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PubMed2001

Energy nutrients modulate the splanchnic sequestration of dietary nitrogen in humans: a compartmental analysis.

We used a previously developed compartmental model to assess the postprandial distribution and metabolism of dietary nitrogen (N) in the splanchnic and peripheral areas after the ingestion of a single meal containing milk protein either alone (MP) or with additional sucrose (SMP) or fat (FMP). The addition of fat was predicted to enhance splanchnic dietary N anabolism only transiently, without significantly affecting the global kinetics of splanchnic retention and peripheral uptake. In contrast, the addition of sucrose, which induced hyperinsulinemia, was predicted to enhance dietary N retention and anabolism in the splanchnic bed, thus leading to reduced peripheral dietary amino acid availability and anabolism. The incorporation of dietary N into splanchnic proteins was thus predicted to reach 18, 24, and 35% of ingested N 8 h after MP, FMP, and SMP, respectively. Such a model provides insight into the dynamics of the system in the nonsteady postprandial state and constitutes a useful, explanatory tool to determine the region-specific utilization of dietary N under different nutritional conditions.

Amino Acids↗
PubMed1992

Minimal compartmental model of circulatory mixing of indocyanine green.

A model of indocyanine green (ICG) disposition from the moment of its injection in blood was developed. ICG disposition was characterized in five dogs deeply anesthetized with halothane, which decreased cardiac output and prolonged intravascular mixing. After ICG injection into the right atrium, femoral arterial blood samples were collected every 3 s for the 1st min and less frequently to 20 min. ICG concentrations were measured by high-performance liquid chromatography and modeled with SAAM 30.1. A fully identifiable recirculatory compartmental model with time delays was used to describe ICG disposition. The central blood volume averaged 23.4 ml/kg, and total blood volume averaged 78.9 ml/kg. Fifty-three percent of the cardiac output flowed through 14% of the peripheral blood volume while the remaining 47% flowed through 86% of the peripheral volume. This new model is isomorphic with a parallel channel, lumped-parameter circulation model and provides more information than stochastic, noncompartmental recirculatory pharmacokinetic techniques. This intravascular mixing model can be applied to determine the contribution of the circulation to drug distribution.

Analysis of Variance↗
PubMed1996

Compartmentalized lung cytokine release in response to intravascular and alveolar endotoxin challenge.

Lung cytokine generation has been implicated in pulmonary injury and systemic inflammatory responses. In bufferperfused rabbit lungs, intravascular endotoxin (10 ng/ml perfusate; total amount 7 micrograms) provoked the liberation of 212,100 +/- 119,700 pg tumor necrosis factor-alpha (TNF-alpha) into the vascular space within 3 h. This was augmented to 3,564,400 +/- 1,285,900 pg in the presence of 1% serum. Bronchoalveolar lavages demonstrated the absence of buffer-admixed endotoxin and transition of only minor fractions of the vascular TNF-alpha load into the alveolar space. Aerosolization of 22 micrograms endotoxin liberated 824,400 +/- 48,750 pg TNF-alpha into the alveolar compartment, which was even increased to 16,980,000 +/- 6,066,350 pg on co-nebulization of serum. No endotoxin and only minor amounts of the alveolar TNF-alpha burden spilled over into the vascular compartment. Vascular pressures and lung vascular permeability did not change. We conclude that both intravascular and alveolar endotoxin challenge provokes excessive lung TNF-alpha generation, amplified manyfold in the presence of small serum quantities. For both routes of application, however, the cytokine responses were found to be largely compartmentalized under the given conditions of integer lung barrier properties.

Aerosols↗
PubMed2003

A nonlinear compartmental model of Sr metabolism. I. Non-steady-state kinetics and model building.

