the ATP-binding cassette (ABC) family of transporters, including P-glycoprotein and cystic fibrosis transmembrane conductance regulator (CFTR), are ATP-permeable channels. The physiological relevance of this novel transport mechanism is largely unknown. In the present study, intra- and extracellular ATP content, cellular ATP release, and O2 consumption before and after adenosine 3',5'-cyclic monophosphate (cAMP) stimulation were determined to assess the role of CFTR in the transport of ATP under physiological conditions. The functional expression of CFTR by the stable transfection of mouse mammary carcinoma cells, C1271, with human epithelial CFTR cDNA resulted in a stimulated metabolism, since both basal and cAMP-inducible O2 consumption were increased compared with mock-transfected cells. The stimulated (but not basal) O2 consumption was inhibited by diphenyl-2-carboxylic acid (DPC), a known inhibitor of CFTR. CFTR expression was also associated with the cAMP-activated and DPC-inhibitable release of intracellular ATP. The recovery of intracellular ATP from complete depletion after metabolic poisoning was also assessed under basal and cAMP-stimulated conditions. The various maneuvers indicate that CFTR may be an important contributor to the release of cellular ATP, which may help modify signal transduction pathways associated with secretory Cl- movement or other related processes. Changes in the CFTR-mediated delivery of nucleotides to the extracellular compartment may play an important role in the onset and reversal of the cystic fibrosis phenotype.

Adenosine Triphosphate↗
PubMed1985

Balanced contribution of glycolytic and adenylate pool in supply of metabolic energy in platelets.

When platelets are treated with H2O2 the metabolic ATP content decreases sharply (Holmsen, H., and Robkin, L. (1977) J. Biol. Chem. 252, 1752-1757). Here we report that the loss of metabolic energy is fully recovered in phosphorylated glycolytic intermediates. A mixture of antimycin A/2-deoxy-D-glucose/D-gluconic acid-1,5-lactone blocks mitochondrial ATP resynthesis and prevents the entry of sugars into the glycolytic sequence. The energy-rich phosphates in the adenylate and the glycolytic pool are then consumed in a specific order. First, the glycolytic pool is consumed at a rate of 4.5 mumol of ATP equivalents/min/10(11) cells, and metabolic ATP and ADP are kept stable; then the consumption of the glycolytic pool decreases and metabolic ATP and ADP are consumed, together keeping up with the same rate of energy consumption. Thrombin stimulation increases the energy consumption to about 17 mumol of ATPeq/min/10(11) cells which is now furnished by both the glycolytic and the adenylate pool, again with a preferential consumption of the former. The results show that H2O2 triggers a shift of energy-rich phosphates from the adenylate to the glycolytic pool and that the latter remains rapidly accessible to energy consumption thereby stabilizing the level of metabolic ATP. The adenylate energy charge is independent of the distribution of energy among the two pools, which extends its importance to the regulation of energy supply and demand beyond the adenylate pool.

Adenine Nucleotides↗
PubMed2006

Regulation of myocardial substrate metabolism during increased energy expenditure: insights from computational studies.

In response to exercise, the heart increases its metabolic rate severalfold while maintaining energy species (e.g., ATP, ADP, and Pi) concentrations constant; however, the mechanisms that regulate this response are unclear. Limited experimental studies show that the classic regulatory species NADH and NAD+ are also maintained nearly constant with increased cardiac power generation, but current measurements lump the cytosol and mitochondria and do not provide dynamic information during the early phase of the transition from low to high work states. In the present study, we modified our previously published computational model of cardiac metabolism by incorporating parallel activation of ATP hydrolysis, glycolysis, mitochondrial dehydrogenases, the electron transport chain, and oxidative phosphorylation, and simulated the metabolic responses of the heart to an abrupt increase in energy expenditure. Model simulations showed that myocardial oxygen consumption, pyruvate oxidation, fatty acids oxidation, and ATP generation were all increased with increased energy expenditure, whereas ATP and ADP remained constant. Both cytosolic and mitochondrial NADH/NAD+ increased during the first minutes (by 40% and 20%, respectively) and returned to the resting values by 10-15 min. Furthermore, model simulations showed that an altered substrate selection, induced by either elevated arterial lactate or diabetic conditions, affected cytosolic NADH/NAD+ but had minimal effects on the mitochondrial NADH/NAD+, myocardial oxygen consumption, or ATP production. In conclusion, these results support the concept of parallel activation of metabolic processes generating reducing equivalents during an abrupt increase in cardiac energy expenditure and suggest there is a transient increase in the mitochondrial NADH/NAD+ ratio that is independent of substrate supply.

