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Biomedical subjects

G G Bach

Publications and source records attributed to G G Bach.

At least 19 recordsLinked to original sources
PubMed2000

Uptake of lactate by the liver: effect of red blood cell carriage.

Multiple-indicator dilution experiments with labeled lactate were performed in the livers of anesthetized dogs. A mixture of (51)Cr-labeled erythrocytes, [(3)H]sucrose, and L-[1-(14)C]lactate or a mixture of (51)Cr-labeled erythrocytes, [(14)C]sucrose, and L-[2-(3)H]lactate was injected into the portal vein, and samples were obtained from the hepatic vein. Data were evaluated using a model comprising flow along sinusoids, exchange of lactate between plasma and erythrocytes and between plasma and hepatocytes, and, in the case of L-[1-(14)C]lactate, metabolism to H[(14)C]O(-)(3) within hepatocytes. The coefficient for lactate efflux from erythrocytes was 0.62 +/- 0.24 s(-1), and those for influx into and efflux from hepatocytes were 0.44 +/- 0.13 and 0.14 +/- 0.07 s(-1), respectively. The influx permeability-surface area product of the hepatocyte membrane for lactate (P(in)S, in ml x s(-1) x g(-1)) varied with total flow rate (F, in ml s(-1) x g(-1)) according to P(in)S = (3.1 +/- 0.5)F + (0.021 +/- 0.014). Lactate in plasma, erythrocytes, and hepatocytes was close to equilibrium, whereas lactate metabolism was rate limiting.

Acetates↗
PubMed1996

Kinetics of pulmonary uptake of serotonin during exercise in dogs.

The multiple indicator-dilution technique was employed in the exercising dog to evaluate the effect of increasing activity on the pulmonary extraction and kinetics of removal of tracer 3H-labeled serotonin (5-HT) and on the measured central blood volume and tracer-accessible extravascular lung water. 51Cr-labeled red blood cells, 125I-labeled albumin, and 14C-labeled 1,8-octanediol were injected with labeled 5-HT at rest and at two increasing levels of exercise (lower and higher in 9 dogs). Blood flow approximately tripled at the highest level of exercise, and the central blood volume increased linearly with increasing blood flow. The tracer-accessible extravascular lung water increased in the transition from rest to low-level exercise and stabilized at an average proportion of 0.85 of the gravimetric extravascular lung water at the higher values of blood flow. The average labeled 5-HT extraction at rest was 42 +/- 11%, and this slowly decreased with increase in flow. The calculated permeability-surface area product for 5-HT increased approximately directly with increasing blood flow. We conclude that exercise results in an increase in the central blood volume that is accompanied by an increase in the tracer-accessible extravascular lung water (lung tissue recruitment) over low exercise levels, with no change at higher levels of exercise, and that the pulmonary capillary surface area subserving 5-HT uptake increases almost linearly with flow over the range of flows attained.

Animals↗
PubMed1995

Tracer oxygen distribution is barrier-limited in the cerebral microcirculation.

The kinetics of tracer oxygen distribution in the brain microcirculation of the awake dog were investigated with the multiple indicator dilution technique. A bolus containing 51Cr-labeled red blood cells, previously totally desaturated and then resaturated with [18O]2 (oxygen), 125I-albumin, 22Na, and [3H]water, was injected into the carotid artery, and serial anaerobic blood samples were collected from the sagittal sinus over the next 30 seconds. The outflow recovery curves were analyzed with a distributed-in-space two-barrier model for water and a one-barrier model for oxygen. The analysis provided an estimate of flow per gram brain weight as well as estimates for the tracer water and oxygen rate constants for blood-to-brain exchange and tracer oxygen parenchymal sequestration. Flow to tissue was found to vary between different animals, in concert with parallel changes in oxygen consumption. The 18O2 outflow curves showed an early peak, coincident with and more than half the magnitude of its vascular reference curve (labeled red blood cells), whereas the [3H]water curve increased abruptly to a low-in-magnitude curve at low flow values and to a small early peak at high flow values. Analysis indicates that the transfers of both 18O2 and [3H]water indicators from blood to brain are barrier-limited, with the former highly so because of the large red blood cell capacity for oxygen, and that the proportion of the tracer oxygen returning to the circulation from tissue is a small fraction of the total tracer emerging at the outflow.