A model of Sr metabolism was developed by using plasma and urinary Sr kinetic data obtained in groups of postmenopausal women who received four different oral doses of Sr and collected during the Sr administration period (25 days) and for 28 days after cessation of treatment. A nonlinear compartmental formalism that is appropriate for study of non-steady-state kinetics and allows dissociation of variables pertaining to Sr metabolism (system 1) from those indirectly operating on it (system 2) was used. At each stage of model development, the dose-dependent model response was fitted to the four sets of data considered simultaneously (1 set per dose). A seven-compartment model with internal Sr distribution and intestinal, urinary, and bone metabolic pathways was selected. It includes two kinds of nonlinearities: those accounting for saturable intestinal and bone processes, which behave as intrinsic nonlinearities because they are directly dependent on Sr, and extrinsic nonlinearities (dependent on system 2), which suggest the cooperative involvement of plasma Sr changes in modulating some intestinal and bone mineral metabolic pathways. With the set of identified parameter values, the initial steady-state model predictions are relevant to known physiology, and some peculiarities of model behavior for long-term Sr administration were simulated.

Female↗
PubMed2003

A nonlinear compartmental model of Sr metabolism. II. Its physiological relevance for Ca metabolism.

We have studied the peculiarities of the nonlinear compartmental model for human Sr metabolism (Staub JF, Foos E, Courtin B, Jochemsen R, and Perault-Staub AM. Am J Physiol Regul Integr Comp Physiol 284: R819-R834, 2003), including its physiological reliability in the context of Sr-Ca similarity-dissimilarity. We found it to be relevant to Ca metabolism, except for discrimination against Sr relative to Ca at urinary and intestinal levels. The main findings are as follows: 1) the saturable part of intestinal absorption, shared by Sr and Ca, does not seem to be responsible for the discrimination of the transcellular pathway; 2) although there is little discrimination in bone, the physicochemical behaviors of Sr and Ca at the bone surface differ, at least quantitatively; and 3) Sr behaves as a "tracer" for Ca metabolic pathways and, under non-steady-state conditions, can also reveal self-regulatory processes. It is suggested that they depend on Ca2+ (cationic)-sensing receptors that are apparently more sensitive to Sr than to Ca. Acting on gastrointestinal and osteoblast lineage cells, these slow processes might contribute to adaptive, rather than homeostatic, regulation of Ca metabolism. Understanding these features could help clarify the pharmacological and therapeutic effects of oral Sr.

Calcium↗
PubMed1977

A numerical method for fitting compartmental models directly to tracer data.

A numerical method is presented for obtaining the exchange rates of a metabolic compartmental system, working directly from the time course of tracer activity and excretion after bolus injection. The conventional mathematical formulation of this problem, in terms of sums of exponential functions, is bypassed, enabling implementation of the method in a short computer program. An important by-product of the method is a set of variance-covariance estimates for the fitted parameters. The method is tested on "classic" data, both simulated and real. Its capabilities and limitations are demonstrated, and the strategy of its effective application is discussed.

Humans↗
PubMed1984

Compartmental vs. noncompartmental modeling for two accessible pools.

We examine the limitations of noncompartmental vs. compartmental modeling when two accessible pools are available in kinetic experiments. Focus is on the estimation of mean residence time, whole-body mass, and steady-state equivalent distribution volume. Examples illustrate these points.

Kinetics↗
PubMed1991

Compartmental analysis and glomerular filtration in chick embryos.

We have developed microtechniques that allow the determination of compartmental fluid distribution and glomerular filtration rate in chick embryos during three significant developmental periods: phase 1, the developmental period when the mesonephros alone is functioning; phase 2, periods of simultaneous meso/metanephric kidney function; and phase 3, the period during late development when the metanephros completely replaces the degenerated mesonephros. Water content of tissues is greater in younger embryos (89.4 +/- 0.2%, day 10) compared with older animals (78.3 +/- 0.5%, day 18). Although all major tissue components show an absolute increase in mass during this period, the embryo proper increases at five times the rate of the extraembryonic tissues. Glomerular filtration rate increases during development from 0.61 +/- 0.08 ml/h at day 10 to 2.31 +/- 0.11 ml/h at day 18. Glomerular filtration rate scales to body mass with an allometric exponent identical to adult birds only if total tissue mass (embryo + membranes) is considered. Our data suggest that significant errors in allometry will be encountered when scaling measurements are made on embryonic or fetal amniotes without taking into consideration the extraembryonic tissues.

Animals↗
PubMed1994

Estimation of rate constants for serotonin uptake and compartmentation in normal human platelets.

