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1.
间歇性低氧适应的心脏保护 总被引:9,自引:0,他引:9
间歇性低氧(intermittent hypoxia,IH)是指一定时间间断地暴露于低氧环境,而其余时间处于常氧环境。IH是机体某种生理和病理状态下的低氧形式。研究表明:间歇性低氧适应(IHadaptation),类似缺血预适应(ischemic preconditioning,IPC)和长期高原低氧适应(long-termhigh-altitude hypoxic adaptation,LHA),具有明显的心脏保护作用,表现为增强心肌对缺血/再灌注损伤的耐受性、限制心肌梗死面积和形态学改变、抗细胞凋亡、促进缺血/再灌注心脏舒缩功能的恢复,以及抗心律失常。尽管IH对心脏的保护作用不容质疑,但其作用机制远未阐明。IH心脏保护作用可能涉及氧的运输、能量代谢、神经体液调节、抗氧化酶、应激蛋白、腺苷系统、ATP敏感钾通道、线粒体及其钙调控、一氧化氮和蛋白激酶等多方面机制,并受低氧处理方式、动物年龄和性别等因素影响。IH心脏保护持续时间明显长于IPC,而对机体的不良影响远小于LHA,具有潜在的应用价值。 相似文献
2.
Lactate and glucose as energy substrates during, and after, oxygen deprivation in rat hippocampal acute and cultured slices 总被引:5,自引:0,他引:5
Cater HL Chandratheva A Benham CD Morrison B Sundstrom LE 《Journal of neurochemistry》2003,87(6):1381-1390
The effects of raised brain lactate levels on neuronal survival following hypoxia or ischemia is still a source of controversy among basic and clinical scientists. We have sought to address this controversy by studying the effects of glucose and lactate on neuronal survival in acute and cultured hippocampal slices. Following a 1-h hypoxic episode, neuronal survival in cultured hippocampal slices was significantly higher if glucose was present in the medium compared with lactate. However, when the energy substrate during the hypoxic period was glucose and then switched to lactate during the normoxic recovery period, the level of cell damage in the CA1 region of organotypic cultures was significantly improved from 64.3 +/- 2.1 to 74.6 +/- 2.1% compared with cultures receiving glucose during and after hypoxia. Extracellular field potentials recorded from the CA1 region of acute slices were abolished during oxygen deprivation for 20 min, but recovered almost fully to baseline levels with either glucose (82.6 +/- 10.0%) or lactate present in the reperfusion medium (108.1 +/- 8.3%). These results suggest that lactate alone cannot support neuronal survival during oxygen deprivation, but a combination of glucose followed by lactate provides for better neuroprotection than either substrate alone. 相似文献
3.
Burelle Y Wambolt RB Grist M Parsons HL Chow JC Antler C Bonen A Keller A Dunaway GA Popov KM Hochachka PW Allard MF 《American journal of physiology. Heart and circulatory physiology》2004,287(3):H1055-H1063
Adaptation of myocardial energy substrate utilization may contribute to the cardioprotective effects of regular exercise, a possibility supported by evidence showing that pharmacological metabolic modulation is beneficial to ischemic hearts during reperfusion. Thus we tested the hypothesis that the beneficial effect of regular physical exercise on recovery from ischemia-reperfusion is associated with a protective metabolic phenotype. Function, glycolysis, and oxidation of glucose, lactate, and palmitate were measured in isolated working hearts from sedentary control (C) and treadmill-trained (T: 10 wk, 4 days/wk) female Sprague-Dawley rats submitted to 20 min ischemia and 40 min reperfusion. Training resulted in myocardial hypertrophy (1.65 +/- 0.05 vs. 1.30 +/- 0.03 g heart wet wt, P < 0.001) and improved recovery of function after ischemia by nearly 50% (P < 0.05). Glycolysis was 25-30% lower in T hearts before and after ischemia (P < 0.05), whereas rates of glucose oxidation were 45% higher before ischemia (P < 0.01). As a result, the fraction of glucose oxidized before and after ischemia was, respectively, twofold and 25% greater in T hearts (P < 0.05). Palmitate oxidation was 50-65% greater in T than in C before and after ischemia (P < 0.05), whereas lactate oxidation did not differ between groups. Alteration in content of selected enzymes and proteins, as assessed by immunoblot analysis, could not account for the reduction in glycolysis or increase in glucose and palmitate oxidation observed. Combined with the studies on the beneficial effect of pharmacological modulation of energy metabolism, the present results provide support for a role of metabolic adaptations in protecting the trained heart against ischemia-reperfusion injury. 相似文献
4.