Animals↗
PubMed1993

Distributed-in-space product formation in vivo: linear kinetics.

Distributed-in-space conversion of precursor substrate to product within an organ is explored when all formed product is released into the bloodstream. When precursor removal kinetics are linear (conversion occurring proportionately to concentration) and the process is uniformly distributed along the length, exponentially decreasing concentration profiles for precursor result. The vascular profile for product rises in complementary fashion; the sum of precursor and product is constant along the length. Symmetric permeability barriers are found to produce concentration stepdowns of precursor from blood to tissue and, for product, converse stepdowns from tissue to blood. Tracer precursor, introduced as an impulse input, within this steady state, is converted to product, details varying with the number of barriers. Nevertheless, a particular common feature is found in the solutions. The analytic expression for locally generated tracer product is found, in each case, to contain the impulse response to tracer product introduced at the origin. Therefore, to simplify experimental analysis and to superpose a set of constraints on computational approaches to parameter estimation, one should introduce, simultaneously with tracer precursor, tracer product labeled in an identifiably different manner.

Animals↗
PubMed1993

Distributed-in-space product formation in vivo: enzymic kinetics.

Distributed-in-space Michaelis-Menten enzymic conversion of precursor substrate to product within an organ is explored when all formed product is released into the bloodstream. In the nonlinear saturating enzymic case, length-wise precursor concentration profiles are found to vary from a falling exponential to a slowly declining linear profile, with rise in input concentration. The vascular profile for product rises in complimentary fashion; the sum of precursor and product is constant along the length. Symmetric permeability barriers produce stepdowns in precursor concentration from blood to tissue and, for product, converse stepdowns from tissue to blood are produced. Tracer precursor, introduced as an impulse input within this steady state, is converted to product with details of its distribution varying with the number of barriers for precursor. During this conversion, reversible tracer precursor association with enzyme leads to an enzymic space effect perceived as a saturating additional compartment, largest at tracer bulk levels, and decreasing with increase in underlying bulk concentration. While tracer product is not delayed by enzyme association, its outflow profile varies with the amount and location of enzyme, the enzymic rate constants, and the barriers for product between enzyme and the blood.

Animals↗
PubMed1992

Uptake of a protein-bound polar compound, acetaminophen sulfate, by perfused rat liver.

The hepatocytic entry of acetaminophen sulfate conjugate was examined in the rat liver, perfused with red cells with and without albumin, by use of the multiple-indicator dilution technique. [3H]acetaminophen sulfate was injected into the portal vein in a bolus of blood containing 51Cr-labeled red blood cells (a vascular reference), sucrose (a low-molecular-weight interstitial reference) or 125I-labeled albumin (a high-molecular-weight interstitial reference, included when albumin was present), and the time courses of their outflow into the hepatic venous blood were observed. The [3H]acetaminophen sulfate, which binds partially to albumin, emerged between albumin and sucrose in the presence of albumin, processed the upslope of the sucrose curve and showed a late low-in-magnitude tailing; the precession disappeared in the absence of albumin. Biliary excretion of [3H]acetaminophen sulfate was less than 1% of the dose. Quantitative evaluation with a barrier-limited, space-distributed variable transit time model (including rapidly equilibrating albumin binding) accounted for the albumin effect on [3H]acetaminophen sulfate behavior and demonstrated a low liver cell permeability for the acetaminophen sulfate and a small interstitial binding space for its nonalbumin-bound fraction in excess of that for sucrose, which in the absence of albumin was of similar dimensions.

Acetaminophen↗
PubMed1992

Flow-limited tracer oxygen distribution in the isolated perfused rat liver: effects of temperature and hematocrit.

