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PubMed1991

Compartmental model of leucine kinetics in humans.

The complexity of amino acid and protein metabolism has limited the development of comprehensive, accurate whole body kinetic models. For leucine, simplified approaches are in use to measure in vivo leucine fluxes, but their domain of validity is uncertain. We propose here a comprehensive compartmental model of the kinetics of leucine and alpha-ketoisocaproate (KIC) in humans. Data from a multiple-tracer administration were generated with a two-stage (I and II) experiment. Six normal subjects were studied. In experiment I, labeled leucine and KIC were simultaneously injected into plasma. Four plasma leucine and KIC tracer concentration curves and label in the expired CO2 were measured. In experiment II, labeled bicarbonate was injected into plasma, and labeled CO2 in the expired air was measured. Radioactive (L-[1-14C]leucine, [4,5-3H]KIC, [14C]bicarbonate) and stable isotope (L-[1-13C]leucine, [5,5,5-2H3]KIC, [13C]bicarbonate) tracers were employed. The input format was a bolus (impulse) dose in the radioactive case and a constant infusion in the stable isotope case. A number of physiologically based, linear time-invariant compartmental models were proposed and tested against the data. The model finally chosen for leucine-KIC kinetics has 10 compartments: 4 for leucine, 3 for KIC, and 3 for bicarbonate. The model is a priori uniquely identifiable, and its parameters were estimated with precision from the five curves of experiment I. The separate assessment of bicarbonate kinetics (experiment II) was shown to be unnecessary. The model defines masses and fluxes of leucine in the organism, in particular its intracellular appearance from protein breakdown, its oxidation, and its incorporation into proteins. An important feature of the model is its ability to estimate leucine oxidation by resolving the bicarbonate model in each individual subject. Finally, the model allows the assessment of the domain of validity of the simpler commonly used models.

Adult↗
PubMed1989

Compartmental modeling of the hepatic transport of taurocholate in the rat in vivo.

Compartmental analysis was used to study the hepatobiliary transport of taurocholate (TC) in the rat in vivo. The available data are the following: [14C]TC kinetics in blood and bile, weighting factors associated with these data and computed from a theoretical variability model, and TC excretion rate in bile. The lumped model that best fits the data contains five compartments: three compartments for TC distribution in blood and two compartments for the liver. It includes a compartmental representation of the laminar flow of bile in the collecting catheter. This model overestimates TC concentration in blood. A perfusion model that includes a compartment representing explicitly the sinusoidal TC concentration gradient was developed. TC concentration in blood estimated by this model is in good agreement with direct measurements, showing that the perfused model has a better descriptive capacity than the lumped model. The amounts of TC estimated in the two hepatic compartments are similar to values previously published.

Animals↗
PubMed1989

Rabbit myocardial 82Rb kinetics and a compartmental model for blood flow estimation.

Quantification of regional myocardial blood flow (MBF) with rubidium-82 (82Rb) and positron emission tomography (PET) requires the validation of a tracer kinetic model that adequately describes the kinetics of 82Rb in tissue. We performed 134 82Rb kinetic experiments in 24 isolated, arterially perfused rabbit interventricular septa at different flow rates (0.5-4.5 ml.min-1.g-1) and under the following conditions: varied concentrations of glucose (2.8-11 mM), insulin (0-5 mU/ml), and potassium (5-8 mM); varied pH (7.2-7.8); varied workload; and the addition of acetylstrophanthidin (1.0 microM). The measured 82Rb tissue time-activity curves consisted of two exponential components, with half times inversely related to MBF. The size of the slow component decreased as MBF increased (from 70% at 0.3 ml.min-1.g-1 to 30% at 2.0 ml. min-1.g-1). The kinetics were not strongly dependent on the conditions studied and were consistent with a compartmental model containing two communicating compartments. The volume of the fast exchangeable compartment and the transport rate constant from the fast to the slow compartment were found to be independent of MBF. Values of MBF were estimated with the compartmental model from 82Rb kinetics, and they correlated well with the directly measured MBF (r = 0.91; slope = 1.03).

Animals↗
PubMed1996

Metabolic compartmentation of lactate in the glucose-perfused rat heart.

