[In vitro consumption of glucose and ATP synthesis in brain tissue in animals in shock].
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Adenosine Triphosphate↗
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[The effect of lipid emulsions on blood platelets. 3. Behavior of ATP, glycogen and glucose consumption].
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Adenosine Triphosphate↗
Nucleotide requirement and effects of fatty acids on protein synthesis and degradation in brown adipose tissue mitochondria.
The objective of this work was to evaluate whether changes in respiratory status of isolated brown-fat mitochondria influence synthesis and degradation of proteins within the organelles. Mitochondrial protein synthesis is subject to regulation, as a 24-h fast in mice reduced [35S]methionine incorporation without affecting the stability of the newly synthesized proteins. Proteins synthesized in isolated mitochondria were labile and degraded in a process stimulated by ATP. ATP hydrolysis was required within the organelle, as ATP-stimulated protein breakdown was inhibited by atractyloside, an inhibitor of adenine nucleotide transport, and by arsenate and vanadate, which inhibit ATPases. Additions of ATP and ADP were equally effective at reducing mitochondrial oxygen consumption. However, ATP added exogenously was better at supporting protein synthesis and degradation than ATP generated by oxidative phosphorylation when mitochondria were incubated with ADP, substrates, and Pi. GDP also reduced oxygen consumption and stimulated degradation of mitochondrial translation products. Addition of fatty acids in the presence or absence of carnitine-CoA increased mitochondrial respiration but had no effect on protein synthesis or degradation. Addition of carbonyl cyanide m-chlorophenylhydrazone (mCCP) had no effect on ATP-stimulated protein degradation. These results indicate that synthesis and stability of mitochondrial translation products are not significantly influenced by changes in the activity of the uncoupling protein brought about by additions of adenine nucleotides and fatty acids.
Adenosine Triphosphate↗
Stimulation of mitochondrial oxygen consumption in isolated cardiomyocytes after hypoxia-reoxygenation.
An increase in mitochondrial matrix free calcium has been shown to occur during oxygen and substrate deprivation of the perfused heart which predisposes to calcium overload and inhibition of mitochondrial function on reoxygenation. In the current study we have assessed the effect of substrate free hypoxia on mitochondrial oxygen consumption and ATP synthesis in isolated rat cardiomyocytes. Myocytes were subjected to 40 min of substrate-free hypoxia and the oxygen consumption measured together with the effects on ATP and PCr synthesis. After hypoxia myocytes showed a fall in ATP to 10% of the control value. Within 5 sec of reoxygenation the ATP level recovered to a new steady state level of 30% of the original value. The rate of oxygen consumption of hypoxic/reoxygenated cells was 3-4 fold higher than that of cells maintained under normoxic controls but in the presence of oligomycin the difference was only 1.5-fold higher, indicating a greater requirement for mitochondrial synthesis of ATP following reoxygenation. Reoxygenation in the absence of extracellular Ca2+ resulted in a lower rate of oxygen consumption (50% of the rate measured in the presence of 1 mM-Ca2+) but did not affect the steady state concentration of ATP attained 5 min after reoxygenation. These results support the idea that the increased O2 consumption of myocytes following hypoxia/reoxygenation is due to an increased demand for ATP synthesis by mitochondria and is a response to the NA+ and Ca2+ loading of the cells which occurs under these conditions. This increased demand is likely to result in a greater generation of free radicals such as superoxide by the respiratory chain which could impair cellular function over the long term.
Adenine Nucleotides↗
[The calcium-antagonistic fundamental effects of Verapamil on myocardial fibers and smooth muscle cells of the blood vessels].