Adenosine Diphosphate↗
PubMed1998

Interplay between cytoplasmic Ca2+ and the ATP/ADP ratio: a feedback control mechanism in mouse pancreatic islets.

In pancreatic beta cells, the increase in the ATP/ADP ratio that follows a stimulation by glucose is thought to play an important role in the Ca2+-dependent increase in insulin secretion. Here we have investigated the possible interactions between Ca2+ and adenine nucleotides in mouse islets. Measurements of both parameters in the same single islet showed that the rise in the ATP/ADP ratio precedes any rise in the cytoplasmic free-Ca2+ concentration ([Ca2+]i) and is already present during the initial transient lowering of [Ca2+]i produced by the sugar. Blockade of Ca2+ influx with nimodipine did not prevent the concentration-dependent increase in the ATP/ADP ratio produced by glucose and even augmented the ratio at all glucose concentrations which normally stimulate Ca2+ influx. In contrast, stimulation of Ca2+ influx by 30 mM K+ or 100 microM tolbutamide lowered the ATP/ADP ratio. This lowering was of rapid onset and reversibility, sustained and prevented by nimodipine or omission of extracellular Ca2+. It was, however, not attenuated after blockade of secretion by activation of alpha2-adrenoceptors. The difference in islet ATP/ADP ratio during blockade and stimulation of Ca2+ influx was similar to that observed between threshold and submaximal glucose concentrations. The results suggest that the following feedback loop could control the oscillations of membrane potential and [Ca2+]i in beta cells. Glucose metabolism increases the ATP/ADP ratio in a Ca2+-independent manner, which leads to closure of ATP-sensitive K+ channels, depolarization and stimulation of Ca2+ influx. The resulting increase in [Ca2+]i causes a larger consumption than production of ATP, which induces reopening of ATP-sensitive K+ channels and arrest of Ca2+ influx. Upon lowering of [Ca2+]i the ATP/ADP ratio increases again and a new cycle may start.

Adenosine Diphosphate↗
PubMed2006

Peroxynitrite can affect platelet responses by inhibiting energy production.

Peroxynitrite (ONOO-) strongly inhibits agonist-induced platelet responses. However, the mechanisms involved are not completely defined. Using porcine platelets, we tested the hypothesis that ONOO- reduces platelet aggregation and dense granule secretion by inhibiting energy production. It was found that ONOO- (25-300 microM) inhibited collagen-induced dense granule secretion (IC50 = 55 +/- 7 microM) more strongly than aggregation (IC(50) = 124 +/- 16 microM). The antiaggregatory and antisecretory effects of ONOO- were only slightly (5-10%) reduced by 1H-[1,2,4]-oxadiazolo-[4,3-alpha]quinoxalin-1-one (ODQ), an inhibitor of soluble guanylate cyclase. In resting platelets ONOO- (50-300 microM) enhanced glycolysis rate and reduced oxygen consumption, in a dose dependent manner. The ONOO- effects on glycolysis rate and oxygen consumption were not abolished by ODQ. The extent of glycolysis stimulation exerted by ONOO- was similar to that produced by respiratory chain inhibitors (cyanide and antimycin A) or an uncoupler (2,4-dinitrophenol). Stimulation of platelets by collagen was associated with a rise in mitochondrial oxygen consumption, accelerated lactate production, and unchanged intracellular ATP content. In contrast to resting cells, in collagen-stimulated platelets, ONOO- (200 microM) distinctly decreased the cellular ATP content. The glycolytic activity and oxygen consumption of resting platelets were not affected by 8-bromoguanosine 3',5'-cyclic monophosphate. Blocking of the mitochondrial ATP production by antimycin A slightly reduced collagen-induced aggregation and strongly inhibited dense granule secretion. Treatment of platelets with ONOO- (50-300 microM) resulted in decreased activities of NADH : ubiquinone oxidoreductase, succinate dehydrogenase and cytochrome oxidase. It is concluded that the inhibitory effect of ONOO- on platelet secretion and to a lesser extent on aggregation may be mediated, at least in part, by the reduction of mitochondrial energy production.

