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

1977 ◽  
Vol 232 (5) ◽  
pp. R175-R184 ◽  
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.

scholarly journals Activity of phosphorylase in total global ischaemia in the rat heart A phosphorus-31 nuclear-magnetic-resonance study

1981 ◽  
Vol 196 (1) ◽  
pp. 171-178 ◽  
Author(s):  
I A Bailey ◽  
S R Williams ◽  
G K Radda ◽  
D G Gadian
Keyword(s):  
Inhibitory Effect ◽  
Heart Tissue ◽  
Nuclear Magnetic Resonance Study ◽  
Cytosolic Ph ◽  
Global Ischaemia ◽  
Rat Hearts ◽  
Perfused Rat Hearts ◽  
Tissue Acidosis ◽  
Good Agreement

1. The uptake and subsequent phosphorylation of deoxyglucose into perfused rat hearts was monitored by 31P n.m.r. 2. The accumulated deoxyglucose 6-phosphate provided (a) an independent method for measuring cytosolic pH in the normoxic and ischaemic heart tissue and (b) a way of studying the activity of phosphorylase during ischaemia. 3. The cytosolic pH measured from the 31P n.m.r. resonance position of deoxyglucose 6-phosphate is in good agreement under all conditions studied with that obtained previously from the Pi resonances. This eliminates any possible doubts about the use of Pi for measuring intracellular pH. 4. Deoxyglucose 6-phosphate in vitro inhibits phosphorylase b but not phosphorylase a. Its inhibitory effect on glycogenolysis during ischaemia is monitored by measuring tissue acidosis by n.m.r. In the initial stages of ischaemia phosphorylase activity is not inhibited, whereas after about 5 min approx. 50% of the activity is inhibited. These observations are interpreted in terms of the relative contributions of phosphorylase a and the AMP-dependent phosphorylase b activities during ischaemia.

Lipid and glycogen metabolism in the hypoxic heart: effects of epinephrine

1975 ◽  
Vol 229 (4) ◽  
pp. 885-889 ◽  
Author(s):  
Crass MF ◽  
GM Pieper
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Free Fatty Acids ◽  
Fatty Acid Oxidation ◽  
Glycogen Metabolism ◽  
Acid Oxidation ◽  
Triglyceride Fatty Acid ◽  
Rat Hearts ◽  
Perfused Rat Hearts

The metabolism of cardiac lipids and glycogen in hypoxic and well-oxygenated perfused rat hearts was studied in the presence or absence of epinephrine. Heart lipids were pre-labeled in vivo with [1-14C]palmitate. Triglyceride disappearance (measured chemically and radiochemically) was observed in well-oxygenated hearts and was stimulated by epinephrine (4.1 X 10(-7)M). Utilization of tissue triglycerides was inhibited in hypoxic hearts in the presence or absence of added epinephrine. Hypoxia resulted in a small increase in tissue 14C-free fatty acids and inhibition of 14C-labeled triglyceride fatty acid oxidation. Epinephrine had no stimulatory effect on fatty acid oxidation in hypoxic hearts. Utilization of 14C-labeled phospholipids (and total phospholipids) was similar in well-oxygenated and hypoxic hearts with or without added epinephrine. These results suggested that the antilipolytic effects of hypoxia were predominant over the lipolytic effects of epinephrine. Glycogenolysis was stimulated threefold by epinephrine in well-oxygenated hearts. Hypoxia alone was a potent stimulus to glycogenolysis. Addition of epinephrine to perfusates of hypoxic hearts resulted in a slight enhancement of glycogenolysis.