《European journal of cell biology》2023,102(2):151298
Lactate has long been acknowledged to be a metabolic waste product, but it has more recently been found as a fuel energy source in mammalian cells. Podocytes are an important component of the glomerular filter, and their role in maintaining the structural integrity of this structure was established. These cells rely on a constant energy supply and reservoir. The utilization of alternative energy substrates to preserve energetic homeostasis is a subject of extensive research, and lactate appears to be one such candidate. Therefore, we investigated the role of lactate as an energy substrate and characterize the lactate transport system in cultured rat podocytes during sufficient and insufficient glucose supplies. The present study, for the first time, demonstrated the presence of lactate transporters in podocytes. Moreover, we observed modified the amount of these transporters in response to limited glucose availability and after l-lactate supplementation. Simultaneously, exposure to l-lactate preserved cell survival during insufficient glucose supply. Interestingly, during glucose deprivation, lactate exposure allowed the steady flow of glycolysis and prevented glycogen reserves depletion. Summarizing, podocytes utilize lactate as an energy substrate and possess a developed system that controls lactate homeostasis, suggesting that it plays an essential role in podocyte metabolism, especially during fluctuations of energy availability. 相似文献
5.
Abstract: The low cerebral energy requirements of most mammals at birth reflect an immaturity of the central nervous system, and it has been suggested that energy demands in fetuses are even less well developed than in newborns. Furthermore, fetal cerebral energy requirements are presumed to be met predominantly or exclusively by anaerobic glycolysis. To clarify these issues, we investigated cerebral oxidative metabolism in 9-, 14-, 16-, and 19-day-old chick embryos and in newly hatched peeps. Animals were decapitated and quick-frozen in liquid Freon 0-5 min post-mortem. Forebrain extracts were prepared and assayed for ATP, phosphocreatine, glucose, and lactate. Alterations in these metabolites post-decapitation were used to calculate cerebral metabolic rates (Δ∼P) and rates of maximal anaerobic glycolysis (Δ lactate). Rates of lactate accumulation during cerebral ischemia increased progressively from embryonic day 9 through hatching. Cerebral metabolic rates were not different in 9-, 14-, and 16-day-old embryos, but increased steadily thereafter. The extent to which total cerebral energy utilization could be derived from anaerobic glycolysis (Δ lactate/Δ∼ P) increased from a low at day 9 (0.29) to a maximum at day 16 (0.78). The data suggest that, despite the low cerebral metabolic activity of the chick embryo, at no time during development is anaerobic glycolysis capable of entirely supporting the energy needs of the developing brain. 相似文献
6.
A rat four vessel occlusion model was utilized to examine the effects of ischemia/reperfusion on cortical window superfusate levels of amino acids, glucose, and lactate. Superfusate aspartate, glutamate, phosphoethanolamine, taurine, and GABA were significantly elevated by cerebral ischemia, then declined during reperfusion. Other amino acids were affected to a lesser degree. Superfusate lactate rose slightly during the initial ischemic period, declined during continued cerebral ischemia and then was greatly elevated during reperfusion. Superfusate glucose levels declined to near zero levels during ischemia and then rebounded beyond basal levels during the reperfusion period. Inhibition of neuronal lactate uptake with alpha-cyano-4-hydroxycinnamate dramatically elevated superfusate lactate levels, enhanced the ischemia/reperfusion evoked release of aspartate but reduced glutamine levels. Topical application of an alternative metabolic fuel, glutamine, had a dose dependent effect. Glutamine (1 mM) elevated basal superfusate glucose levels, diminished the decline in glucose during ischemia, and accelerated its recovery during reperfusion. Lactate levels were elevated during ischemia and reperfusion. These effects were not evident at 5 mM glutamine. At both concentrations, glutamine significantly elevated the superfusate levels of glutamate. Topical application of sodium pyruvate (20 mM) significantly attenuated the decline in superfusate glucose during ischemia and enhanced the levels of both glucose and lactate during reperfusion. However, it had little effect on the ischemia-evoked accumulation of amino acids. Topical application of glucose (450 mg/dL) significantly elevated basal superfusate levels of lactate, which continued to be elevated during both ischemia and reperfusion. The ischemia-evoked accumulations of aspartate, glutamate, taurine and GABA were all significantly depressed by glucose, while phosphoethanolamine levels were elevated. These results support the role of lactate in neuronal metabolism during ischemia/reperfusion. Both glucose and glutamine were also used as energy substrates. In contrast, sodium pyruvate does not appear to be as effectively utilized by the ischemic/reperfused rat brain since it did not reduce ischemia-evoked amino acid efflux. 相似文献
7.