Several studies using exogenous pyruvate as substrate have suggested that there are separate intracellular pyruvate pools in cardiac cells. Such heterogeneity in intracellular pyruvate has important implications for our understanding of both oxidative and nonoxidative glucose metabolism. Because pyruvate is not a major substrate for the heart in vivo, we wished to determine if there was pyruvate compartmentation with glucose as substrate. Hearts were isolated from male Sprague-Dawley rats and retrogradely perfused (Langendorff) with a modified Krebs-Henseleit buffer containing [1-13C[glucose for 5-115 min. At the end of each experiment, hearts were freeze-clamped and extracted for determination of the fractional enrichment of alanine, lactate, and acetyl CoA using 1H- and 13C-nuclear magnetic resonance spectroscopy. The fractional enrichment of alanine at the C-3 position was significantly higher than that for lactate at 55 min [43.6 +/- 2.8 vs. 27.2 +/- 4.6% (SD), n = 5, P < 0.003]. The differences in steady-state enrichment between lactate and alanine were not due to differences in the rate of labeling of these metabolites. The mean steady-state lactate enrichment was higher in the perfusate samples compared with the tissue samples from the same experiments (46.6 +/- 2.2 vs. 30.5 +/- 2.5%, n = 3, P < 0.005). Because fractional enrichment of alanine, acetyl CoA, and perfusate lactate are similar, we suggest that there is a separate nonexchanging pool of lactate rather than cytosolic compartmentation of pyruvate that has been previously proposed.

Animals↗
PubMed1996

Subcellular compartmentalization of Gs alpha in cardiac myocytes and its redistribution in heart failure.

Intracellular compartmentalization of G proteins may contribute to regulating signal transduction pathways in normal and failing myocardium. To test this hypothesis, we used postembedment immunogold electron microscopy to characterize the subcellular distribution of Gs alpha in normal canine and porcine left ventricular myocytes and in myocytes from a pacing-induced heart failure model in pigs in which beta-adrenergic signaling is impaired. Gs alpha was highly compartmentalized in normal canine myocytes and was localized specifically to the sarcolemma, intercalated disks, T-tubule and sarcoplasmic reticulum (SR) triads, and myoplasm. The highest Gs alpha concentration was observed in the intercalated disks. Only 20 +/- 5% of total cellular Gs alpha was localized to the sarcolemma. The triads and myoplasm compartments contained 45 +/- 13 and 27 +/- 8% of total cellular Gs alpha, respectively. The distribution of Gs alpha in normal porcine and canine myocytes was similar. However, in failing porcine myocytes Gs alpha was redistributed from the sarcolemma and T-tubule and SR triads to the myoplasm. The proportion of total cellular Gs alpha in the sarcolemma fell from 22 +/- 5 in normal to 11 +/- 4% in failing myocytes (P < 0.005), and the proportion in T-tubule and SR triads fell from 55 +/- 5 to 40 +/- 5% (P < 0.01), with a quantitatively corresponding increase in the proportion in the myoplasm from 19 +/- 3 to 43 +/- 4% (P < 0.0001). Thus redistribution of Gs alpha from the sarcolemma and the T-tubule and SR triads, where it may transduce beta-adrenergic signals, to internal sites where such actions may be precluded, might contribute to the pathophysiology of heart failure.

Animals↗
PubMed2003

A compartmental model of magnesium metabolism in healthy men based on two stable isotope tracers.

The aim of this study was to build a compartmental model of magnesium (Mg) kinetics by using data collected from six healthy adult men after oral administration of 26Mg and intravenous administration of 25Mg. Blood, urine, and feces were collected for 12 days after administration of the isotopes. Isotopic ratios were determined by inductively coupled plasma-mass spectrometry. Data were analyzed for each subject using SAAMII. We began with a compartmental model previously proposed (Avioli LV and Berman M. J Appl Physiol 21: 1688-1694, 1966) and developed an alternative approach to resolve the discrepancy between model-predicted curves and experimental data. This analysis enables the exploration of 25% of total body Mg that exchanges rapidly from plasma compartment with two extraplasma pools. One of the extraplasma compartments contains 80% of the exchangeable Mg with a transport rate of 48 +/- 13 mg/h. The second exchanges 179 +/- 88 mg of Mg/h. The model permitted estimation of kinetic parameters as well as fractional Mg absorption and fecal endogenous excretion.