We used the multiple-indicator dilution technique to examine the kinetics of tracer oxygen distribution and uptake in the rat liver perfused in a nonrecirculating fashion with blood. 51Cr-labeled 18O2-saturated erythrocytes, labeled albumin, sucrose and water (the tracers for oxygen and vascular, interstitial and cellular references) were injected simultaneously into the portal vein. Timed anaerobic samples were collected from the hepatic vein and analyzed by mass spectrometry for relative 18O2 enrichment and radioactivity. In a set of experiments performed at 32 degrees C, oxygen uptake was substantially diminished; tracer oxygen profiles approached those expected for a completely recovered, flow-limited substance. At 37 degrees C, much larger tracer oxygen sequestration occurred. Experiments were carried out at each temperature at higher and lower hematocrit, and oxygen consumption at each temperature was found to be independent of hematocrit. The tissue space of distribution for tracer oxygen relative to the total sinusoidal vascular content was influenced by the hematocrit: it was smaller at higher hematocrit and larger at lower hematocrit, as expected. The derived partition coefficient of oxygen for liver cells relative to plasma (expressed in terms of the liver and plasma water spaces) was, on average, 2.62 ml/ml; it was independent of the hematocrit. Analysis of the indicator dilution experiments indicates that the tracer oxygen is distributed into tissue in a flow-limited rather than a barrier-limited fashion, and that with this, an ongoing concomitant intracellular sequestration of tracer can be seen.

Animals↗
PubMed1992

Pulmonary angiotensin-converting enzyme substrate hydrolysis during exercise.

We examined exercise-induced changes in indicator-dilution estimates of the angiotensin-converting enzyme first-order kinetic parameter, the ratio of a normalized maximal enzymatic conversion rate to the Michaelis constant (Amax/Km), which, under stable enzymatic conditions, will vary with the pulmonary vascular surface area accessible to vascular substrate, the extravascular lung water (an index of the proportion of lung tissue perfused), and the central blood volume (from pulmonary trunk to aorta). Experiments were performed in 10 mongrel dogs at rest and through two increasing levels of treadmill exercise, with the use of two vascular space tracers (labeled erythrocytes and albumin), a water space tracer ([1,8-14C]-octanediol), and a vascular endothelium surface area marker, benzoyl-Phe-Gly-Pro ([3H]BPGP), which is a pharmacologically inactive angiotensin-converting enzyme substrate. The exercise-induced increase in cardiac output was accompanied by a linear increase in central blood volume, and dilutional extravascular lung water rapidly increased to an asymptotic proportion close to 100% of postmortem vascular lung water. There was an average 55% [3H]BPGP hydrolysis, which did not vary with flow, and the computed Amax/Km increased linearly with exercise. We conclude that exercise results in complete lung tissue recruitment and increases the pulmonary vascular surface area available for BPGP hydrolysis linearly with flow, so that pulmonary vascular recruitment continues after full tissue recruitment.

Amino Acid Sequence↗
PubMed1989

Handling of tracer norepinephrine by the dog liver.

Norepinephrine handling by the dog liver was appraised by carrying out tracer-transient, multiple-indicator-dilution studies within steady-state conditions in a basal situation, during norepinephrine infusion and after the uptake inhibitor desipramine. In controls, tracer norepinephrine extraction averaged 61%, whereas bulk norepinephrine extraction was approximately 31%; intrahepatic secretion of unlabeled norepinephrine accounted for the difference. Infusion of norepinephrine, raising arterial levels more than an order of magnitude, constricted the hepatic vascular space but did not change tracer extraction; norepinephrine secretion remained essentially unchanged, and with this, bulk extraction approached tracer extraction. A theoretical analysis of norepinephrine uptake was developed. Analysis of tracer data with this indicated that the permeability surface products for influx and efflux, expressed per gram liver, did not change. Desipramine did not affect the uptake kinetics, indicating that the uptake process was virtually completely nonneurogenic. Late efflux of tracer normetanephrine product was detected but was small prior to recirculation. The study demonstrates that norepinephrine secretion ordinarily coexists with uptake and provides an approach to quantitating both.

