Computer simulation of metabolism in pyruvate-perfused rat heart. IV. Model behavior

The behavior of a computer model of energy metabolism was determined for perfused rat hearts utilizing pyruvate as sole exogenous fuel and subjected to a rapid increase in work load. Computer-generated metabolite profiles, which are solutions of the differential equations for 1 min elapsed time, closely match 12 experimental curves (involving 120 concentration measurements) and exhibit the following properties. The computed cytosolic pyruvate level oscillates due to large changes in the rates of the processes that produce and consume this metabolite. Cytosolic Mg2+ seems to act as a coordinated controller of glycolytic enzymes; its transient increase permits a transient increase of glycolysis without an accumulation of glucose 6-phosphate. Lactate is exported to the interstitium by a lactate permease and then reimported and oxidized. As a result, the malate-aspartate shuttle reverses direction, and the Krebs cycle is “unspanned.”

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Computer simulation of rat heart metabolism after adding glucose to the perfusate

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1977.232.5.r175 ◽

1977 ◽

Vol 232 (5) ◽

pp. R175-R184 ◽

Cited By ~ 2

Author(s):

M. J. Achs ◽

D. Garfinkel

Keyword(s):

Krebs Cycle ◽

Acid Oxidation ◽

Allosteric Enzyme ◽

Heart Metabolism ◽

Rat Hearts ◽

Cardiac Energy Metabolism ◽

Perfused Rat Hearts ◽

Alpha Ketoglutarate Dehydrogenase

An experiment where perfused rat hearts receiving no substrate are suddenly given glucose with insulin in the perfusate is simulated with a computer model of cardiac energy metabolism. Mitochondrial metabolism is quantitatively reorganized under cytoplasmic control, with fatty acid oxidation undergoing a two-step decrease. There is an unspanning of the Krebs cycle (different reactions going at different rates) due primarily to slowing of alpha-ketoglutarate dehydrogenase; this ends when cytoplasmic glucose reaches a new steady state. Mitochondria in vitro are known to have higher pH than their surroundings; it is found here that this also holds in situ. Under these conditions, glycolysis is coherently substrate controlled, as is phosphofructokinase, usually considered the typical example of an allosteric enzyme. Limitations on simple methods of analyzing metabolic data of this type, e.g., use of lactate/pyruvate ratios to calculate NADH/NAD ratios, are discussed. Here a large volume of enzyme and other biochemical information has been integrated into a physiologically meaningful system.

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Effect of Amytal on metabolism of perfused rat heart: relationship between glycolysis and oxidative phosphorylation

AJP Cell Physiology ◽

10.1152/ajpcell.1979.237.5.c221 ◽

1979 ◽

Vol 237 (5) ◽

pp. C221-C230 ◽

Cited By ~ 23

Author(s):

K. Nishiki ◽

M. Erecinska ◽

D. F. Wilson

Keyword(s):

Tricarboxylic Acid Cycle ◽

Atp Production ◽

Glycolytic Activity ◽

Rat Hearts ◽

Glycolytic Intermediates ◽

Perfused Rat Hearts ◽

Mitochondrial Origin ◽

Tricarboxylic Acid Cycle Intermediates ◽

Pyruvate Level ◽

Convenient Model

In perfused rat hearts, infusion of increasing concentration of Amytal caused progressive inhibition of respiration and increase in glycolytic activity. At maximal inhibition of respiration, with glucose as the substrate, glycolysis provided about 60% of the total ATP produced. The myocardial content of ATP remained constant irrespective of the infused Amytal concentration but [CrP]/[Cr] and [ATP]/[ADP]f[Pi] progressively decreased. Changes in the concentrations of glycolytic intermediates were observed, the most pronounced of which were increases in fructose 1,6-diphosphate and lactate contents and a decrease in the pyruvate level. Myocardial levels of oxaloacetate, malate, and alanine were elevated and so was alanine release from the tissue. Substitution of glucose with pyruvate caused a large increase in the concentrations of the tricarboxylic acid cycle intermediates and consequent accumulation of reducing equivalents in the mitochrondria. With the latter substrate, in the presence of Amytal, the rates of mitochondrial ATP production were higher than those with glucose as the substrate. The metabolic picture of the Amytal block resembles biochemical manifestations of human myopathies of mitochondrial origin, and therefore Amytal inhibition is a convenient model system for exploration of intermediary metabolism in these defects.

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Substrate dependence of metabolic state and coronary flow in perfused rat heart

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1985.249.4.h799 ◽

1985 ◽

Vol 249 (4) ◽

pp. H799-H806 ◽

Cited By ~ 10

Author(s):

J. W. Starnes ◽

D. F. Wilson ◽

M. Erecinska

Keyword(s):

Energy Metabolism ◽

Coronary Flow ◽

Work Load ◽

Creatine Phosphate ◽

High Energy ◽

Cardiac Cells ◽

O2 Consumption ◽

Rat Hearts ◽

Perfused Rat Hearts ◽

Perfused Hearts

The effect of substrate source on the regulation of energy metabolism and coronary flow was studied in isolated perfused rat hearts. Compared with glucose-perfused hearts, those perfused at the same work load with palmitate or acetate demonstrated increases (P less than 0.01) in O2 consumption of 16 and 18%, respectively, and increases (P less than 0.01) in coronary flow of 30 and 32%, respectively. Parallel substrate-related changes occurred in the levels of high-energy phosphate compounds: tissue creatine, ADP free, and inorganic phosphate (Pi) were significantly decreased, leading to increases (P less than 0.01) in [creatine phosphate]/[creatine] and [ATP]free/[ADP]free[Pi]. These changes were accompanied by increased reduction of intramitochondrial pyridine nucleotides. Omitting orthophosphate from perfusate lowered intracellular Pi and modified cardiac function, but substrate-related differences were similar to those in Pi containing media. Differences in intracellular pH among substrates were observed, which may contribute in some instances to differences in energy metabolism and coronary flow. When work load was altered in glucose- and acetate-perfused hearts, both O2 consumption and coronary flow were linearly related to cytosolic [ATP]free/[ADP]free[Pi], and slopes of regression lines were similar for both substrates. These correlations support the view that [ATP]free/[ADP]free[Pi] is a major determinant of O2 consumption by cardiac cells and of coronary flow.

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