Effects of valproic acid on cardiac metabolism

2004 ◽  
Vol 82 (10) ◽  
pp. 927-933 ◽  
Author(s):  
Thomas Daniels ◽  
Maureen Gallagher ◽  
George Tremblay ◽  
Robert L Rodgers
Keyword(s):  
Valproic Acid ◽  
Fatty Acid ◽  
Cardiac Metabolism ◽  
Acid Oxidation ◽  
Oxidation Rates ◽  
Coa Ligase ◽  
Rat Hearts ◽  
Chain Acyl ◽  
Oxidation Of Glucose

We investigated whether the antiepileptic valproic acid (VPA) might interfere with oxidative metabolism in heart, as it does in liver. We administered VPA to working rat hearts perfused with radiolabeled carbohydrate and fatty acid fuels. Measurements included oxidation rates of (i) glucose, pyruvate, or lactate in the presence of palmitate and (ii) palmitate, octanoate, or butyrate in the presence of glucose. Oxidation rates were quantified as the rate of appearance of14CO2or3H2O from14C- or3H-labeled substrates. In hearts perfused with palmitate, VPA (1 mmol/L) strongly inhibited the oxidation of pyruvate and lactate but slightly stimulated the oxidation of glucose. VPA also inhibited lactate or pyruvate uptake into erythrocytes in vitro. In hearts perfused with glucose, VPA strongly inhibited the oxidation of palmitate and octanoate but had no effect on butyrate oxidation. The absence of valproate CoA ligase activity in cell-free homogenates indicated that the inhibition of fatty acid oxidation by VPA did not require prior activation to valproyl-CoA. The results are consistent with the hypothesis that VPA selectively interferes with myocardial fuel oxidation by mechanisms that are independent of conversion to the CoA thioester.Key words: myocardial, glucose, lactate, pyruvate, palmitate, octanoate, butyrate, metabolism, medium-chain acyl-CoA ligase.

scholarly journals Regional variation and differential sensitivity of rat heart protein synthesis in vivo and in vitro

1985 ◽  
Vol 225 (2) ◽  
pp. 487-492 ◽  
Author(s):  
V R Preedy ◽  
D M Smith ◽  
N F Kearney ◽  
P H Sugden
Keyword(s):  
Protein Synthesis ◽  
Regional Variation ◽  
Subcellular Fractionation ◽  
Differential Sensitivity ◽  
Ventricular Muscle ◽  
Rat Hearts ◽  
Perfused Rat Hearts ◽  
The Right

In vivo, fractional rates of protein synthesis in atrial muscle of hearts taken from fed rats were 70% greater than in ventricular muscle. After 3 days starvation, atrial protein synthesis is inhibited, but the inhibition is less than in ventricles. A crude subcellular fractionation of the aqueous homogenates by centrifugation at 32000g showed that the supernatant and precipitate proteins were synthesized at the same rate in the ventricles. The fractional rates of protein synthesis and RNA/protein ratios in the right ventricle were 10% greater than in the left ventricle. Protein synthesis in both of these regions was inhibited equally by starvation. In vitro, rates of protein synthesis in atria and ventricles of anterogradely perfused rat hearts were stimulated by saturating insulin concentrations and were inhibited by starvation, but the effects in atria were smaller than in ventricles. Rates of protein synthesis in atria in vitro were 80-95% of rates in vivo. The heart therefore shows considerable regional variation in rates of protein synthesis in vivo and in vitro, and the sensitivity of protein synthesis in the various regions to interventions such as insulin and starvation differs.

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

1979 ◽  
Vol 237 (3) ◽  
pp. R174-R180 ◽  
Author(s):  
M. J. Achs ◽  
M. C. Kohn ◽  
D. Garfinkel
Keyword(s):  
Krebs Cycle ◽  
Work Load ◽  
Transient Increase ◽  
Elapsed Time ◽  
Rat Hearts ◽  
Metabolite Profiles ◽  
Perfused Rat Hearts ◽  
Pyruvate Level ◽  
Iv Model ◽  
Malate Aspartate Shuttle

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.”

scholarly journals Effects of insulin, biguanide antihyperglycaemic agents and β-adrenergic agonists on pathways of myocardial proteolysis

