Glen G. Bach

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.

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.

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.

On the Uptake of Materials by the Intact Liver THE CONCENTRATIVE TRANSPORT OF RUBIDIUM-86

In this study we use the multiple indicator dilution technique to outline the kinetic mechanisms underlying the uptake of rubidium, a cation which, in the steady state, is concentrated by hepatic parenchymal cells. We inject a mixture of (51)Cr-labeled red blood cells (a vascular reference substance), (22)Na (which is confined to the extracellular space, the expected extravascular distribution space for rubidium, in the absence of cellular uptake), and (86)Rb into the portal vein and obtain normalized outflow patterns, expressed as outflowing fractions of each injected mass per milliliter vs. time. The labeled red cell curve rises to the highest and earliest peak and decays rapidly. That for labeled sodium rises to a later and lower peak, and decays less rapidly. Its extrapolated recovery is equal to that for the red cells. The observed (86)Rb curve consists of two parts: an early clearly defined peak of reduced area, related to the (22)Na peak in timing; and a later tailing, obscured by recirculation, so that total outflow recovery cannot be defined (even though it would be expected to be the same). We model the concentrative uptake of (86)Rb and find two corresponding outflow fractions: throughput material, which sweeps past the cell surface as a wave delayed with respect to the vascular reference (tracer which has not entered cells); and exchanging material (tracer which has entered cells and later returns to the circulation). We find that the outflow form of the rubidium curve, the presence of both a relatively clearly defined throughput component and a relatively prolonged low-in-magnitude tailing, is consequent to the concentrative character of the transport mechanism, to the presence of an influx rate constant many times the efflux rate constant. The modeling which we develop is general, and has potential application in situations where transport is nonconcentrative.

Direct initiation of spherical detonations in gaseous explosives

This paper summarizes the salient results of a recent theoretical and experimental study of the propagation of spherical detonation waves initiated by a laser-induced spark. In this study, theoretical solutions of the blast-wave model were obtained using a novel analytical technique that yields a complete description of the spherical detonation wave from its initial overdriven state to its asymptotic C-J condition. Based on the approximation that hydrodynamic motion is not influenced by chemical reactions, solutions were also obtained for the propagation of spherical blast waves with finite kinetic rates. Three regimes of propagation were established experimentally: the subcritical energy regime, where decoupling of shock and reaction zone occurs; the supercritical energy regime, where the initially overdriven spherical detonation decays asymptotically to its C-J state; and the critical energy regime, where decoupling first occurs followed by the reestablishment of a highly asymmetrical multi-head detonation.

MEMBRANE TRANSPORT AND THE HEPATIC CIRCULATION

This conference has been assembled to consider the hepatic circulation and its changes in those pathological conditions which cause portal hypertension. It is our task to consider the manner in which the hepatic circulation normally provides for the nutrition of the hepatic parenchyma, and the manner in which the distribution of various substrates occurs, as the result of passive processes of distribution within the hepatic parenchyma and of specific carrier transport mechanisms localized to the cellular membranes of the hepatic parenchymal cells. One of the major characteristics of the liver which will be emphasized in this paper will be the special design of the hepatic circulation. The sinusoids are densely distributed and form an interconnected network of blood spaces which, in the mammalian liver, are separated only by the thickness of a single sheet of parenchymal cells. Blocd flow to these sinusoids is so rich that carbon black injected into an animal quickly appears in virtually every channel in the 1iver.l In addition, the sue of the sinusoids and the sue of the cells making up the hepatic cell plates is such that diffusion equilibration of substances which freely enter extravascular spaces would be expected to occur exceedingly rapidly. Nowhere in the mammalian body does the design of the microcirculation appear to be more specifically designed to facilitate a rapid approach to diffusion equilibration than in the liver. In most tissues the extravascular space is separated from the vascular space by a capillary lining, a barrier to diffusion equilibration. In the liver the lining of the sinusoids is discontinuous, and the extracellular .space becomes immediately accessible to substances dissolved in the plasma. The purpose of this paper is to consider the disposition of substances presented to the cells of the liver by distribution into this immediately accessible extracellular space when these substances interact with the cells of the liver in the following ways: by concentrative membrane carrier transport; by equilibrative membrane carrier transport; and by membrane camer transport succeeded by intracellular metabolic sequestration or effective removal from the system, within the time range being considered. In each of these situations a recognizably different pattern of events occurs. It is the purpose of the present paper to describe the characteristics of each of these patterns in a mathematical model, to demonstrate that the model has validity in terms of the real system, and thereby to provide a basis for the quantitative examination of experimental data. The kinds of data needed for this examination must be secured over a short time and, optimally, will be

