The Computation of Parameters in Isotopic Tracer Systems not in a Steady‐State

Ottaway, J. H.; Mowbray, John

doi:10.1111/j.1432-1033.1973.tb02922.x

Cited by 8 publications

(13 citation statements)

References 11 publications

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“…Accurate chemical flux measurements are also necessary and together with suitable computing methods [13] ( A ) and perfusate CO, (0) after introdu.ctzon of 0.1 rnM [2-14C] intact cell, our conception of intraceuular organisation. I n this study, a well-researched area of metabolism was deliberately chosen and the results demonstrate clearly our ignorance of the extent to which "soluble systems'' are compartmented in cardiac cytoplasm a t least.…”

Section: Discussionmentioning

confidence: 99%

“…There was little error involved in this, because the pyruvate curve could not vary greatly and the correction to lactate involved was only about 5O/, of the total radioactivity in lactate. However as explained in the following theoretical paper [13], in the actual optimisation which produced the estimates of the rate constants, total amounts in the tracer and chemical pools respectively were used, so that no question of interpolation arose. In this paper specific activities are used in general, as the argument is easier to follow.…”

Section: Redistribution Of Label In Lactate and Pyruvatementioning

confidence: 99%

“…However, the fit to the experimental data was not so good. About 15 variants on the basic model deduced from the considerations outlined above were tested for fit to the experimental data by the optimisation procedures described by in the following paper [13]; both tracer and chemical data were fitted to each model. These variants will not be described in detail.…”

Section: Model a The Exchange Of Lactate And Intracellulur Pyruvate mentioning

confidence: 99%

“…7 14C is found to accumulate in lactate at a rate consistent with the transfer ratea for model D set out below (Fig.3). The values of the rate parameters and constants obtained [13] using Model D are given in Table 3.…”

Section: R Of Model D Points To Tricarboxylic Acid)mentioning

confidence: 99%

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The Effect of Insulin and Growth Hormone on the Flux of Tracer from Labelled Lactate in Perfused Rat Heart

Mowbray

Ottaway

1973

European Journal of Biochemistry

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~[2-14C]Lactate tracer was added at 30 min to the perfused rat-heart preparation described in the previous paper. The specific activities of perfusate and tissue lactate and pyruvate were measured over the period up to 60 min.2. Perfusate and heart lactate radioactivity equilibrated rapidly : not so perfusate and heart pyruvate.3. No pyruvate was lost from the tissue: the sole precursor of perfusate pyruvate was lactate. I n the presence of insulin all pyruvate taken up from perfusate was obligatorily reduced to lactate.4. A proportion of pyruvate in the heart did not become labelled and there is good reason to believe this is not an artifact. 5. Rate parameters at different steps in pyruvate metabolism have been determined by computer modelling. Both hormones modify these parameters : in particular pyruvate dehydrogenase appears to undergo rapid 7-fold activation.6. The rate of exchange of label between lactate and intracellular labelled pyruvate was used to calculate the [NAD]/[NADH] ratios in the exchange compartment and in mitochondria. Both hormones reduced the ratio about 5 times by comparison with control. The results emphasise the disparity between perfusate lactate/pyruvate ratio and the redox potential of cardiac cytoplasm.7. The data strongly support the compartmentization in more than one distinct cytoplasmic space of some glycolytic enzymes in cardiac tissue. The relationship of these "compartments?? to heart morphology is briefly discussed.8. Evidence is presented that growth hormone exerts a much greater rapid "insulin-like" effect than has hitherto been suspected.It is possible by the use of tracer to obtain a great deal of information about the organisation of and the rate parameters of enzymes affecting pyruvate metabolism in the intact beating rat heart (see also the preceding paper [l]). Steady state or, in the case of pyruvate, reproducible nonsteady state conditions have been found and the material fluxes measured [l]. Although in reversibly interconnected compartmental systems it does not matter which compartment is initially labelled [2], perfusate lactate was chosen because of its size and constancy [I].In this study of the kinetics of tracer distribution, alanine has been neglected, on the principle of perturbation [2] since its known rate of incorporation in protein is very low [3] and its accumulation