1990 ◽  
Vol 266 (3) ◽  
pp. 713-718 ◽  
Author(s):  
D P Thorne ◽  
T D Lockwood
Keyword(s):  
Protein Degradation ◽  
Insulin Concentration ◽  
Inhibitory Effects ◽  
Beta Agonists ◽  
Rat Hearts ◽  
Lysosomal Proteolysis ◽  
Subsequent Exposure ◽  
Perfused Rat Hearts ◽  
Perfusion Period

Pathways of bulk protein degradation controlled by insulin and isoprenaline (isoproterenol) were distinguished in Langendorff-perfused rat hearts. Proteins were biosynthetically labelled in vitro with [3H]leucine, followed by addition of 2 mM non-radioactive leucine to competitively prevent reincorporation. Rapidly degraded proteins were eliminated during a 3 h preliminary perfusion period without insulin. One third of bulk myocardial protein degradation was inhibited by isoprenaline as described previously. An insulin concentration of 5 nM maximally inhibited proteolysis, beginning within 2 min. Inhibition reached 32% within 1.25 h and 35% after 1.5 h. The minimum effective insulin concentration was approx. 10-50 pM, which caused 10-20% inhibition. Following 3 h of perfusion without insulin, the lysosomal inhibitor, chloroquine (30 microM), inhibited 38% of bulk degradation. The 35% proteolytic inhibition caused by insulin was followed by very little further inhibition on subsequent concurrent infusion of chloroquine, i.e. the inhibitory effects of insulin and chloroquine were not additive. In contrast, prior inhibition of lysosomal proteolysis by insulin or chloroquine did not prevent the subsequent additive inhibition caused by isoprenaline. Insulin and beta-agonists additively inhibited approx. two-thirds of bulk degradation. The biguanide antihyperglycaemic agent phenformin (2 microM) inhibited 35% of bulk degradation, beginning at 2 min and reaching a near maximum at approx. 1.25-1.5 h. Following inhibition of proteolysis with phenformin (20 microM), subsequent infusion of chloroquine (30 microM) produced only a slight additional inhibition. Following inhibition of 35% of degradation by 1.5 h of perfusion with insulin (5 nM), subsequent exposure to phenformin (2 microM) produced only a slight additional inhibition which did not exceed 38% of basal proteolysis. Thus insulin and phenformin both inhibit lysosomal proteolysis; however, the adrenergic-responsive pathway is distinct.

Effect of fatty acid oxidation on efficiency of energy production in rat heart

1985 ◽  
Vol 249 (4) ◽  
pp. H723-H728 ◽  
Author(s):  
J. F. Hutter ◽  
H. M. Piper ◽  
P. G. Spieckerman
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
O2 Consumption ◽  
Mitochondrial Fatty Acid Oxidation ◽  
Rat Hearts ◽  
Mitochondrial Fatty Acid ◽  
Perfused Rat Hearts ◽  
On Line ◽  
Exact Amount

Myocardial fatty acid oxidation has been reported to be accompanied by an elevated O2 consumption compared with carbohydrate oxidation. The exact amount of this additional O2 consumption is controversial. Different investigators have observed an O2 wasting effect that is too large to be explained by the different ATP-to-O2 ratios of these substrates. With the use of isolated perfused rat hearts, O2 consumption and hemodynamic measurements were computer analyzed to provide on-line estimates of the ratio between O2 consumption and demand (EQ). Increasing palmitate or octanoate concentrations decreased the respiratory quotient, which was accompanied by a disproportionate increase of EQ. Inhibition of fatty acid oxidation by an inhibitor of acylcarnitine transferase or a blockade of mitochondrial thiolase caused a drastic reduction of fatty acid oxidation. The fatty acid-induced enhancement of O2 consumption was decreased to a much smaller extent, indicating that there are two different mechanisms responsible for the O2-wasting effect, one that depends on mitochondrial fatty acid oxidation and another that is not affected by an inhibition of this pathway.