Adult↗
PubMed1978

Calibrating compartmental models of neurons.

Numerical parameters for a compartmental model of a neuron can be chosen to conform both to the neuron's structure and to its measured steady-state electrical properties. A systematic procedure for assigning parameters is described that makes use of the matrix of coefficients of the set of differential equations that embodies the compartmental model. The inverse of this matrix furnishes input resistances and voltage attenuation factors for the model, and an interactive modification of the original matrix and its inverse may be used to fit the model to anatomic and electrical measurements.

Electrophysiology↗
PubMed2005

A compartmental capillary, convolution integration model to investigate nutrient transport and metabolism in vivo from paired indicator/nutrient dilution curves.

Thirty-three paired indicator/nutrient dilution curves across the mammary glands of four cows were obtained after rapid injection of para-aminohippuric acid (PAH) plus glucose into the external iliac artery. For the measurement of extracellular volume and kinetics of nutrient uptake from indicator dilution curves, several models of solute dispersion and disappearance have been proposed. The Crone-Renkin models of exchange in a single capillary assume negligible washout of solutes from the extracellular space and do not describe entire dilution curves. The Goresky models include a distribution of capillary transit times to generate whole system outflow profiles but require two indicators to parametize extracellular behavior. A compartmental capillary, convolution integration model is proposed that uses one indicator to account for the extracellular behavior of the nutrient after a paired indicator/nutrient injection. With the use of an iterative approach to least squares, unique solutions for nonexchanging vessel transit time t(mu) and its variance sigma were obtained from all 33 PAH curves. The average of heterogeneous vascular transit times was approximated as 2sigma = 8.5 s. The remainder of indicator dispersion was considered to be due to washout from a well-mixed compartment representing extracellular space that had an estimated volume of 5.5 liters or 24% of mammary gland weight. More than 99% of the variation in the time course of venous PAH concentration after rapid injection into the arterial supply of the mammary glands was explained in an unbiased manner by partitioning the organ into a heterogeneous nonexchanging vessel subsystem and a well-mixed compartmental capillary subsystem.

Animals↗
PubMed1993

Glycolysis-citric acid cycle interrelation: a new approach and some insights in cellular and subcellular compartmentation.

In the development of an integrated approach to study metabolic compartmentation and regulation in brain, we have emphasized the importance, versatility, and need to exploit the recent methodological advances in (1) NMR spectroscopy, (2) primary cultures of neurons and glial cells, and (3) subcellular fractionation (especially brain mitochondrial isolation). The integrated approach has the advantage of being able to draw data and inferences based on some combination of results derived from in vivo, cellular, and subcellular studies. For example, some in vivo NMR data may suggest that an enzymatic step may be rate-limiting in a particular pathway. This information may be used to frame testable hypotheses and questions that can be investigated in experiments involving primary cultures of neural cells and subcellular fractions. Subsequently, the data from such in vitro studies could serve as the bases for constructing the hypothetical framework for predicting the regulatory role, in vivo, of the enzyme in the pathway. We have discussed the known as well as the as yet ill-defined facets of the cellular and subcellular aspects of the glycolysis-citric acid cycle interrelation and have attempted to illustrate how such an integrated approach could be applied to generate testable hypotheses for investigating the mechanisms concerned with metabolic compartmentation and regulation in brain. In the process of the illustration, we discuss some of the evidence in support of the general hypothesis that the transfer of reducing equivalents across the inner mitochondrial membrane plays a major role in mediating the coupling of the glycolytic flux to that of the citric acid cycle. We have given some indications as to how this hypothesis could be further investigated employing our approach. Moreover, we hope that other workers will find this integrated approach useful in designing multidisciplinary studies to investigate mechanistic issues related to this important theme.

Animals↗
PubMed2004

Fluorescence resonance energy transfer-based analysis of cAMP dynamics in live neonatal rat cardiac myocytes reveals distinct functions of compartmentalized phosphodiesterases.

