Comparison of the Effects of Anoxia and Whole Heart Ischemia on Carbohydrate Utilization in Isolated Working Rat Hearts

Rovetto, Michael J.; Whitmer, Jeffrey T.; Neely, James R.

doi:10.1161/01.res.32.6.699

Cited by 294 publications

(88 citation statements)

References 43 publications

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“…This probably is due to the fact that lactate can easily traverse the cell membranes and would be washed away by the continued rapid perfusion during hypoxia. This is in agreement with earlier experiments on lactate production and accumulaton in anoxic and ischemic rat hearts [21]. If, however, hypoxia is induced under reduced coronary flow rates of the perfusate, steady-state concentrations of lactate and other compounds which can leave the cells may approach levels observable by 'H NMR.…”

Section: Resultssupporting

confidence: 92%

High resolution proton NMR studies of perfused rat hearts

et al. 1984

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High resolution 'H NMR spectra of perfused rat hearts have been obtained under normoxic, ischemic and hypoxic conditions. Several myocardial metabolites including taurine, carnitine, lactate and tissue glycerides are detected in the 'H NMR spectra. Changes in oxygen availability induce perturbations in the levels of some metabolites, in particular, lactate. Experiments with fasted rats and with substrate-free perfusion suggest that the glycerides detected in 'H spectra are metabolically mobilizable but have a slow rate of turnover. These results demonstrate that utility of 'H NMR in monitoring myocardial metabolism. 'H-NMRPerfused rat heart Myocardial metabolism

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Section: Resultssupporting

confidence: 92%

High resolution proton NMR studies of perfused rat hearts

et al. 1984

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“…This would increase intracellular concentrations of glucose 6-phosphate and inhibit glucose phosphorylation (48,55,56). In vertebrate hearts, extreme (e.g., anoxic) conditions result in fractional velocities that remain relatively low (8-25% of V max ) despite activation of rates of glucose uptake and phosphorylation (21,43,57). In contrast, glycogenolytic rates would be expected to increase with power output.…”

Section: Flux Rates and Flux Capacitiesmentioning

confidence: 99%

Relationships between enzymatic flux capacities and metabolic flux rates: Nonequilibrium reactions in muscle glycolysis

Suarez

Staples²,

Lighton³

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

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The rules that govern the relationships between enzymatic f lux capacities (V max ) and maximum physiological f lux rates (v) at enzyme-catalyzed steps in pathways are poorly understood. We relate in vitro V max values with in vivo f lux rates for glycogen phosphorylase, hexokinase, and phosphofructokinase, enzymes catalyzing nonequilibrium reactions, from a variety of muscle types in fishes, insects, birds, and mammals. Flux capacities are in large excess over physiological f lux rates in low-f lux muscles, resulting in low fractional velocities (%V max ‫؍‬ v͞V max ؋ 100) in vivo. In high-f lux muscles, close matches between f lux capacities and f lux rates (resulting in fractional velocities approaching 100% in vivo) are observed. These empirical observations are reconciled with current concepts concerning enzyme function and regulation. We suggest that in high-f lux muscles, close matches between enzymatic f lux capacities and metabolic f lux rates (i.e., the lack of excess capacities) may result from space constraints in the sarcoplasm.Studies of structural and functional design in animals have led to valuable insights into the relationships between functional capacities and maximum physiological requirements or loads (1-3). At the biochemical level, biological design has been studied in terms of relationships between protein structure and function (4), pathway stoichiometry (5, 6), and mechanisms of regulation (5, 7). However, the synthesis and turnover of the thousands of metabolic enzymes possessed by each cell type is a costly enterprise (8), and the various compartments in cells appear to be highly crowded (9, 10). Current evidence suggests that there are probably upper limits to the design of biochemical capacities (11,12). Despite this, the rules that govern the design of functional capacities at the biochemical level are poorly understood. What are the relationships between enzymatic capacities for flux and maximum physiological flux rates through pathways? How much enzyme, in Diamond's words (13), is ''enough but not too much?'' Locomotory and cardiac muscles are ideally suited for the examination of capacity͞load relationships at the biochemical level because the maximum rate at which they do mechanical work defines the maximum rate at which ATP is hydrolyzed and, therefore, the maximum rate at which ATP resynthesizing pathways must operate. Herein, we present patterns of relationships, thus far unrecognized, between enzymatic flux capacities at nonequilibrium reactions in glycolysis and rates of glycolytic flux in muscles during exercise. Sources and Analysis of DataData concerning flux rates (v) and flux capacities (enzyme V max values) at three nonequilibrium steps in the glycolytic pathway, the hexokinase, glycogen phosphorylase, and phosphofructokinase reactions, are considered. These are taken from our own studies and published work from other laboratories. Most of the reactions in glycolysis lie close to equilibrium in vivo and are catalyzed by enzymes whose V max values may exceed p...