Biochemical and pharmacological experiments led to a model describing a thrombin-releasable (vesicular) compartment and two non-thrombin-releasable compartments for 5-hydroxytryptamine (5-HT, serotonin) in normal human platelets (J. L. Costa, K. L. Kirk, D. L. Murphy, and H. Stark. Br. J. Pharmacol. 72: 449-459, 1981). With tritiated 5-HT as substrate, the amounts of total and nonreleasable intraplatelet tritiated material were measured. Moreover, in the last set of experiments, the amounts of extraplatelet tritiated material and extraplatelet tritiated 5-HT were also measured. With these data, identification of the kinetic constants for movement between the various compartments was possible. A recent extension of the similarity transformation approach to nonlinear compartmental models was used to carry out the a priori identifiability analysis. Then numerical identification was performed by implementing and achieving efficient methods from optimal control theory. Under our experimental conditions, the main results are as follows: 1) the vesicular compartment corresponds to the platelet storage 5-HT compartment, 2) instead of pools I and II proposed previously, only a single nonreleasable thrombin-resistant pool could be detected, and 3) the optimized model computed to suit the first set of experiments fits homologous intraplatelet results obtained under similar experimental conditions in the last set of experiments and also fits one of the two supplementary extraplatelet investigations.

Blood Platelets↗
PubMed1994

Confocal microscopic analysis of fluorescein compartmentation within crab urinary bladder cells.

Fluorescein (FL), a fluorescent organic anion, is compartmentalized in cells of organic anion-secreting epithelia, e.g., OK cells, teleost proximal tubule, and crab (Cancer borealis) urinary bladder, a proximal tubule analogue. To further examine the processes involved, FL uptake and distribution were studied in C. borealis urinary bladder cells using epifluorescence and laser confocal microscopy combined with video-image analysis. Intracellular FL was about evenly split between diffuse and punctate compartments after in vitro or in vivo loading. Treatments that affected FL transport into cells (incubation with p-aminohippuric acid or glutarate) altered the FL content of both compartments. However, nocodazole, a microtubule inhibitor, did not affect diffuse FL but significantly reduced punctate FL. Finally, confocal analysis indicated that individual sites of punctate FL accumulation moved in the secretory direction at 0.83 micron/min. Nocodazole nearly abolished this movement and significantly reduced transepithelial organic anion secretion. Thus, in crab urinary bladder, a substantial fraction of total cellular FL is sequestered in vesicles, and these vesicles move in the secretory direction, by a microtubule-dependent process.

Animals↗
PubMed1996

Zinc kinetics in preterm infants: a compartmental model based on stable isotope data.

Zinc is an essential nutrient for growth; however, little is known about zinc kinetics (absorption, distribution, and excretion) in preterm infants (< 38-wk gestation). Zinc kinetics were studied in two preterm infants (gestational ages, 32 and 33 wk) following oral or intravenous administration of a stable isotope (70Zn). Plasma, red blood cells (RBC), urine, and feces were sampled for up to 30 days. Isotope enrichment was measured in tissues by inductively coupled plasma (ICP)-mass spectrometry, and zinc was determined by ICP-atomic emission spectrometry. Data were analyzed by compartmental analysis using SAAM31. Zinc intake increased during the studies, and, because body zinc was not in steady state, both tracer (70Zn) and tracee (Zn) data were fitted using analogous models. A model for adults [M. E. Wastney, R. L. Aamodt, W. F. Rumble, and R. I. Henkin. Am. J. Physiol. 251 (Regulatory Integrative Comp. Physiol. 20): R398-R408, 1986] was modified to fit data from the preterm infants. RBC data were fitted using one compartment (vs. 2 in adults), and an adult RBC subsystem was included in the model to account for zinc introduced during blood transfusions. Exchange of zinc between compartments that were not sampled was based on zinc distribution in neonates. Absorption was 42 and 34%, and endogenous fecal excretion, based on intravenous data, was 15 micrograms.kg-1.day-1. The model can be used to quantify changes in zinc kinetics of preterm infants with age, weight, and zinc intake for evaluating nutritional requirements with growth.

Administration, Oral↗
PubMed1997

Compartmental analysis of zinc kinetics in mature male rats.