Cardiac myocytes have provided a key paradigm for the concept of the compartmentalized cAMP generation sensed by AKAP-anchored PKA. Phosphodiesterases (PDEs) provide the sole route for degrading cAMP in cells and are thus poised to regulate intracellular cAMP gradients. PDE3 and PDE4 represent the major cAMP degrading activities in rat ventriculocytes. By performing real-time imaging of cAMP in situ, we establish the hierarchy of these PDEs in controlling cAMP levels in basal conditions and on stimulation with a beta-adrenergic receptor agonist. PDE4, rather than PDE3, appears to be responsible for modulating the amplitude and duration of the cAMP response to beta-agonists. PDE3 and PDE4 localize to distinct compartments and this may underpin their different functional roles. Our findings indicate the importance of distinctly localized PDE isoenzymes in determining compartmentalized cAMP signaling.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2006

Compartmentation of cyclic nucleotide signaling in the heart: the role of A-kinase anchoring proteins.

The activation of the cyclic nucleotide protein kinase A (PKA) and PKG by their respective second messengers is responsible for the modulation of many cellular functions in the heart including cardiac hypertrophy, strength of contraction, and ion flux. However, several studies have revealed that a general increase in cyclic nucleotide concentration in the cell is not sufficient for the specific regulation of target proteins. These studies found that PKA and PKG must be colocalized with their targets to ensure spatial-temporal control of substrate phosphorylation. This compartmentation of cyclic nucleotide signaling is accomplished by tethering the protein kinases with their respective substrates through the association with scaffolding proteins. For cAMP signaling, A-kinase anchoring proteins (AKAPs) provide a molecular mechanism for cAMP compartmentation, allowing for the precise control of PKA-mediated phosphorylation events. (cAMP, PKA, AKAP, PKG).

Adaptor Proteins, Signal Transducing↗
PubMed1991

Compartmentation of cAMP in adult canine ventricular myocytes. Relation to single-cell free Ca2+ transients.

Isolated adult canine ventricular myocytes were used to study the role of compartmentation of cAMP in the diverse functional responses to various drugs that elevate cAMP. Myocytes presented with the beta-agonist isoproterenol accumulated cAMP with a half maximally effective concentration (EC50) of 3.55 x 10(-8) M. Approximately 45% of the total cAMP was recovered in the particulate fraction of digitonin-lysed myocytes under these conditions. With phosphodiesterase inhibition (10 microM isobutylmethylxanthine), isoproterenol-stimulated cAMP production was up to 3.4-fold greater, but the proportion of total cAMP residing in the particulate fraction declined to less than 20%. Similar results were obtained with forskolin, a direct activator of adenylate cyclase. Treatment with isoproterenol shortened the duration at 50% maximum peak height (T 1/2) and increased the peak fluorescence ratio of electrically triggered single-cell free Ca2+ transients in fura-2-loaded canine myocytes. Isoproterenol dose-response curves gave EC50 values of 1.7 x 10(-9) and 4.4 x 10(-9) M for effects on T 1/2 and peak height, respectively. Alterations in peak height and T 1/2 of Ca2+ transients also showed a dose dependency on isobutylmethylxanthine and forskolin. Comparison of myocyte cAMP content with the corresponding changes in free Ca2+ transients demonstrated a close correlation between particulate cAMP and the extent of shortening or increase in peak height of the fura-2 Ca2+ transients (r = 0.92 for each). However, when these two parameters were plotted as a function of total cAMP, the resulting curves were nonlinear and divergent for each agent tested. The results support the hypothesis that differences in responses to agents that augment cAMP can be explained in part by compartmentation of cAMP. Furthermore, Ca2+ mobilization seems to be most affected by cAMP located in the particulate compartment of canine cardiac myocytes.

Adrenergic beta-Agonists↗
PubMed1984

Kinetic compartmental analysis of carnitine metabolism in the human carnitine deficiency syndromes. Evidence for alterations in tissue carnitine transport.