Endothelial inhibition of myofilament calcium response in intact cardiac myocytes

1995 ◽  
Vol 269 (5) ◽  
pp. H1538-H1544 ◽  
Author(s):  
C. B. Pepper ◽  
D. Lang ◽  
M. J. Lewis ◽  
A. M. Shah
Keyword(s):  
Endothelial Cells ◽  
Cardiac Myocytes ◽  
Vascular Endothelial Cell ◽  
Vascular Endothelial ◽  
Isotonic Contraction ◽  
Cultured Cell ◽  
Rat Hearts ◽  
Perfused Rat Hearts ◽  
Coronary Endothelial Cells

Recent studies suggest that factors released by endothelial cells can modify contraction of isolated cardiac preparations. We compared the effects of 1) coronary effluent collected from Langendorff-perfused rat hearts and 2) cultured vascular endothelial cell superfusate on isolated fura 2-loaded rat ventricular cardiac myocytes. Coronary and cultured cell effluent produced similar effects. Isotonic contraction amplitude was reduced by 31.6 +/- 2.6 and 70.2 +/- 9.1%, respectively; myocyte diastolic length increased by 0.8 +/- 0.2 and 1.5 +/- 0.4 microns, and time to 50% relaxation fell by 6.2 +/- 1.8 and 10.1 +/- 2.0% (all P < 0.05; n = 29 and 15 myocytes, respectively). A small fall in the amplitude of the intracellular Ca2+ transient was observed (8.5 +/- 1.5 and 10.9 +/- 3.5%, respectively; both P < 0.01), insufficient to account for the reduction in twitch amplitude. In intact myocytes tetanized in the presence of thapsigargin, the steady-state myofilament response to Ca2+ was reduced by coronary and cultured cell effluent. These results suggest that both coronary endothelial cells in situ and cultured endothelial cells tonically release a factor(s) that reduces myofilament Ca2+ response.

scholarly journals Peroxisomal Fatty Acid Oxidation Is a Substantial Source of the Acetyl Moiety of Malonyl-CoA in Rat Heart

2004 ◽  
Vol 279 (19) ◽  
pp. 19574-19579 ◽  
Author(s):  
Aneta E. Reszko ◽  
Takhar Kasumov ◽  
France David ◽  
Kathryn A. Jobbins ◽  
Katherine R. Thomas ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Acetyl Coa ◽  
Mitochondrial Fatty Acid Oxidation ◽  
Fatty Acid Chain ◽  
Rat Hearts ◽  
Malonyl Coa ◽  
Mitochondrial Fatty Acid ◽  
Perfused Rat Hearts

Little is known about the sources of acetyl-CoA used for the synthesis of malonyl-CoA, a key regulator of mitochondrial fatty acid oxidation in the heart. In perfused rat hearts, we previously showed that malonyl-CoA is labeled from both carbohydrates and fatty acids. This study was aimed at assessing the mechanisms of incorporation of fatty acid carbons into malonyl-CoA. Rat hearts were perfused with glucose, lactate, pyruvate, and a fatty acid (palmitate, oleate or docosanoate). In each experiment, substrates were13C-labeled to yield singly or/and doubly labeled acetyl-CoA. The mass isotopomer distribution of malonyl-CoA was compared with that of the acetyl moiety of citrate, which reflects mitochondrial acetyl-CoA. In the presence of labeled glucose or lactate/pyruvate, the13C labeling of malonyl-CoA was up to 2-fold lower than that of mitochondrial acetyl-CoA. However, in the presence of a fatty acid labeled in its first acetyl moiety, the13C labeling of malonyl-CoA was up to 10-fold higher than that of mitochondrial acetyl-CoA. The labeling of malonyl-CoA and of the acetyl moiety of citrate is compatible with peroxisomal β-oxidation forming C12and C14acyl-CoAs and contributing >50% of the fatty acid-derived acetyl groups that end up in malonyl-CoA. This fraction increases with the fatty acid chain length. By supplying acetyl-CoA for malonyl-CoA synthesis, peroxisomal β-oxidation may participate in the control of mitochondrial fatty acid oxidation in the heart. In addition, this pathway may supply some acyl groups used in protein acylation, which is increasingly recognized as an important regulatory mechanism for many biochemical processes.

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