A compartmental model of zinc kinetics in mature male rats was developed. The model was based on zinc and radioisotopic zinc measured in samples of plasma, skeletal muscle, kidneys, testes, spleen, bone, and intestinal segments collected at various times for up to 4 days after 65Zn was injected intravenously. Zinc intake, excretion of zinc and 65Zn in urine and feces, and the whole body retention of 65Zn were also determined. Other data used to develop the model included published information on zinc concentration and zinc kinetics in tissues that were not sampled. In the model, the intestinal tract was represented by five compartments. Plasma, spleen, kidneys, and testes were each represented by an individual compartment. In contrast, two compartments each were used to represent exchangeable zinc in liver, bone, skeletal muscle, skin, and red blood cells. The present model extends earlier models of zinc kinetics, describes the distribution of zinc in the whole body, and may provide a means to evaluate the influence of either pathophysiological conditions or dietary extremes on the metabolism of zinc.

Animals↗
PubMed2000

Development of a compartmental model of human zinc metabolism: identifiability and multiple studies analyses.

A compartmental model of zinc metabolism has been developed from stable isotope tracer studies of five healthy adults. Multiple isotope tracers were administered orally and intravenously, and the resulting enrichment was measured in plasma, erythrocytes, urine, and feces for as long as 3 wk. Data from total zinc measurements and model-independent calculations of various steady-state parameters were also modeled with the kinetic data. A structure comprised of 14 compartments and as many as 25 unknown kinetic parameters was developed to adequately model the data from each of the individual studies. The structural identifiability of the model was established using the GLOBI2 identifiability analysis software. Numerical identifiability of parameter estimates was evaluated using statistical data provided by SAAM. A majority of the model parameters was estimated with sufficient statistical certainty to be considered well determined. After the fitting of the model and data from the individual studies using SAAM/CONSAM, results were submitted to SAAM extended multiple studies analysis for aggregation into a single set of population parameters and statistics. The model was judged to be valid based on criteria described elsewhere.

Adult↗
PubMed1986

PGI2 synthesis and excretion in dog kidney: evidence for renal PG compartmentalization.

To assess the concept of compartmentalization of renal prostaglandins (PG), we compared entry of PGE2 and the PGI2 metabolite 6-keto-PGF1 alpha into the renal vascular and tubular compartments, in sodium pentobarbital-anesthetized dogs. Renal arterial 6-keto-PGF1 alpha infusion increased both renal venous and urinary 6-keto-PGF1 alpha outflow. In contrast, renal arterial infusion of arachidonic acid (AA) or bradykinin (BK) increased renal venous 6-keto-PGF1 alpha outflow but had no effect on its urinary outflow. Both urinary and renal venous PGE2 outflows increased during AA or BK infusion. Ureteral stopped-flow studies revealed no postglomerular 6-keto-PGF1 alpha entry into tubular fluid. During renal arterial infusion of [3H]PGI2 and inulin, first-pass 3H clearance was 40% of inulin clearance; 35% of urinary 3H was 6-keto-PGF1 alpha, and two other urinary metabolites were found. During renal arterial infusion of [3H]6-keto-PGF1 alpha and inulin, first-pass 3H clearance was 150% of inulin clearance; 75% of urinary 3H was 6-keto-PGF1 alpha, and only one other metabolite was found. We conclude that in the dog PGE2 synthesized in the kidney enters directly into both the renal vascular and tubular compartments, but 6-keto-PGF1 alpha of renal origin enters directly into only the renal vascular compartment.

6-Ketoprostaglandin F1 alpha↗
PubMed1985

Compartmental analysis of the efflux of l-[3H]norepinephrine from isolated perfused rat lungs.

Isolated rat lungs, pretreated with 100 microM pargyline and 100 microM U-0521 (3',4'-dihydroxy-2-methylpropriophenone) to block metabolism of norepinephrine (NE), were perfused with 0.3 microM 3H-labeled l-norepinephrine (1-[3H]-NE) for 30 min. Efflux samples were then collected for 30 min during washout of the tissue with amine-free Krebs solution. Compartmental analysis (nonlinear least-squares regression) of the efflux of tissue l-[3H]NE content vs. time indicates that NE is accumulated in a large slowly equilibrating compartment (t 1/2 = 58.15 +/- 6.84 min) in addition to distribution in the vascular (blue dextran tracer) and extracellular ([3H]sorbitol tracer) fluid compartments of the lung. Pretreatment of the lungs with 100 microM cocaine hydrochloride reduces the total l-[3H]NE space from 7.44 +/- 1.91 to 2.48 +/- 0.23 ml/g (P less than 0.05) by selectively decreasing the size of the slow NE compartment from 6.99 +/- 1.97 to 1.67 +/- 0.14 ml/g (P less than 0.05). The large size, cocaine sensitivity, and long efflux half time of this compartment suggest that neuronal uptake contributes to the pulmonary vascular inactivation of l-[3H]NE.