Energy deprivation increases sensitivity to killing by hyperthermia. Hypoxic cells become dramatically sensitive to heat under glycolytic inhibition or glucose deprivation. To define the role of glucose metabolism in hypoxic cells in the presence or absence of elevated temperatures, cell culture studies were carried out to determine whether the enhanced cell killing of glucose-deprived hypoxic cells could be reversed by nucleoside supplementation. The results with HeLa cells showed that purine ribonucleosides were capable of reversing the enhanced heat-induced cytotoxicity under appropriate cultural conditions. Pyrimidine ribonucleosides and deoxyribonucleosides were ineffective. Based on the known metabolism of purine ribonucleosides, it is postulated that protection from hyperthermic killing by purine nucleosides comes about as a result of increased energy production via the purine nucleotide cycle. 相似文献
8.
Energy metabolism in hypoxic astrocytes: Protective mechanism of fructose-1,6-bisphosphate 总被引:2,自引:0,他引:2
Judith A. Kelleher Pak H. Chan Thelma Y. Y. Chan George A. Gregory 《Neurochemical research》1995,20(7):785-792
The protective effects of fructose-1,6-biphosphate (FBP) during hypoxia/ischemia are thought to result from uptake and utilization of FBP as a substrate for glycolysis or from stimulation of glucose metabolism. To test these hypotheses, we measumed CO2 and lactate production from [6-14C]glucose, [1-14C]glucose, and [U-14C]FBP in normoxic and hypoxic cultured astrocytes with and without FBP present. FBP had little effect on CO2 production by glycolysis, but increased CO2 production by the pentose phosphate pathway. Labeled FBP produced very small amounts of CO2. Lactate production from [1-, and 6-14C]glucose increased similarly during hypoxic hypoxia; the increase was independent of added FBP. Labeled lactate from [U-14C]FBP was minimal. We conclude that exogenous FBP is not used by astrocytes as a substrate for glycolysis and that FBP alters glucose metabolism. 相似文献
9.
Topical glucose and accumulation of excitotoxic and other amino acids in ischemic cerebral cortex. 总被引:1,自引:0,他引:1
Pre-ischemic hyperglycemia aggravates brain damage due to transient global ischemia as demonstrated by exacerbation of brain lesions. Lactacidosis and elevated glutamate levels have been implicated as mechanisms of the increased damage. Our objective was to determine the effects of different levels of glucose (0, 66.5, 450 mg/dL) in cortical superfusates on the ischemia/reperfusion-evoked release of amino acids from the rat cerebral cortex. Physiologic levels of glucose significantly reduced the amount of aspartate, glutamate and gamma-aminobutyric acid and the supra-physiologic levels of glucose reduced the amount of aspartate and phosphoethanolamine released from the cortex during ischemia/reperfusion in comparison with no glucose. The decrease in glutamate release may be due to increased availability of glucose for glycolysis with the subsequent formation of ATP and lactate, which has been shown to act as an energy source for neurons. The decreased levels may also reflect the continued energy-dependent uptake of glutamate by glial cells. 相似文献
10.