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Section: Discussionmentioning

confidence: 99%

Section: Redistribution Of Label In Lactate and Pyruvatementioning

confidence: 99%

Section: Model a The Exchange Of Lactate And Intracellulur Pyruvate mentioning

confidence: 99%

Section: R Of Model D Points To Tricarboxylic Acid)mentioning

confidence: 99%

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The Effect of Insulin and Growth Hormone on the Flux of Tracer from Labelled Lactate in Perfused Rat Heart

Mowbray

Ottaway

1973

European Journal of Biochemistry

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“…Such inhibition might be effected by maintaining a high NTD/NDP ratio. In support of this proposal they cited [14] mammalian mitochondrial values of ATP/ADP -1 and GTP/GDP -100. The proposed inhibition of STK to permit ketone body metabolism, when that very metabolism requires citric acid cycle flux, presents a difficulty, but our discovery of the existence of two STK enzymes, each specific for its nucleotide substrate, offers a solution.…”

Section: Resultsmentioning

confidence: 93%

Distinct physiological roles of animal succinate thiokinases Association of guanine nucleotide‐linked succinate thiokinase with ketone body utilization

Jenkins

Weitzman

1986

FEBS Letters

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Two distinct succinate thiokinases have recently been shown to exist in animal tissues, one specific for guanine nucleotide and the other for adenine nucleotide. Their physiological roles have here been investigated by comparing the levels of the two enzymes in liver and brain of normal and diabetic rats. A marked rise in the level of brain guanine nucleotide-linked succinate thiokinase in the diabetic condition is consistent with an enhanced utilization of ketone bodies and hence with the associated elevated demand for succinylCoA for the activation of acetoacetate. Taken together with the reported mitochondrial values of the ATP/ ADP and GTP/GDP ratios, the results are interpreted to indicate that the adenine nucleotide-linked enzyme functions as a component of the citric acid cycle whereas the guanine nucleotide-linked enzyme functions in the opposite metabolic direction to produce succinyl-CoA from succinate. Succinate thiokinase Guanine nucleotide Diabetes Streptozotocin MetabolismKetone body utilization (Brain)

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Compartmentation of glycolysis and glycogenolysis in the perfused rat heart

et al. 2004

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Developing methods that can detect compartmentation of metabolic pathways in intact tissues may be important for understanding energy demand and supply. In this study, we investigated compartmentation of glycolysis and glycogenolysis in the isolated perfused rat heart using (13)C NMR isotopomer analysis. Rat hearts previously depleted of myocardial glycogen were perfused with 5.5 mm [U-(13)C]glucose plus 50 mU/mL insulin until newly synthesized glycogen recovered to new steady-state levels ( approximately 60% of pre-depleted values). After a short wash-out period, the perfusate glucose was then switched to [1-(13)C]glucose, and glycolysis and glycogenolysis were stimulated by addition of glucagon (1 microg/ml). A (13)C NMR multiplet analysis of the methyl resonance of lactate provided an estimate of pyruvate derived from glucose vs glycogen while a multiplet analysis of the C4 resonance of glutamate provided an estimate of acetyl-CoA derived from glycolytic pyruvate vs glycogenolytic pyruvate. These two indices were not equivalent and their difference was further magnified in the presence of insulin during the stimulation phase. These combined observations are consistent with functional compartmentation of glycolytic and glycogenolytic enzymes that allows pyruvate generated by these two processes to be distinguished at the level of lactate and acetyl-CoA.

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The Computation of Parameters in Isotopic Tracer Systems not in a Steady‐State

Cited by 8 publications

References 11 publications

The Effect of Insulin and Growth Hormone on the Flux of Tracer from Labelled Lactate in Perfused Rat Heart

The Effect of Insulin and Growth Hormone on the Flux of Tracer from Labelled Lactate in Perfused Rat Heart

Distinct physiological roles of animal succinate thiokinases Association of guanine nucleotide‐linked succinate thiokinase with ketone body utilization

Compartmentation of glycolysis and glycogenolysis in the perfused rat heart

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