Ca ions regulate the amount of ATP which is metabolized in the contractile system to produce mechanical energy. Since the consumption of ATP quantitatively determines the myocardial respiration rate, oxygen consumption is also Ca-dependent. Therefore, Ca-antagonistic compounds such as verapamil, D600 or nifedipine, by reducing the Ca supply to the beating heart, not only restrict ATP breakdown and mechanical activity but also myocardial oxygen demand. Moreover, Ca-antagonistic drugs lower the tone of vascular smooth muscle. This action leads to coronary vasodilation and a reduction in heart load because the peripheral vascular resistance is also diminished. All these factors contribute to an improvement of the cardiac energy balance in patients with coronary disease.
Adenosine Triphosphate↗
Effect of ATP level and its metabolic turnover in liver on the proteosynthesis postmortem.
The level of ATP in liver tissue kept at 37 degrees C decreases rapidly. Its concentration decreases to 20% of the original one 2 hr postmortem and disappears completely in the following 2 hr. The decrease of ATP concentration is independent of both the degree of mechanical disintegration of the tissue (mash, homogenate) and of the presence of inhibitors of ATP biosynthesis (2,4-dinitrophenol, monoiodoacetate). The application of precursors of ATP biosynthesis, labeled with suitable radionuclides (32Pi and [14C]ADP), makes it possible to prove that ATP is formed in the absence of inhibitors. Increased biosynthesis of ATP simultaneously enables an increase in metabolic turnover. Higher consumption of ATP, under conditions of its higher biosynthesis, is the reason for the identical decrease of ATP concentration in liver postmortem, independently of the intensity of its biosynthesis. The gradual fall of ATP level postmortem causes a corresponding decrease of proteosynthesis. At that moment when ATP disappears, proteosynthesis is stopped as well. However, the synthesis of proteins can continue even in this period if exogenous source of energy (ATP) is added.
2,4-Dinitrophenol↗
[Interrelationship between the rate of ATP-consuming processes and ATP concentration in intact erythrocytes].
The behaviour of ATP concentrations in intact erythrocytes upon glucose addition to the erythrocyte suspension at a constant rate was studied. At different rates of glucose addition lower than the rate of glucose consumption at normalcy, the corresponding ATP concentrations are established, which are dependent on the rate of glucose influx. The 20% decrease of ATP concentration from the physiological value is observed at a 2-fold decrease of the flux. The results obtained made it possible to establish the dependence of the total rate of ATP consumption on ATP concentration in intact erythrocytes. This dependence is non-linear and shows a dramatic rise in the proximity of the physiological point.
Adenosine Triphosphate↗
The toxicological relevance of paracetamol-induced inhibition of hepatic respiration and ATP depletion.
In order to elucidate the role of mitochondrial dysfunction in paracetamol-induced hepatotoxicity, the effects of paracetamol on the oxygen consumption and ATP content of the isolated perfused rat liver were correlated with parameters of hepatic viability and hepatotoxicity. Paracetamol at 5 g/L reduced the oxygen consumption of the livers by about 80% and hepatic ATP content by 96%. Hepatotoxicity was evident from the nearly complete interruption of bile secretion, a marked release of enzymes [glutamate-pyruvate transaminase (GPT), lactate dehydrogenase (LDH)] in the perfusate, a depletion of hepatic glutathione and an accumulation of calcium in the liver. Paracetamol-induced hepatotoxicity could be prevented completely by using livers from non-fasted rats as well as by addition of fructose to the perfusate of livers from fasted animals. Both treatments resulted in an increased energy supply from anaerobic glycolysis as evidenced by a large release of lactate and pyruvate into the perfusate, but did not inhibit paracetamol-induced decline of oxygen consumption. The decrease in hepatic oxygen consumption depended on the dose of paracetamol and occurred first at a concentration of 0.2 g/L (-10%). LDH and GPT release, on the other hand, was elevated at 2 and 5 g/L and calcium accumulation occurred at 5 g/L paracetamol only. Inhibition of mixed-function oxidases by dithiocarb did not prevent the decrease in oxygen consumption and the resulting hepatic injury induced by paracetamol. The oral administration of the high dose of 5 g/kg paracetamol in vivo to rats exerted strong hepatotoxicity but produced maximal serum levels of 800 mg/L paracetamol only and did not decrease hepatic oxygen consumption as measured in vitro. Our results show that in the isolated perfused rat liver in vitro, only high concentrations of paracetamol can produce "chemical hypoxia" by attacking mitochondria so as to cause hepatic injury. Such high concentrations of paracetamol are not attained in vivo, however. "Chemical hypoxia", thus, seems not to be relevant to the well-known hepatotoxic action of paracetamol.