Animals↗
PubMed1988

Changes in compartmental ventilation in association with eye movements during REM sleep.

The effect of phasic eye movement activity on ventilation during rapid-eye-movement (REM) sleep was studied in seven healthy young adults by use of the respiratory inductive plethysmograph. Mean ventilation (VE) and ventilatory components during REM sleep were not significantly different from that seen in either stages 1-2 or 3-4 sleep. The percent of rib cage contribution to ventilation in REM sleep, 29.3 +/- 5.1%, was reduced compared with 54.4 +/- 5.8% in stage 1-2 and 52.2 +/- 4.3% in stage 3-4 sleep (P less than 0.005). When one separated breaths by the degree of associated phasic eye movement activity, it became apparent that breathing during REM sleep is very heterogeneous. Increasing eye movement activity was associated with inhibition of ventilation with a reduction in VE from 5.1 +/- 0.3 to 3.8 +/- 0.3 l/min. Tidal volume and frequency both fell, whereas inspiratory duration was unchanged. Compartmental ventilation was also affected, with the fall in the rib cage contribution from 37.8 +/- 6.4 to 15.3 +/- 5.6%. Chest wall and abdominal movement became more asynchronous as phasic-eye-movement activity increased and frank paradoxical breathing was seen.

Adult↗
PubMed1991

Spectral vs. compartmental averaging of VA/Q distributions: confidence limits.

We have investigated the method of statistical averaging as a nonparametric approach to obtain a representative ventilation-perfusion (VA/Q) distribution that exemplifies the family of compatible solutions for multiple inert gas elimination data. The variability of the compatible solutions was examined by determining the standard deviation of the statistical average. For six inert gases, it can be predicted that a distribution with up to seven contiguous nonzero VA/Q compartments can be uniquely recovered, whereas the compatible family becomes more diverse, the broader the distribution. For a given compatible family consisting of multimodal distributions with various phase relationships, the average distribution was found to display an uncharacteristically unimodal shape as a result of modal smoothing. To avoid this possible artifact, an alternative approach was adopted in which statistical averaging was performed in the frequency domain. For both deterministic and empirical data, the energy spectra of all feasible VA/Q distributions displayed a well-defined low-frequency band that was invariant within the compatible family and with a bandwidth that approximated the predicted sampling cutoff frequency. The nonuniqueness of the result was ascribable to a variable high-frequency band that was due to an aliasing effect. For a wide range of clinical data, the representative distributions resulting from compartmental and spectral averaging were indistinguishable from each other and had little variability both in the VA/Q and frequency domains. For these cases, therefore, the resolving power of the recovery algorithm was not critical. Finally, an efficient method of finding the average distribution was proposed.

Biometry↗
PubMed2005

Calcium dynamics and compartmentalization in leech neurons.

Calcium dynamics in leech neurons were studied using a fast CCD camera. Fluorescence changes (DeltaF/F) of the membrane impermeable calcium indicator Oregon Green were measured. The dye was pressure injected into the soma of neurons under investigation. DeltaF/F caused by a single action potential (AP) in mechanosensory neurons had approximately the same amplitude and time course in the soma and in distal processes. By contrast, in other neurons such as the Anterior Pagoda neuron, the Annulus Erector motoneuron, the L motoneuron, and other motoneurons, APs evoked by passing depolarizing current in the soma produced much larger fluorescence changes in distal processes than in the soma. When APs were evoked by stimulating one distal axon through the root, DeltaF/F was large in all distal processes but very small in the soma. Our results show a clear compartmentalization of calcium dynamics in most leech neurons in which the soma does not give propagating action potentials. In such cells, the soma, while not excitable, can affect information processing by modulating the sites of origin and conduction of AP propagation in distal excitable processes.

Action Potentials↗