Effect of Lactacidosis on Pyridine Nucleotide Stability During Ischemia in Mouse Brain 总被引:5,自引:0,他引:5
Frank A. Welsh Tetsuya Sakamoto Ann E. McKee Renée E. Sims 《Journal of neurochemistry》1987,49(3):846-851
Brain levels of NADH and NAD+ were measured in three models of cerebral ischemia to determine whether degradation of the pyridine nucleotides is enhanced in models that generate high concentrations of lactic acid. Complete ischemia (decapitation), in which lactate increased to 14 mmol/kg, caused a gradual decrease in the NAD pool to 50% of control by 2 h. During focal ischemia (occlusion of the middle cerebral artery), the decrease in the NAD pool was less pronounced (82% of control at 2 h) despite the accentuated accumulation of lactate to 33 mmol/kg. In a third model (unilateral hypoxia-ischemia), pretreatment of animals with glucose augmented the ischemic elevation of lactate from 30 mmol/kg to 40 mmol/kg and greatly impaired restoration of energy metabolites during recirculation. However, glucose pretreatment had no effect on the size of the NAD pool during ischemia or early recovery. These results, therefore, demonstrate that the pyridine nucleotide pool is not rapidly degraded during ischemic insults that accumulate high concentrations of lactic acid. The stability of the NAD pool may have been enhanced by the limited increase in brain levels of NADH that occurred in these models of incomplete ischemia. 相似文献
11.
Jagdip S. JaswalWendy Keung Wei WangJohn R. Ussher Gary D. Lopaschuk 《Biochimica et Biophysica Acta (BBA)/Molecular Cell Research》2011,1813(7):1333-1350
Cardiac ischemia and its consequences including heart failure, which itself has emerged as the leading cause of morbidity and mortality in developed countries are accompanied by complex alterations in myocardial energy substrate metabolism. In contrast to the normal heart, where fatty acid and glucose metabolism are tightly regulated, the dynamic relationship between fatty acid β-oxidation and glucose oxidation is perturbed in ischemic and ischemic-reperfused hearts, as well as in the failing heart. These metabolic alterations negatively impact both cardiac efficiency and function. Specifically there is an increased reliance on glycolysis during ischemia and fatty acid β-oxidation during reperfusion following ischemia as sources of adenosine triphosphate (ATP) production. Depending on the severity of heart failure, the contribution of overall myocardial oxidative metabolism (fatty acid β-oxidation and glucose oxidation) to adenosine triphosphate production can be depressed, while that of glycolysis can be increased. Nonetheless, the balance between fatty acid β-oxidation and glucose oxidation is amenable to pharmacological intervention at multiple levels of each metabolic pathway. This review will focus on the pathways of cardiac fatty acid and glucose metabolism, and the metabolic phenotypes of ischemic and ischemic/reperfused hearts, as well as the metabolic phenotype of the failing heart. Furthermore, as energy substrate metabolism has emerged as a novel therapeutic intervention in these cardiac pathologies, this review will describe the mechanistic bases and rationale for the use of pharmacological agents that modify energy substrate metabolism to improve cardiac function in the ischemic and failing heart. This article is part of a Special Issue entitled: Mitochondria and Cardioprotection. 相似文献
12.
Quantitative on-line monitoring of hippocampus glucose and lactate metabolism in organotypic cultures using biosensor technology 总被引:4,自引:0,他引:4
Gramsbergen JB Leegsma-Vogt G Venema K Noraberg J Korf J 《Journal of neurochemistry》2003,85(2):399-408
Quantitative glucose and lactate metabolism was assessed in continuously perfused organotypic hippocampal slices under control conditions and during exposure to glutamate and drugs that interfere with aerobic and anaerobic metabolism. On-line detection was possible with a system based on slow perfusion rates, a half-open (medium/air interface) tissue chamber and a flow injection analytic system equipped with biosensors for glucose and lactate. Under basal conditions about 50% of consumed glucose was converted to lactate in hippocampal slice cultures. Using medium containing lactate (5 mm) instead of glucose (5 mm) significant lactate uptake was observed, but this uptake was less than the net uptake of lactate equivalents in glucose-containing medium. Glucose deprivation experiments suggested lactate efflux from glycogen stores. The effects of drugs compromising or stimulating energy metabolism, i.e. 2-deoxyglucose, 3-nitropropionic acid, alpha-cyano-4-hydroxycinnamate, l-glutamate, d-asparate, ouabain and monensin, were tested in this flow system. The data show that maintaining Na+ and K+ gradients consumed much of the energy but do not support the hypothesis that l-glutamate stimulates glycolysis in hippocampal slice cultures. 相似文献
13.