Acetaminophen↗
Amelioration of impaired cerebral metabolism after severe acidotic ischemia by tirilazad posttreatment in dogs.
BACKGROUND AND PURPOSE: Acidosis may contribute to ischemic injury by mobilizing iron because the iron chelator deferoxamine improves early metabolic recovery from hyperglycermic ischemia. Mobilized iron may then promote oxygen radical-induced lipid peroxidative injury during reperfusion. We tested the hypothesis that administration of the antioxidant tirilazad at the start of reperfusion improves early metabolic recovery after severe acidotic ischemia and ameliorates depletion of the endogenous antioxidant glutathione. METHODS: In anesthetized dogs, arterial glucose concentration was increased to 500 to 600 mg/dL and global incomplete cerebral ischemia was produced for 30 minutes by ventricular fluid infusion to reduce perfusion pressure to 10 to 12 mm Hg. Metabolic recovery and intracellular pH were measured by phosphorus MR spectroscopy. In the first experiment, four groups of eight dogs each received either vehicle or 0.25, 1, or 2.5 mg/kg of tirilizad mesylate at reperfusion. Cerebral blood flow was measured with microspheres. In the second experiment, two groups of eight dogs each each received either vehicle or 2.5 mg/kg of tirilazad at reperfusion, and cortical glutathione was measured at 3 hours of reperfusion. RESULTS: Cerebral blood flow decreased to approximately 6 mL/min per 100 g and intracellular pH decreased to approximately 5.6 during ischemia in all groups. In the vehicle group, ATP recovery was transient and pH remained less than 6.0. Cerebral blood flow, O2 consumption, and ATP eventually declined to near-zero levels by 3 hours. Recovery was improved by tirilazad posttreatment in a dose-dependent fashion. At the highest dose, cerebral blood flow and O2 consumption were sustained near preischemic levels, and five of eight dogs had recovery of ATP greater than 50% and of pH greater than 6.7. Recovery of ATP and phosphocreatine became significantly greater than that in the vehicle group by 17 minutes of reperfusion despite similar levels of early hyperemia, indicating that the drug was acting before the onset of hypoperfusion. Cortical glutathione concentration in the vehicle group was 27% less than that in the tirilazad group and 34% less than that in nonischemic controls. CONCLUSIONS: Decreased depletion of the endogenous antioxidant glutathione is consistent with tirilazad acting as an antioxidant in vivo. Improvement in high-energy phosphate recovery 17 minutes after starting tirilazad infusion during reperfusion is consistent with an early onset of a functionally significant oxygen radical injury. Thus, severe acidosis appears to contribute to early ischemic injury through an oxygen radical mechanism sufficient to impede metabolic recovery.
Acidosis↗
Effect of As2O3 on gluconeogenesis.