Animals↗
PubMed1996

Compensatory mechanisms associated with the hyperdynamic function of phospholamban-deficient mouse hearts.

Phospholamban ablation is associated with significant increases in the sarcoplasmic reticulum Ca(2+)-ATPase activity and the basal cardiac contractile parameters. To determine whether the observed phenotype is due to loss of phospholamban alone or to accompanying compensatory mechanisms, hearts from phospholamban-deficient and age-matched wild-type mice were characterized in parallel. There were no morphological alterations detected at the light microscope level. Assessment of the protein levels of the cardiac sarcoplasmic reticulum Ca(2+)-ATPase, calsequestrin, myosin, actin, troponin I, and troponin T revealed no significant differences between phospholamban-deficient and wild-type hearts. However, the ryanodine receptor protein levels were significantly decreased (25%) upon ablation of phospholamban, probably in an attempt to regulate the release of Ca2+ from the sarcoplasmic reticulum, which had a significantly higher diastolic Ca2+ content in phospholamban-deficient compared with wild-type hearts (16.0 +/- 2.2 versus 8.6 +/- 1.0 mmol Ca2+/kg dry wt, respectively). The increases in Ca2+ content were specific to junctional sarcoplasmic reticulum stores, as there were no alterations in the Ca2+ content of the mitochondria or A band. Assessment of ATP levels revealed no alterations, although oxygen consumption increased (1.6-fold) to meet the increased ATP utilization in the hyperdynamic phospholamban-deficient hearts. The increases in oxygen consumption were associated with increases (2.2-fold) in the active fraction of the mitochondrial pyruvate dehydrogenase, suggesting increased tricarboxylic acid cycle turnover and ATP synthesis. 31P nuclear magnetic resonance studies demonstrated decreases in phosphocreatine levels and increases in ADP and AMP levels in phospholamban-deficient compared with wild-type hearts. However, the creatine kinase activity and the creatine kinase reaction velocity were not different between phospholamban-deficient and wild-type hearts. These findings indicate that ablation of phospholamban is associated with downregulation of the ryanodine receptor to compensate for the increased Ca2+ content in the sarcoplasmic reticulum store and metabolic adaptations to establish a new energetic steady state to meet the increased ATP demand in the hyperdynamic phospholamban-deficient hearts.

Animals↗
PubMed1993

Mitochondrial dehydrogenase activity affects adaptation of cardiac oxygen consumption to demand.

The effect of regulation of mitochondrial dehydrogenase activities on the mean response time of mitochondrial oxygen consumption, which characterizes the delay between changes in ATP hydrolysis and changes in oxygen consumption, was investigated in isolated rabbit hearts and perfused with Tyrode solution at 28 degrees C. Perfusion with ruthenium red (RR) blocks mitochondrial calcium uptake and thus decreases mitochondrial dehydrogenase activities. Perfusion with pyruvate increases pyruvate dehydrogenase activity. The mean response time was 11.8 +/- 0.7 s (means +/- SE) during control, 12.2 +/- 1.2 s during perfusion with 0.9 microgram/ml RR, and 20.7 +/- 3.4 s during perfusion with 2.1 micrograms/ml RR. Blockade with 0.9 microgram/ml RR, which is presumably partial, did not slow the response, suggesting that mitochondrial calcium uptake may not be rate limiting. Strong blockade of mitochondrial calcium uptake increases the mean response time, presumably due to decreased calcium activation of the mitochondrial dehydrogenases. Perfusion with pyruvate significantly decreased the mean response time to 10.0 +/- 1.4 s compared with 11.9 +/- 0.7 s during perfusion with glucose. This decrease with pyruvate is not compatible with a shift to regulation by high-energy phosphates but may reflect increased mitochondrial oxidative capacity caused by increased NADH levels.

Adaptation, Physiological↗
PubMed1985

Regulation of renal ammoniagenesis in the dog with chronic metabolic acidosis: effect of a glutamine load.