Animals↗
PubMed1984

Effect of beta-adrenergic blockade on in vivo norepinephrine release in canine heart.

The beta-adrenergic blockade-induced reduction in myocardial norepinephrine overflow during sympathetic stimulation was examined by use of the multiple indicator-dilution technique. A kinetic model incorporating the effects of flow, capillary permeability surface product for norepinephrine, the interstitial uptake rate constant for neurotransmitter, and plasma norepinephrine input and output values was used to estimate the rate of local release of norepinephrine into the interstitial space. The model was tested by first examining the effects of two drugs that increase myocardial norepinephrine overflow during sympathetic stimulation by differing mechanisms: desmethylimipramine, a norepinephrine uptake inhibitor, and phentolamine, an alpha-adrenergic blocker. The uptake inhibitor was demonstrated to reduce interstitial uptake and the alpha-blocker to increase local neurotransmitter release, without change in blood flow. The beta-adrenergic blocker, in contrast, reduced coronary blood flow and decreased the capillary norepinephrine permeability surface product but did not change the rate of local release. The decreased norepinephrine overflow after beta-blockade was deduced to result from the decrease in transcapillary flux and secondary increase in interstitial uptake.

Adrenergic beta-Antagonists↗
PubMed1983

Uptake of monohydric alcohols by liver: demonstration of a shared enzymic space.

Multiple-indicator dilution studies of the hepatic uptake of straight-chain C1-C5 monohydric alcohols were carried out in anesthetized dogs, with either no preceding or saturating infusions of ethanol, and at different steady-state levels for the C2 experiments. Labeled red cells were utilized as a vascular reference, and labeled water was used as a second reference entering liver cells. Kinetic analysis of the data provided estimates of both an uptake rate constant and the space of distribution available to label. From the decrease in the uptake rate constant for labeled ethanol with bulk concentration, we calculated a maximal removal rate of 0.025 mumol X s-1 X (ml liver water)-1 and a Michaelis constant (Km) of 0.32 mM. Especially for the labeled C3-C5 alcohols, a space in excess of that available to water was found, and the bulk of this was dissipated by ethanol infusion. The increment, the "shared enzymic space", which varies with enzymic concentration and inversely with Km, was used to calculate Km values for the other alcohols.

Alcohol Dehydrogenase↗
PubMed1983

Effects of saturating metabolic uptake on space profiles and tracer kinetics.

Vascular and steady-state lengthwise concentrations evolving in tissue as a consequence of saturable uptake processes are explored when there is no effective barrier between blood and tissue, when there is one effective barrier (the liver), and when barriers are present at both capillary and cell membrane. Falling exponential profiles develop at low-input concentrations and grade over into much smaller linear decreases at high concentrations. Uptake behind an effective barrier produces a step-down in concentration. With no effective barriers, a tracer impulse propagates to the outflow in a delayed fashion, reversible binding to the enzymic removal mechanism increasing its space of distribution and delaying it further and irreversible uptake diminishing its area. As bulk concentration is increased, proportional tracer uptake diminishes and ultimately approaches zero. With barriers in the system, tracer output consists of an impulse damped by cell entry, followed by outflow recovery of material that has escaped cell uptake. Increase in bulk concentration is found to saturate the uptake mechanism, with a proportionate increase in the returning material.

Animals↗
PubMed1977

The capillary and sarcolemmal barriers in the heart. An exploration of labeled water permeability.