1) The effect of As2O3 and As2O5 on gluconeogenesis from various substrates in the liver and kidney of rats was investigated. 2) A concentration-dependent inhibition by As2O3 was found. The effect was not dependent on the amount of investigated material (hepatocytes or kidney tubules). For either hepatocytes or kidney tubules the extent of inhibition depended strongly on the substrate used. The highest degree of inhibition was observed in incubations with pyruvate. The inhibition of glucose formation was accompanied to a lesser extent by a diminution in O2 consumption and ATP content. The effect was also dependent on the substrate used. Maximum effect was found in incubations with pyruvate. 3) Oleate, 0.5 mmol/l, increased gluconeogenesis from pyruvate. The effect was not abolished by As2O3. 4) A decrease in the content of acetyl-CoA, 3-hydroxybutyrate, and reduced glutathione was found in suspensions of isolated rat kidney tubules or hepatocytes incubated with As2O3. 5) About 10 times higher concentrations of As2O5 were necessary to induce a similar extent of inhibition of gluconeogenesis, decrease in O2 consumption, and in ATP content as compared with As2O3. The extent of the As2O5 effect depended on the concentration of the toxicant and on the substrate used. Gluconeogenesis from pyruvate exhibited the highest sensitivity to As2O5. 6) All findings can be largely explained by inhibition of pyruvate dehydrogenase as the central target for arsenicals. The subsequent depletion of acetyl CoA results in impaired formation of reducing equivalents in the citric acid cycle, decrease in high energy phosphates and, acetyl CoA being a strong positive modulator of pyruvate carboxylase, in gluconeogenesis inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)
Acetoacetates↗
The regulatory principles of glycolysis in erythrocytes in vivo and in vitro. A minimal comprehensive model describing steady states, quasi-steady states and time-dependent processes.
A simple mathematical model for glycolysis in erythrocytes is presented which takes into account ATP synthesis and consumption. The system is described by four ordinary differential equations. Conditions in vivo are described by a stable steady state. The model predicts correctly the metabolite concentrations found in vivo. The parameters involved are in agreement with data on the separate steps. The metabolite changes found in pyruvate kinase-deficient erythrocytes and the species variations among erythrocytes from different animals are described satisfactorily. The roles of the enzymes in the control of metabolites and glycolytic flux are expressed in the form of a control matrix and control strengths [R. Heinrich & T.A. Rapoport (1974) Eur. J. Biochem. 42, 89-95] respectively. Erythrocytes from various species are shown to be adapted to a maximal ATP-consumption rate. The calculated eigenvalues reveal the pronounced time-hierarchy of the glycolytic reactions. Owing to the slowness of the 2,3-bisphospho-glycerate phosphatase reaction, quasi-steady states occur during the time-interval of about 0.5-2h incubation, which are defined by perturbed 2,3-bisphosphoglycerate concentrations. The theoretical predictions agree with experimental data. In the quasi-steady state the flux control is exerted almost entirely by the hexokinase-phosphofructokinase system. The model describes satisfactorily the time-dependent changes after addition of glucose to starved erythrocytes. The theoretical consequences are discussed of the conditions in vitro with lactate accumulation and the existence of a time-independent conservation quantity for the oxidized metabolites. Even in this closed system quasi-steady states occur which are characterized by approximately constant concentrations of all glycolytic metabolites except for the accumulation of lactate, fructose 1,6-bisphosphate and triose phosphate.
Adenosine Triphosphatases↗
Relationships between the rate of synthesis of ATP and the concentrations of reactants and products of ATP hydrolysis in maize root tips, determined by 31P nuclear magnetic resonance.
Using 31P NMR spectroscopy, we have measured the rate of ATP synthesis, and the free concentrations of ATP, ADP, cytoplasmic Pi, and H+ in maize root tips under a wide range of conditions. We show that the ratio [ATP]/[ADP] in normoxic root tips is greater than 25. We found no simple relationship between the concentration of ATP and the rate of ATP synthesis: when the rate of ATP synthesis decreases in response to different treatments, the concentration of ATP can increase, decrease, or remain unchanged. Clear relationships were obtained, however, when the rate of synthesis of ATP was plotted against the logarithm of the ratio psi, defined as [ATP]/[ADP][Pi][H+]. Two curves were obtained, depending on which of two situations pertained. First, if mitochondrial ATP synthesis was inhibited, e.g., by KCN or hypoxia, ln psi decreased monotonically as rates of ATP synthesis decreased. The decrease in ln psi may account for decreases in the rates of biosynthetic reactions dependent on ATP, such as protein synthesis, as they approach equilibrium. Second, if consumption of ATP for biosynthetic reactions was inhibited, by treatment with succinate, ln psi increased as rates of ATP synthesis decreased. The increase in ln psi may account for decreases in the rate of ATP synthesis, as oxidative phosphorylation approaches equilibrium.