The human primary carnitine deficiency syndromes are potentially fatal disorders affecting children and adults. The molecular etiologies of these syndromes have not been determined. In this investigation, we considered the hypothesis that these syndromes result from defective transport of carnitine into tissues, particularly skeletal muscle. The problem was approached by mathematical modeling, by using the technique of kinetic compartmental analysis. A tracer dose of L-[methyl-3H]carnitine was administered intravenously to six normal subjects, one patient with primary muscle carnitine deficiency (MCD), and four patients with primary systemic carnitine deficiency (SCD). Specific radioactivity was followed in plasma for 28 d. A three-compartment model (extracellular fluid, muscle, and "other tissues") was adopted. Rate constants, fluxes, pool sizes, and turnover times were calculated. Results of these calculations indicated reduced transport of carnitine into muscle in both forms of primary carnitine deficiency. However, in SCD, the reduced rate of carnitine transport was attributed to reduced plasma carnitine concentration. In MCD, the results are consistent with an intrinsic defect in the transport process. Abnormal fluctuations of the plasma carnitine, but of a different form, occurred in MCD and SCD. The significance of these are unclear, but in SCD they suggest abnormal regulation of the muscle/plasma carnitine concentration gradient. In 8 of 11 subjects, carnitine excretion was less than dietary carnitine intake. Carnitine excretion rates calculated by kinetic compartmental analysis were higher than corresponding rates measured directly, indicating degradation of carnitine. However, we found no radioactive metabolites of L-[methyl-3H]carnitine in urine. These observations suggest that dietary carnitine was metabolized in the gastrointestinal tract.

Adult↗
PubMed1993

Analysis of segmental phosphate absorption in intact rats. A compartmental analysis approach.

Available information supports the dominance of the proximal intestine in inorganic phosphate (Pi) absorption. However, there is no strategy for analyzing segmental Pi absorption from a spontaneously propelled meal in an intact animal. We propose a solution using compartmental analysis. After intragastric administration of a 32P-labeled Pi liquid meal containing a nonabsorbable marker, [14C]polyethylene glycol (PEG), rats were killed at 2, 10, 20, 30, 60, 120, and 240 min. The gastrointestinal tract was removed and divided into seven segments, from which 32P and [14C]PEG were recovered. Data was expressed as a percentage of the dose fed, i.e., (32P[in segment] divided by 32P[fed]) and [14C]PEG[in segment] divided by [14C]PEG[fed]), respectively. A compartmental model was constructed and the rate constants for intersegmental transit and segmental absorption were estimated. The "goodness of fit" between the simulated model and the actual data indicates the estimated rate constants reflect in vivo events. The duodenum, with the highest transit and absorption rates, accounted for a third of the total absorption. However, the terminal ileum, with a lower absorption rate but a longer transit time, absorbed an equal amount of Pi. This approach allows the analysis of the mechanism and the regulation of Pi absorption under more authentic in vivo conditions.

Animals↗
PubMed2003

Compartmentation of glutamine, glutamate, and GABA metabolism in neurons and astrocytes: functional implications.

The classical concept regarding compartmentation of brain metabolism pertinent to the two neurotransmitter amino acids, glutamate and GABA (gamma-aminobutyrate), operates with different pools of glutamate and glutamine in different cell types, that is, pools that have different sizes and turnover rates. As a result of more sophisticated technology (e.g., nuclear magnetic resonance spectroscopy and mass spectrometry used in relation to cultured neurons and astrocytes), a more complex scenario is emerging. Hence, both neurons and astrocytes exhibit a compartmentalized metabolism that very likely relates to individual cells containing mitochondrial populations having different metabolic roles. Models for this in neurons and astrocytes, respectively, are presented. The functional implications of this for the homeostatic mechanisms regulating the levels of neurotransmitter glutamate and GABA are discussed in relation to development of therapeutic strategies for neurological disorders in which these transmitters are believed to play important roles.

Animals↗
PubMed2003

Evolution of energy metabolism and its compartmentation in Kinetoplastida.