Targeting fatty acid and carbohydrate oxidation--a novel therapeutic intervention in the ischemic and failing heart 总被引:1,自引:0,他引:1
Jaswal JS Keung W Wang W Ussher JR Lopaschuk GD 《Biochimica et biophysica acta》2011,1813(7):1333-1350
Cardiac ischemia and its consequences including heart failure, which itself has emerged as the leading cause of morbidity and mortality in developed countries are accompanied by complex alterations in myocardial energy substrate metabolism. In contrast to the normal heart, where fatty acid and glucose metabolism are tightly regulated, the dynamic relationship between fatty acid β-oxidation and glucose oxidation is perturbed in ischemic and ischemic-reperfused hearts, as well as in the failing heart. These metabolic alterations negatively impact both cardiac efficiency and function. Specifically there is an increased reliance on glycolysis during ischemia and fatty acid β-oxidation during reperfusion following ischemia as sources of adenosine triphosphate (ATP) production. Depending on the severity of heart failure, the contribution of overall myocardial oxidative metabolism (fatty acid β-oxidation and glucose oxidation) to adenosine triphosphate production can be depressed, while that of glycolysis can be increased. Nonetheless, the balance between fatty acid β-oxidation and glucose oxidation is amenable to pharmacological intervention at multiple levels of each metabolic pathway. This review will focus on the pathways of cardiac fatty acid and glucose metabolism, and the metabolic phenotypes of ischemic and ischemic/reperfused hearts, as well as the metabolic phenotype of the failing heart. Furthermore, as energy substrate metabolism has emerged as a novel therapeutic intervention in these cardiac pathologies, this review will describe the mechanistic bases and rationale for the use of pharmacological agents that modify energy substrate metabolism to improve cardiac function in the ischemic and failing heart. This article is part of a Special Issue entitled: Mitochondria and Cardioprotection. 相似文献
14.
AMP-activated protein kinase (AMPK) control of fatty acid and glucose metabolism in the ischemic heart 总被引:6,自引:0,他引:6
Myocardial ischemia is the leading cause of all cardiovascular deaths in North America. Myocardial ischemia is accompanied by profound changes in metabolism including alterations in glucose and fatty acid metabolism, increased uncoupling of glucose oxidation from glycolysis and accumulation of protons within the myocardium. These changes can contribute to a poor functional recovery of the heart. One key player in the ischemia-induced alteration in fatty acid and glucose metabolism is 5'AMP-activated protein kinase (AMPK). Accumulating evidence suggest that activation of AMPK during myocardial ischemia both increases glucose uptake and glycolysis while also increasing fatty acid oxidation during reperfusion. Gain-of-function mutations of AMPK in cardiac muscle may also be causally related to the development of hypertrophic cardiomyopathies. Therefore, a better understanding of role of AMPK in cardiac metabolism is necessary to appropriately modulate its activity as a potential therapeutic target in treating ischemia reperfusion injuries. This review attempts to update some of the recent findings that delineate various pathways through which AMPK regulates glucose and fatty acid metabolism in the ischemic myocardium. 相似文献
15.
Ex vivo analysis of lactate and glucose metabolism in the rat brain under different states of depressed activity 总被引:2,自引:0,他引:2
Serres S Bezancon E Franconi JM Merle M 《The Journal of biological chemistry》2004,279(46):47881-47889
Brain metabolism of glucose and lactate was analyzed by ex vivo NMR spectroscopy in rats presenting different cerebral activities induced after the administration of pentobarbital, alpha-chloralose, or morphine. The animals were infused with a solution of either [1-(13)C]glucose plus lactate or glucose plus [3-(13)C]lactate for 20 min. Brain metabolite contents and enrichments were determined from analyses of brain tissue perchloric acid extracts according to their post-mortem evolution kinetics. When amino acid enrichments were compared, both the brain metabolic activity and the contribution of blood glucose relative to that of blood lactate to brain metabolism were linked with cerebral activity. The data also indicated the production in the brain of lactate from glycolysis in a compartment other than the neurons, presumably the astrocytes, and its subsequent oxidative metabolism in neurons. Therefore, a brain electrical activity-dependent increase in the relative contribution of blood glucose to brain metabolism occurred via the increase in the metabolism of lactate generated from brain glycolysis at the expense of that of blood lactate. This result strengthens the hypothesis that brain lactate is involved in the coupling between neuronal activation and metabolism. 相似文献
16.