Adenosine Diphosphate↗
Mitochondrial coupling in vivo in mouse skeletal muscle.
The coupling of mitochondrial ATP synthesis and oxygen consumption (ratio of ATP and oxygen fluxes, P/O) plays a central role in cellular bioenergetics. Reduced P/O values are associated with mitochondrial pathologies that can lead to reduced capacity for ATP synthesis and tissue degeneration. Previous work found a wide range of values for P/O in normal mitochondria. To measure mitochondrial coupling under physiological conditions, we have developed a procedure for determining the P/O of skeletal muscle in vivo. This technique measures ATPase and oxygen consumption rates during ischemia with 31P magnetic resonance and optical spectroscopy, respectively. This novel approach allows the independent quantitative measurement of ATPase and oxygen flux rates in intact tissue. The quantitative measurement of oxygen consumption is made possible by our ability to independently measure the saturations of hemoglobin (Hb) and myoglobin (Mb) from optical spectra. Our results indicate that the P/O in skeletal muscle of the mouse hindlimb measured in vivo is 2.16 +/- 0.24. The theoretical P/O for resting muscle is 2.33. Systemic treatment with 2,4-dinitrophenol to partially uncouple mitochondria does not affect the ATPase rate in the mouse hindlimb but nearly doubles the rate of oxygen consumption, reducing in vivo P/O to 1.37 +/- 0.22. These results indicate that only a small fraction of the oxygen consumption in resting mouse skeletal muscle is nonphosphorylating under physiological conditions, suggesting that mitochondria are more tightly coupled than previously thought.
2,4-Dinitrophenol↗
Effects of seven anthracycline antibiotics on electrocardiogram and mitochondrial function of rat hearts.
Daunomycin, adriamycin and 5 semisynthetic anthracycline antibiotics inhibited oxygen consumption or ATP production of rat heart mitochondria in vitro. The no-effect levels varied depending on the substrate used and ranged from 1 nmole per mg mitochondrial protein. Mitochondrial functions were also studied in hearts of rats treated with repeated i.p. injections of the 7 antibiotics. Decrease in oxygen consumption without change in ATP production was observed with adriamycin and NSC-149584. Daunomycin, NSC-164011, NSC-143496 NSC-143114 affected primarily ATP production. The most potent compounds were daunomycin and adriamycin which damaged mitochondrial function at cummulative doses of approximately 10 mg/kg. ECGs were monitored in groups of equally treated rats. Cardiotoxicity manifested itself by progressive widening of the QRS complex often followed by the development of a S-wave trough. The most toxic compounds also induced intraventricular block, bradycardia and heart failure. The development of the ECG changes showed a good correlation with the impairment of mitochondrial function.
Adenosine Triphosphate↗
[Adenosine.amino acid].
Somnogenic effect of adenosine came to be widely known by experiments of the central administration of fowls and dogs in the early 1970s. This effect was subsequently confirmed in rats by the use of metabolically stable analogues of adenosine. Now, there is a hypothesis that adenosine, which is a metabolite of adenosine triphosphate (ATP) and the main source of energy, conveys a feedback signal to check the rise in the consumption of ATP, and then induces the state of sleep with low consumption of energy. Based on the pharmacological and structural characteristics, the receptors for adenosine are now divided into A1, A2a, A2b, and A3. Cholinergic neurons in DBH, PPT, and LDT which are involved in the promotion of wakefulness, are presumed to be the target structure of adenosine to promote sleep by causing a depressant effect on the neuronal excitation through A1 adenosine receptor. On the other hand, it is becoming apparent that A2a adenosine receptors located in the ventral and rostral part of the basal forebrain are also involved in the promotion of SWS and PS with different mechanisms mediated by A1 adenosine receptor.
