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D Garfinkel

Publications and source records attributed to D Garfinkel.

At least 91 records · Page 5Linked to original sources
PubMed1979

Computer simulation of metabolism in pyruvate-perfused rat heart. V. Physiological implications.

The results of a simulation of metabolism in the pyruvate-perfused rat heart subjected to a sudden increase in work load are interpreted to provide a coherent explanation for the observed physiology. Respiration is most closely correlated with the mitochondrial phosphate potential, calculated from the MgATP and MgADP levels. No correlation between respiration and the pH gradient across the mitochondrial membrane was found. The transient falls in pH in the cytosol and perhaps the mitochondria are due largely to carbonic and lactic acidosis and appear to be only weakly coupled. The heart maintains a high ATP level during the transition to increased work by utilizing its energy reserves in order of decreasing availability in response to physiological signals mediated by Mg2+, Ca2+, and cAMP.

Animals↗
PubMed1979

Metabolism of totally ischemic excised dog heart. I. Construction of a computer model.

Construction and fit to the experimental data of a computer model of glycolysis, the Krebs cycle, and related metabolism in an ischemic dog heart preparation, involving 122 metabolites, 65 enzymes, and 406 chemical reactions, is described. The experimental preparation simulated is a dog heart excised from the body, placed in a beaker of Tyrode's solution, and sampled for 100 min; the model required only moderate modification from models representing perfused rat hearts, and little modification from a model of another ischemic dog heart preparation. Common underlying mechanisms for the ischemia are indicated, although this preparation appears to evolve more slowly with time, perhpas owing to heavy sedation and diffusion-limited transport. Lactate is, at first, exported and then accumulates intracellularly; pH falls, but not as much in the mitochondria as the cytoplasm; redox couples go reduced, but with counterintuitive time courses; calcium phosphate is calculated to precipitate, as often observed in cardiac ischemia.

Adenine Nucleotides↗
PubMed1979

Metabolism of totally ischemic excised dog heart. II. Interpretation of a computer model.

Analysis of the ischemic dog heart preparation described in the preceding paper indicates that it is an analogue in slow motion of the tissue in the center of a cardiac infarct. It is respiring very slowly and not capable of performing mechanical work. Glycolysis starts up with both glucose and glycogen as inputs. Later hexokinase and to some extent phosphofructokinase become limiting owing to inhibitor accumulation or acidosis. Metabolism then results primarily from cAMP-driven glycogenolysis, largely limited by the glycogen debranching enzymes at later times, with accumultion not only of lactate and alpha-glycerophosphate but of glucose as well. Amino acid levels oscillate with time while fatty acids accumulate at late times. The elevation of cAMP at later times may involve disturbances in its metabolism as well as mechanisms such as adenosine accumulation that are more important in cardiac ischemia than in normal heart. The clinical implications of this behavior are discussed.

Amino Acids↗
PubMed1977

Computer simulation of ischemic rat heart purine metabolism. I. Model construction.

A model is proposed for the partial depletion of the adenine nucleotide pool in the ischemic perfused rat heart which involves seven enzymes: adenylate cyclase, 3',5'-cyclic AMP phosphodiesterase, 5'-nucleotidase, adenosine kinase, adenosine deaminase, purine nucleoside phosphorylase, and inorganic pyrophosphatase. The computer implementation of this model is in terms of rate laws, several of which were obtained by a systematic least-squares fitting procedure. Depletion of the adenine nucleotide pool is initiated by the release of endogenous noradrenaline into the interstitial fluid, which results from a fall in tissue PO2, and the subsequent activation of adenylate cyclase. In this model the substrate for 5'-nucleotidase is a membrane-bound AMP pool formed by hydrolysis of extracellular fluid and functions as a vasodilator; excess adenosine is incorporated into the tissue by a "permease" with Michaelis-Menten kinetics and converted to AMP, inosine, and hypoxanthine. Alternative mechanisms, such as the deamination of AMP by adenylate deaminase and conversion of AMP to adenine by AMP pyrophosphorylase, were rejected primarily on qualitative biochemical grounds.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1977

Computer simulation of ischemic rat heart purine metabolism. II. Model behavior.

The behavior of a model for the partial depletion of adenine nucleotides in the perfused rat heart has been compared for ischemic and high coronary flow anoxic conditions. The accumulation of noradrenaline in the interstitial fluid greatly activates adenylate cyclase ultimately resulting in the degradation of 11.02 micronmol/g dry wt of ATP to adenosine, inosine, and hypoxanthine in 30 min. The high coronary flow rate during anoxic perfusion promotes washout of the noradrenaline from the interstitial fluid so that the hormone accumulates to only one fifth of its highest level in ischemia. This results in only slight activation of adenylate cyclase and in insignificant degradation of ATP in 2 min. The behavior of the model has been examined for two aerobic conditions--a transition from light to heavy work (2 min) and a transition from substrate-free to glucose perfusion (12 min), In both cases adenylate cyclase was not activated above its basal activity, and insignificant depletion of adenine nucleotides is predicted by the model.

Adenine Nucleotides↗
PubMed1977

Distribution of adenine nucleotides in the perfused rat heart.