Although the exchange of labeled water between blood and tissue in the heart has usually been assumed to be flow-limited, the outflow patterns of labeled water, relative to intravascular references, in a multiple indicator dilution experiment, have appeared to be anomalous in terms of the models used to explain the transport of less permeable substances. Data showing a change in the shape of the labeled water outflow curve after vasodilation and after the infusion of toxic doses of 2,4-dinitrophenol led us to propose a new model for labeled water permeation which includes barriers at both the capillary wall and the sarcolemmal membrane. This model explains adequately the form of the outflow curve, provides parameters related to the permeability at the two barriers, and gives an estimate of the ratio of the intracellular to interstitial space. Dinitrophenol infused intra-arterially in a dose sufficient to cause S-T elevation in the electrocardiogram is found to reduce the sarcolemmal water permeability by an order of magnitude, but to have no effect on capillary water permeability. We conclude that water transport in the heart is barrier-limited at both the capillary and sarcolemmal membranes and that sarcolemmal water permeability is probably mediated at least in part by a structure sensitive to the effects of dinitrophenol, presumably a protein channel. Since the outflow patterns of inert gases resemble that of labeled water, it is possible that oxygen distribution is also barrier-limited.

Animals↗
PubMed1975

Red cell carriage of label: its limiting effect on the exchange of materials in the liver.

The red cell membrane is a permeability barrier that limits the equilibration of a variety of solutes between red cell and plasma water. We utilized the multiple indicator dilution technique to investigate the effect of this barrier on the exchange in the liver of a group of tracer substances that are not removed in net fashion from the hepatic circulation: thiourea, urea, and chloride. We demonstrated that, after preequilibration of the label with red cells, a red cell carriage effect appeared (the trapping and translocation of label in the red cells), that this effect was most marked when the permeability of the red cell was relatively low for the substance under consideration (thiourea), and that the effect became small when the permeability of the red cells was large for the exchanging substance (urea and chloride). We developed a theoretical description of the retarding effect of the red cell permeability barrier on the extravascular exchange of label and were able to use this description to obtain estimates of the red cell permeability from the in vivo dilution curves. We examined the effect of plasma injection, of changing the input in such a fashion that the label was not preequilibrated with red cells, and found both experimentally and theoretically, that for substances of low permeability the transit time from these experiments, if multiplied by the total water flow or solute flux, gave an overestimate of both the apparent total volume of distribution and the mass of traced material in the system. This last effect is of great importance for the practical design of many biological experiments. Reliable volume and mass estimates can be made only when the labeled material has been preequilibrated with red cells.

Animals↗
PubMed1973

On the uptake of materials by the intact liver. The transport and net removal of galactose.

D-galactose, a monosaccharide rapidly phosphorylated within liver cells, is irreversibly removed from the portal circulation. We have studied the kinetic relations between the hepatic cell entry process and the metabolic sequestration process, by means of the multiple indicator dilution technique. Labeled red blood cells (a vascular indicator), labeled sucrose (an extracellular reference), and labeled galactose were rapidly injected into the portal vein, and from rapidly sampled hepatic venous blood, normalized outflow-time patterns were secured. The labeled red cell curve rises to the highest and earliest peak, and decays rapidly; and that for labeled sucrose rises to a later and lower peak. Its extrapolated recovery is equivalent to that of the labeled red cells. At low blood galactose concentrations, the labeled galactose appears at the outflow with labeled sucrose, but is much reduced in magnitude, and exhibits a long tailing. Its outflow recovery is much reduced. At high blood galactose concentrations, the initial part of the profile increases towards that for labeled sucrose, the tailing becomes much larger in magnitude, and the outflow recovery becomes virtually complete. We have modeled the uptake of labeled galactose, and find two parts to the predicted outflow pattern, corresponding to our experimental observations; throughput material, which sweeps past the cell surface in the extracellular space; and returning material, which has entered the cells but escaped the sequestration process. Analysis of the data by use of this model provides estimates of both transmembrane fluxes and rates of sequestration. The capacity of the process subserving cell entry is found to be 40 times that for phosphorylation; and, whereas the K(m) value for sequestration is less than 15 mg/100 ml, that for entry is approximately 500 mg/100 ml. Both processes are relatively stereospecific; the entry of the L-stereoisomer is very slow and it undergoes no significant amount of metabolic sequestration. The sequestration process produces a lobular intracellular concentration gradient; and this gradient, in turn, produces some uncertainty in the estimate of the true K(m) value for the sequestration process.

Animals↗