Kinetoplastida are protozoan organisms that probably diverged early in evolution from other eukaryotes. They are characterized by a number of unique features with respect to their energy and carbohydrate metabolism. These organisms possess peculiar peroxisomes, called glycosomes, which play a central role in this metabolism; the organelles harbour enzymes of several catabolic and anabolic routes, including major parts of the glycolytic and pentosephosphate pathways. The kinetoplastid mitochondrion is also unusual with regard to both its structural and functional properties.In this review, we describe the unique compartmentation of metabolism in Kinetoplastida and the metabolic properties resulting from this compartmentation. We discuss the evidence for our recently proposed hypothesis that a common ancestor of Kinetoplastida and Euglenida acquired a photosynthetic alga as an endosymbiont, contrary to the earlier notion that this event occurred at a later stage of evolution, in the Euglenida lineage alone. The endosymbiont was subsequently lost from the kinetoplastid lineage but, during that process, some of its pathways of energy and carbohydrate metabolism were sequestered in the kinetoplastid peroxisomes, which consequently became glycosomes. The evolution of the kinetoplastid glycosomes and the possible selective advantages of these organelles for Kinetoplastida are discussed. We propose that the possession of glycosomes provided metabolic flexibility that has been important for the organisms to adapt easily to changing environmental conditions. It is likely that metabolic flexibility has been an important selective advantage for many kinetoplastid species during their evolution into the highly successful parasites today found in many divergent taxonomic groups.Also addressed is the evolution of the kinetoplastid mitochondrion, from a supposedly pluripotent organelle, attributed to a single endosymbiotic event that resulted in all mitochondria and hydrogenosomes of extant eukaryotes. Furthermore, indications are presented that Kinetoplastida may have acquired other enzymes of energy and carbohydrate metabolism by various lateral gene transfer events different from those that involved the algal- and alpha-proteobacterial-like endosymbionts responsible for the respective formation of the glycosomes and mitochondria.

Journal Article↗
PubMed2001

Compartmental model for aluminium biokinetics.

An open compartmental model for describing aluminium biokinetics is presented with a central compartment consisting of transferrin- and citrate-bound aluminium in blood plasma and interstitial fluid, and three peripheral compartments for organs, muscles and bones and the gastro-intestinal tract. The rate constants describing the transport of aluminium are normalized to an estimated plasma volume and do not depend on the size of the individual. Effects due to changes in compartmental sizes or to transport characteristics are described. The model is applied to biokinetics studies of a volunteer after i.v. administration and of Sprague-Dawley rats with different iron status and with nephrectomization after p.o. administration of 26Al.

Absorption↗
PubMed1983

The role of compartmentalization of epinephrine in the regulation of phenylethanolamine N-methyltransferase synthesis in rat adrenal medulla.

The mechanism of regulation of phenylethanolamine N-methyltransferase (PNMT) in rat adrenal medulla after hypophysectomy and dexamethasone treatment was studied. The activity, amounts, and rates of synthesis and degradation of PNMT were measured in explants of adrenal medullae from sham-operated, hypophysectomized, and hypophysectomized-dexamethasone-treated rats. The storage, uptake, and catabolism of [3H]epinephrine were also measured in these three groups to determine any alteration in the granular vs. extragranular compartmentalization of epinephrine induced by these procedures. In addition, the effect of epinephrine on the rate of the enzyme's synthesis and degradation in cultured explants of medullae was measured. The results indicate that the 40% decrease in the amount of PNMT 1 month after hypophysectomy is due to a 28% decrease in the specific rate of synthesis of this enzyme. Dexamethasone treatment restores both the rate of synthesis of the enzyme and the amount of this enzyme found in the tissue to control levels. Our studies show that there is a 73% increase in uptake of [3H]epinephrine into medullary explants from hypophysectomized rats compared to controls. Fifty-six percent of this [3H]epinephrine was converted to metabolites in both groups, indicating that hypophysectomy produced no change in the rate of catabolism. However, uptake of [3H] epinephrine into medullary storage granules from hypophysectomized rats was decreased by 50%. These studies on the uptake, storage, and catabolism indicate that hypophysectomy favors conditions that increase levels of extragranular epinephrine. This altered compartmentalization is reversed by dexamethasone treatment, which decreases the uptake and increases the binding of epinephrine. Epinephrine added to cultured tissue decreased the rate of biosynthesis of PNMT by 22%, an extent similar to that observed after hypophysectomy. It is concluded that the effect of hypophysectomy on this enzyme is mediated by epinephrine.

Adrenal Medulla↗