Carbohydrate metabolism in brain during convulsions and its modification by phenobarbitone 总被引:6,自引:3,他引:3
Abstract— Assays of citric acid cycle substrates and metabolites of the second stage of the glycolytic pathway have completed a series of studies of glucose metabolism in brains of mice rapidly frozen at intervals during electrically-induced, tonic-clonic convulsions. Citric acid cycle metabolism reached a new equilibrium at a significantly higher rate. However, oxidative metabolism did not keep up with the demand for energy supplies, as indicated by an increasing lactate level and an increasing lactate: pyruvate ratio. Administration of a sub-anaesthetic but anticonvulsant dose of phenobarbitone prior to convulsive electrical stirnulation was associated with as great an increase in anaerobic glycolysis as in mice given no drug prior to stimulation; but oxidative metabolism was not enhanced, as reflected by even greater lactate: pyruvate ratios in mice given phenobarbitone than in mice given no drug prior to convulsive stimulation. 相似文献
17.
Wang P Lloyd SG Zeng H Bonen A Chatham JC 《American journal of physiology. Heart and circulatory physiology》2005,288(5):H2102-H2110
The goal of this study was to determine whether changes in cardiac metabolism in Type 2 diabetes are associated with contractile dysfunction or impaired response to ischemia. Hearts from Zucker diabetic fatty (ZDF) and lean control rats were isolated and perfused with glucose, lactate, pyruvate, and palmitate. The rates of glucose, lactate, pyruvate, and palmitate oxidation rates and glycolysis were determined during baseline perfusion and low-flow ischemia (LFI; 0.3 ml/min for 30 min) and after LFI and reperfusion. Under all conditions, ATP synthesis from palmitate was increased and synthesis from lactate was decreased in the ZDF group, whereas the contribution from glucose was unchanged. During baseline perfusion, the rate of glycolysis was lower in the ZDF group; however, during LFI and reperfusion, there were no differences between groups. Despite these metabolic shifts, there were no differences in oxygen consumption or ATP production rates between the groups under any perfusion conditions. Cardiac function was slightly depressed before LFI in the ZDF group, but during reperfusion, function was improved relative to the control group despite the increased dependence on fatty acids for energy production. These data suggest that in this model of diabetes, the shift from carbohydrates to fatty acids for oxidative energy production did not increase myocardial oxygen consumption and was not associated with impaired response to ischemia and reperfusion. 相似文献
18.
Chavez PN Stanley WC McElfresh TA Huang H Sterk JP Chandler MP 《American journal of physiology. Heart and circulatory physiology》2003,284(5):H1521-H1527
Metabolic interventions improve performance during demand-induced ischemia by reducing myocardial lactate production and improving regional systolic function. We tested the hypotheses that 1) stimulation of glycolysis would increase lactate production and improve ventricular wall motion, and 2) the addition of fatty acid oxidation inhibition would reduce lactate production and further improve contractile function. Measurements were made in anesthetized open-chest swine hearts. Three groups, hyperglycemia (HG), HG + oxfenicine (HG + Oxf), and control (CTRL), were treated under aerobic conditions and during demand-induced ischemia. During demand-induced ischemia, HG resulted in greater lactate production and tissue lactate content but had no significant effect on glucose oxidation. HG + Oxf significantly lowered lactate production and increased glucose oxidation compared with both the CTRL and HG groups. Myocardial energy efficiency was greater in the HG and HG + Oxf groups under aerobic conditions but did not change during demand-induced ischemia. Thus enhanced glycolysis resulted in increased energy efficiency under aerobic conditions but significantly enhanced lactate production with no further improvement in function during demand-induced ischemia. Partial inhibition of free fatty acid oxidation in the presence of accelerated glycolysis increased energy efficiency under aerobic conditions and significantly reduced lactate production and enhanced glucose oxidation during demand-induced ischemia. 相似文献