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“…The role of coronary blood flow in maintaining a suitable intracellular environment in addition to providing the oxygen supply has been emphasized recently in studies comparing the effects of anoxia with those of ischemia (15)(16)(17). Ischemia has been shown to be more detrimental to cellular function and metabolism than is anoxia in which coronary blood flow is maintained at normal rates.…”

mentioning

confidence: 99%

“…Anoxia accelerates glycolysis in cardiac muscle (18)(19), and the rate of glucose utilization is increased by a regional reduction in coronary blood flow (20,21). In contrast, glycolysis is reduced in the working rat heart when coronary blood flow is severely restricted to the whole heart (17). Also, a 60% reduction in blood flow to the whole heart in a working pig heart preparation results in reduced rates of glucose consumption (22).…”

mentioning

confidence: 99%

“…Therefore, glycolysis may have been accelerated in the normal or mildly ischemic tissue and inhibited in the more severely ischemic cells. In the global ischemic models, only the control and one condition of ischemia have been studied (17). Therefore, the purpose of the present work was to study the relationship between coronary blood flow Circulation Research, Vol.…”

mentioning

confidence: 99%

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Effect of coronary blood flow on glycolytic flux and intracellular pH in isolated rat hearts.

Neely¹,

Whitmer²,

Rovetto³

1975

Circulation Research

197

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The rate of coronary blood flow was varied in isolated working rat heart preparations to determine its influence on the rate of glucose utilization, tissue high-energy phosphates, and intracellular pH. A 60% reduction in coronary blood flow resulted in a 30% reduction in oxygen consumption, an accelerated rate of glucose utilization, lower tissue levels of high-energy phosphates, and higher tissue levels of lactate and H + . Ventricular performance deteriorated as reflected by a decrease in heart rate and peak systolic pressure. Further reductions in coronary blood flow resulted in inhibition of glycolysis, a greater decrease in tissue levels of high-energy phosphates, and higher tissue levels of both lactate and H + . These changes in glycolytic flux, tissue metabolites, and ventricular performance were proportional to the degree of restriction in coronary blood flow. The importance of coronary blood flow and washout of the interstitial space in the maintenance of accelerated glycolytic flux in oxygen-deficient hearts is emphasized. It is concluded that acceleration of ATP production from glycolysis can occur only in the marginally ischemic tissue in the peripheral area of tissue supplied by an occluded artery. The central area of tissue which receives a low rate of coronary blood flow will have a reduced rate of ATP production due to both a lack of oxygen and an inhibition of glycolysis.

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Comparison of the Effects of Anoxia and Whole Heart Ischemia on Carbohydrate Utilization in Isolated Working Rat Hearts

Cited by 294 publications

References 43 publications

High resolution proton NMR studies of perfused rat hearts

High resolution proton NMR studies of perfused rat hearts

Relationships between enzymatic flux capacities and metabolic flux rates: Nonequilibrium reactions in muscle glycolysis

Effect of coronary blood flow on glycolytic flux and intracellular pH in isolated rat hearts.

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