We recently emphasized that ATP is an obligatory product of renal glutamine metabolism and that all cells must remain in ATP balance. Based on this, we suggested that the maximum rate of renal ammoniagenesis in dogs with chronic metabolic acidosis may be limited by the rate of ATP utilization in the kidney. Since a large infusion of glutamine led to a twofold increase in renal ammoniagenesis in acidotic dogs, we wished to evaluate the renal metabolic changes that permitted this increment within the constraints of renal ATP balance. A large glutamine infusion did not lead to an augmented rate of ATP hydrolysis because renal oxygen consumption was not increased. Two major metabolic changes could explain this stimulation while maintaining ATP balance: first, ATP production from lactate by the kidney was decreased following the glutamine infusion; second, the metabolic fate of glutamine was changed so that more ammonium per ATP was synthesized (i.e., the rates of amino acid release into the renal vein were markedly enhanced, and gluconeogenesis was now a quantitatively significant process). 3-Mercaptopicolinate, an inhibitor of phosphoenolpyruvate carboxykinase, when infused with glutamine, apparently decreased the calculated rate of gluconeogenesis as expected; however, ammonium production did not decline, because the rate of amino acid release increased further, as did the rate of oxygen consumption. Therefore, a large glutamine infusion increased renal ammoniagenesis in dogs with chronic metabolic acidosis while maintaining ATP balance, because ATP production from other substrates was decreased and because the fate of glutamine metabolism was altered in that less ATP was formed per glutamine utilized.

Acidosis↗
PubMed1978

Is the adenine nucleotide translocator rate-limiting for oxidative phosphorylation?

1. The effects of atractyloside and carboxyatractyloside (between 5 and 40mum) on O(2) uptake, glucose synthesis, urea synthesis, the adenine nucleotide content and the intracellular K(+) concentration were measured in isolated hepatocytes. 2. Urea synthesis was much less inhibited than glucose synthesis by both atractylosides. Measurements of intermediary metabolites of carbohydrate metabolism in freeze-clamped liver after injection of atractyloside into rats indicate that inhibition of gluconeogenesis is due to interference at the cytosolic reactions requiring ATP (phosphoenolpyruvate carboxykinase and 3-phosphoglycerate kinase). 3. The decrease in [ATP]/[ADP]x[P(i)] after addition of atractyloside or carboxyatractyloside was restricted to the cytosol. 4. Dihydroxyacetone can be converted either into glucose with the consumption of 2mol of ATP (per mol of glucose) or into lactate with the production of 2mol of ATP. In the presence of high concentrations of atractyloside and carboxyatractyloside more ATP was produced than was used for the synthesis of glucose from dihydroxyacetone, probably for the maintenance of intracellular [K(+)]. 5. When the rates of respiration were altered by changing substrates, the degrees of inhibition of respiration and translocation by a given concentration of the atractylosides were the same, whereas at a given concentration of HCN the degree of inhibition was high at higher initial rates, and low at lower initial rates. 6. Inhibition of a complex series of reactions by atractyloside does not necessarily indicate that the translocator is a rate-limiting step in that sequence as Th. P. M. Akerboom, H. Bookelman & J. M. Tager [(1977) FEBS. Lett.74, 50-54] assume. This point is discussed.

Adenine Nucleotides↗
PubMed1993

Acidosis slows the response of oxidative phosphorylation to metabolic demand in isolated rabbit heart.

The purpose of this study was to investigate the effect of acidosis on the mean response time of mitochondrial oxygen consumption to steps in heart rate and in left ventricular balloon volume. The mean response time may be viewed as the average delay between a change in adenosine triphosphate (ATP) hydrolysis and oxygen consumption. The mean response time is calculated by subtracting the transport time, required for diffusion of oxygen and for convective transport through the coronary vessels, from the response time measured in the coronary venous effluent. Eight isolated rabbit hearts were perfused according to Langendorff using Tyrode solution at 28 degrees C. Arterial perfusate pH was lowered from 7.30 +/- 0.03 (mean +/- SD) to 6.59 +/- 0.02 by increasing the CO2 tension. At pH 7.3 the mean response time was 12.6 +/- 1.6 s, independent of the time after isolation of the heart. During acidosis, applied 40-75 min after isolation of the heart, the mean response time was 21.4 +/- 0.7 s and increased to 32.6 +/- 4.3 s during acidosis, 85-120 min after isolation. Thus the retardation of the metabolic response by acidosis might depend on the condition of the heart. A decrease of mitochondrial ATP synthetic capacity during acidosis may contribute to the retardation of the metabolic response. Since determination of the mean response time at 37 degrees C is not yet feasible, the experiments were done at 28 degrees C. Extrapolation of our findings to 37 degrees C appears premature.

Adenosine Triphosphate↗