A computer technique for determination of the distribution of adenine nucleotides among compartmented, protonated, and metal-chelated species has been developed for the perfused rat heart. This procedure requires knowledge of tissue levels of creatine, creatine phosphate, ATP, ADP, and AMP and the glycolytic and respiration rates. The method is applicable to any physiological state of the organ and has been applied to transient behavior in aerobic, anoxic, and ischemic hearts. The results suggest that ADP uptake and ATP export by mitochondria are normally linked and equal in rate during aerobic metabolism or short-term anoxia but become separate and unequal during ischemia, so that mitochondrial adenine nucleotides, primarily AMP, accumulate.

Actins↗
PubMed1977

Computer simulation of energy metabolism in anoxic perfused rat heart.

We have modeled the energy metabolism of the perfused rat heart in order to elucidate the interaction of physiological and biochemical control mechanisms. This model which includes glycolysis, the Krebs cycle, and related metabolism, contains 68 submodels of individual enzymes and transport mechanisms including both cytosolic and mitochondrial reactions. The method of model construction, which relies heavily on fitting observed in situ behavior to known algebraic rate laws for isolated enzymes, and its data requirements and necessary assumptions are described. Simulation of a CO-induced anoxic preparation is described in detail. Here glycolysis increases sharply, due to both increased glucose uptake and phosphorylase activation (there is rapid interconversion between a and b forms, both of which are active here); this causes a damped glycolytic oscillation originating with the glycogen-handling enzymes rather than phosphofructokinase. The behavior and physiological consequences of ATPase activity and of a lactate permease which exports lactate to the perfusate are discussed.

Adenine Nucleotides↗
PubMed1977

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

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.

Amino Acids↗
PubMed1977

Gamma-Glutamyltransferase: kinetic properties and assay conditions when gamma-glutamyl-4-nitroanilide and its 3-carboxy derivative are used as donor substrates.

The kinetics of human serum gamma-glutamyltransferase (EC 2.3.2.2) were investigated, with use of glycylglycine as a gamma-glutamyl acceptor substrate and gamma-glutamyl-4-nitroanilide and its carboxy derivative, gamma-glutamyl-3-carboxy-4-nitroanilide, as donor substrates. The simultaneous occurrence of both gamma-glutamyltransfer and autotransfer was established by descending paper chromatography. Constant-ratio double-reciprocal plots confirm that the enzyme mechanism is nonsequential (ping-pong bi-bi). Inhibition by either donor was not found, and inhibition by glycylglycine was only observed at concentrations above those of clinical interest. Kinetic constants obtained by nonlinear regression analysis of initial velocity data were used to determine reagent substrate concentrations for the assay of this enzyme. An assay with use of 4 mmol of gamma-glutamyl-3-carboxy-4-nitroanilide and 100 mmol of glycylglycine per liter yielded equivalent activities to those by assay with use of 4 mmol of gamma-glutamyl-4-nitroanilide and 40 mmol of glycylglycine per liter. These concentrations of the carboxy donor and glycylglycine are also "cost optimal" and present no procedural problems when used.

Anilides↗
PubMed1977

Heterogeneity of Wilson's disease in Israel.

In a survey in Israel of 50 patients with Wilson's disease, it was found that this disease occurred in all ethnic groups. In the Arab patients there was a significantly early age of onset and the disease followed a more severe course than that in the Jewish patients. The overall sex ratio of patients was nearly 1:1, and genetic analysis of 20 families confirmed an autosomal recessive mode of inheritance. The very similar age of onset and type of disease within sibships and the varying ages of onset noted between the Arab and Jewish patients suggest that the disease is genetically heterogeneous.

Adolescent↗
PubMed1976

Determination of the mechanism and kinetic constants for hog kidney gamma-glutamyltransferase.

The initial-velocity kinetics of hog kidney gamma-glutamyltransferase were studied. Glutamate gamma-(4-nitroanilide) and its 3-carboxy derivative, glutamate gamma-(3-carboxy-4-nitroanilide), served as gamma-glutamyl donors, and glycylglycine as an acceptor. Reaction products were identified by paper chromatography and amino acid analysis. Inhibited Ping Pong mechanisms and a comprehensive initial- velocity expression were developed which account for the observed simultaneous gamma-glutamyl transfer and autotransfer, competitive inhibition by glycylglycine, and non-competitive inhibition by the carboxy donor. The validity of the proposed Ping Pong mechanisms are supported by enzyme-velocity data obtained with constant ratios of acceptor to donor concentrations. Kinetic constants were determined by a non-linear regression analysis. With glutamate gamma-(4-nitroanilide) as the donor, Michaelis constants for the donor, acceptor and donor-acting-as-acceptor are 1.87, 24.9, and 2.08 mM respectively. With glutamate gamma-(3-carboxy-4-nitroanilide) as the donor, these Michaelis constants are 1.63, 16.6, and 12.3 mM. Glyclyglycine competitive inhibition constants with the parent donor and its carboxy derivative are 275 and 205 mM respectively; the non-competitive inhibition constant of the carboxy donor is 34 mM.

Anilides↗