Adenosine↗
Metabolic changes in the rat brain after acute and chronic ethanol intoxication: a 31P NMR spectroscopy study.
In this work, 31P phosphorus NMR (31P NMR) studies of the brain have been conducted in rats acutely and chronically intoxicated with ethanol. In both groups, changes in levels of high-energy phosphates were observed: increase of phosphocreatinine (PCr)/beta AaTP and PCr/inorganic phosphate (Pi) in acute and long-term ethanol exposure, and decrease of Pi/beta ATP after acute ethanol administration. These changes in high-energy phosphates, indicative of a reduction of adenosine triphosphate (ATP) and PCr consumption (PCr+ ADP+ H+ ATP+ Cr; ATP ADP+ Pi), suggest a reduction of cerebral metabolism both in acute and chronic ethanol exposure. In addition, in the group of rats chronically intoxicated with ethanol, there were variations in phosphodiester peak intensities (decrease of phosphomonoester (PME)/phosphodiester (PDE), increase of PDE/beta ATP), suggesting increased breakdown of membrane phospholipids. These changes could provide a metabolic explanation for the development of cerebral atrophy in chronic alcoholism.
Adenosine Triphosphate↗
Energy metabolism in normal and hypertrophied right ventricle of the ferret heart.
Using an isolated ferret heart preparation (Langendorff perfusion, perfusion pressure 90 mmHg), energy metabolism has been characterized in right and left ventricles from control and hypertrophied hearts. Hypertrophy was induced by pulmonary artery clipping for 30-45 days (right ventricle wall weight/body weight ratio increased by 70%). Myocardial contents of high energy phosphate compounds, glycogen and lactate, and the activities of some enzymes were biochemically measured in perfused hearts and also after ischemic arrest (30 min global ischemia). In hypertrophied right ventricles, PCr (-46%), Cr (-34%) levels, creatine kinase activity (-18%) were significantly decreased compared with control. ATP and Pi levels were not affected by hypertrophy. The adenylate energy charges were similar (0.85-0.86) in both types of heart. The activities of hexokinase (+26%), aldolase (+212%), pyruvate kinase (+14%) and glucose 6-phosphate dehydrogenase (+107%) were increased by hypertrophy. The LDH isozyme pattern was significantly changed such that LDH3 was decreased by 11%, and LDH4 and LDH5 were increased by a factor 1.4 and 2.9 respectively in hypertrophy. After 30 min of global ischemia, PCr level was decreased by 89 and 79% in control and hypertrophied ventricles respectively. ATP level was depressed by 41 in control and only by 21% in hypertrophied muscles. Altogether, the present data suggested that, in the adult ferret heart, the capacity for the ATP synthesis could be maintained during hypertrophy by the enhancement of the glycolytic pathway. The smaller decline of ATP after ischemia in hypertrophied tissue could be explained by a lower consumption of ATP in the hypertrophied compared to the control heart during the earliest period of ischemia.
Adenosine Triphosphate↗
Nitric oxide inhibits cardiac energy production via inhibition of mitochondrial creatine kinase.
Nitric oxide biosynthesis in cardiac muscle leads to a decreased oxygen consumption and lower ATP synthesis. It is suggested that this effect of nitric oxide is mainly due to the inhibition of the mitochondrial respiratory chain enzyme, cytochrome c oxidase. However, this work demonstrates that nitric oxide is able to inhibit soluble mitochondrial creatine kinase (CK), mitochondrial CK bound in purified mitochondria, CK in situ in skinned fibres as well as the functional activity of mitochondrial CK in situ in skinned fibres. Since mitochondrial isoenzyme is functionally coupled to oxidative phosphorylation, its inhibition also leads to decreased sensitivity of mitochondrial respiration to ADP and thus decreases ATP synthesis and oxygen consumption under physiological ADP concentrations.
Adenosine Diphosphate↗