Initiation criteria for diverging gaseous detonations

Further experiments on the direct initiation of spherical detonation waves in oxy-acetylene mixtures in the pressure range 20–120 torr have been carried out with detailed monitoring of the time history of the energy deposition. The magnitude of the spark energy required for direct initiation is found to depend on the discharge time, increasing in magnitude as the discharge time increases. For a fixed discharge time, the dependence of the magnitude of the source energy is found to be inversely proportional to the mixture composition. On the basis of an average power density correlation [i.e., (total spark energy/(total discharge time) × (source volume)], the discrepancies in the magnitude of the critical initiation energy can be resolved. The order of magnitude of the critical power density required for direct initiation is found to be of comparable order of magnitude as the power density of a self-sustained detonation wave. The dependence of the critical power density on initial pressure is similar to that obtained previously based on source energy (i.e., increases with decreasing pressure or increasing induction delay). Since the power density itself cannot be a meaningful parameter as the source energy can be made vanishingly small with an appropriate reduction in the discharge time or source volume or both, it is proposed that the critical energy in the limit of infinite power density should be used as the universal parameter to correlate with the properties of the explosive mixture. In view of the good agreement between the ideal-point-blast theory and experiments on laser-generated blast waves, even at very early times after the termination of the laser pulse, we concluded that the experimental value of the critical energy using a laser spark should represent the limiting value at infinite power density. A phenomenological model is proposed to gain physical insight into the coupling mechanisms between chemical kinetics and hydrodynamics in a transient flow structure such as that of the spherical wave. The coupling mechanisms are modelled by a global function which leads to an effective energy release at the front which is independent of either the local shock strength or the shock radius. The model recovers the essential features of the three propagation regimes of the reacting blast corresponding to different magnitudes of the source energy. Particularly interesting is the theoretical prediction that unless the source energy is very large, the reacting blast first decays to sub-Chapman-Jouguet velocity and then approaches its final C-J conditions extremely slowly. This prediction finds experimental confirmation in the experimental work of Struck and Brossard. Using an experimentally determined induction-zone thickness of the order of magnitude of the recently defined hydrodynamic thickness, quantitative results on the critical energy as well as transverse wave spacings from the present model were found to agree unexpectedly well with experiments.

Pressure waves generated by spherical flames

Abstract The present paper describes an approximate solution for the description of the shock-hydrodynamic flow structure corresponding to constant velocity expanding cylindrical or spherical flames. The solution is based on a perturbation procedure following the PLK technique. By matching the solutions coming from the inner boundary of the flame (or equivalently a piston) to those from the outer boundary of the shock front, closed form analytical expressions are obtained relating the shock strength to the piston velocity as well as for the various flow distributions. Compared with the exact solution obtained via numerical integration of the self-similar equations. the present approximate solution is found to give excellent results in the range of normal burning velocity of S ≲ 50 m/sec for most common hydrocarbonair mixtures.

IN VIVO COMPARISON OF NON-GASEOUS METABOLITE AND OXYGEN TRANSPORT IN THE HEART

Oxygen transport has traditionally been approached as a specialized subject with little connection to the large amount of data on transport of other substances, equally essential for steady-state metabolism. Heuristically, there is no reason to expect a major difference but measurements of tissue PO2 with oxygen electrodes in organs with high oxygen consumptions have yielded data which are incompatible with the classical Krogh-cylinder model of capillary-tissue oxygen transport. A number of alternative models, including diffusional shunting and flow heterogeneity, have been developed on the assumption that oxygen transport is a special case, with little or no consideration of the overall, nature of organ transport as reflected in the transport of other substances equally essential for metabolism. As we shall show, when examined in this light, oxygen transport is not essentially different from that of other substances. With the understanding afforded by this approach and recent developments based on it, future investigational effort can now be profitably directed at more complex problems, such as the role of impaired oxygen transport in certain pathological states of vital organs.

Liver Cell Entry In Vivo and Enzymic Conversion

The liver is a unique organ from the kinetic point of view. The endothelium lining the hepatic sinusoids is so highly permeable that the organ presents only a simple barrier to parenchymal cell entry of substrates. The situation is not simple, however, because interposed between the vascular lumen and cell membrane there is an interstitial space that modifies access of molecules to the liver cell surface. The barrier itself is generally not passive. The cell membrane structure exhibits all of the usual characteristics: enzymes facilitate the utilization of substrate or the conversion of materials to products within the liver cell. We will review here how tracer methodology has provided insight into these processes.