Carl A. Goresky

The inlet patch: Heterotopic gastric mucosa in the upper esophagus

Careful endoscopic survey of the upper esophagus indicates that a visually recognizable patch of gastric mucosa is grossly visible much more commonly than is generally recognized. Sixteen instances were found in 420 sequential endoscopies, an incidence of 3.8%. The gastric mucosal rest presented as a velvety red patch with a distinct border, varying from a few millimeters in diameter to complete encirclement of the esophagus, was occasionally paired, and was found either at or just below the upper esophageal sphincter. In all instances except one the patch consisted of gastric-type mucosa containing both parietal and chief cells; in the single exception, it consisted of gastric-type mucous glands without parietal cells. Although larger patches can be shown to function under stimulation (they produce a local drop in pH with pentagastrin stimulation), there are usually no apparent associated clinical symptoms.

Transcapillary Exchange En the Working Left Ventricle of the Dog

Sets of multiple indicator dilution curves were obtained from working hearts of dogs with closed chests. A multiple capillary adaptation of a permeability-limited capillary model which assumes that exchanging material returns to the capillary at its site of escape was tested on these curves. The model has only two lumped parameters: a permeability surface product per accessible extravascular volume, and flow per extravascular volume. Labeled red cells and albumin were used as vascular indicators. The model provided close fits for the curves of diffusion-limited indicators (sucrose, inulin, sulfate, sodium, chloride, and urea), and unique values were obtained for both parameters. The accessible extravascular volume obtained by this method was independent of flow whereas the permeability surface product per accessible extravascular volume (a relatively low value for these indicators) increased with flow. In this first group the outflow patterns varied with the size of the test molecule. For a second group of substances (water, ethanol and antipyrine), the outflow patterns were virtually identical and independent of molecular size (i.e., flow-limited). The modeling did not provide an appropriate description of these curves, and analysis indicated that the exchanging indicator may intercommunicate between capillaries in a random fashion, i.e., that the indicator may not return to each capillary at the same site at which it escaped.

Effects of perfusate flow rate on measured blood volume, disse space, intracellular water space, and drug extraction in the perfused rat liver preparation: Characterization by the multiple indicator dilution technique

The effect of hepatic blood flow on the elimination of several highly cleared substrates was studied in the once-through perfused rat liver preparation. A constant and low input concentration of ethanol (2.0 mM), [14C]-phenacetin and [3H]-acetaminophen (0.36 and 0.14 μM, respectively), or meperidine (8.1 μM) was delivered once-through the rat liver preparation in five flow periods (>35 min each); control flow periods at 12 ml/min were interrupted by flow changes to 8 or 16 ml/min. The steady-state hepatic availabilities (F or outflow survivals) at 12 ml/min were ethanol, 0.075±0.038; [14C]-phenacetin, 0.15±0.059; [3 H]-acetaminophen, 0.34±0.051; meperidine, 0.047±0.017. Flow-induced changes were different among the compounds: with reduced flow (8 ml/min), F was decreased for ethanol (0.061 ±0.032) and [3H]-acetaminophen (0.28±0.051), as expected, but was increased for [14C]-phenacetin (0.20 ±0.068) and meperidine (0.05 ±0.03); with an elevation of flow (to 16 ml/min), F was increased for all compounds, as expected of shorter sojourn times: ethanol, 0.13 ±0.065; [14C]-phenacetin, 0.22 ±0.062; [3H]-acetaminophen, 0.43 ±0.063; meperidine, 0.055±0.022. A marked increase in F for ethanol had occurred when flow changed from 12 to 16 ml/min due to nonlinear metabolism; the latter was confirmed by a reduction in the extraction ratios at increasing concentrations (1.8 to 11.4mM); this condition was not present for the other compounds. In order to explain the observations, we used the multiple indicator dilution technique to investigate the flow-induced behaviors of tissue distribution spaces of vascular and intracellular references in the perfused rat liver preparation. After a rapid injection of noneliminated reference materials [51 Cr-labeled RBC (vascular marker),125I-labeled albumin, [14C]-sucrose (extracellular markers), and [3H]-H2O (cellular marker)] into the portal veins of livers perfused at the randomly chosen flow rates (5, 8, 10, 12, 14, or 16 ml/min), the hepatic venous outflow profiles were characterized. Estimated sinusoidal blood volume, total albumin and sucrose distribution spaces, the Disse space, total water space, and the transit time for intracellular water showed strong correlations with blood flow rate. No correlation was found, however, between blood/water flow rate and intracellular water space (a space also accessed by substrates). At < 0.75 ml blood/min/g liver, intracellular water space was decreased, but at > 0.75 ml blood/min/g liver, the observed values were constant (0.635±0.024 ml/g liver) and independent of flow rate. Estimations of the mean transit time for cell water enabled calculations of sequestration rate constants (intrinsic clearance per ml cell water). The estimated sequestration rate constants for meperidine and phenacetin were decreased to 64% when flow was decreased from 12 to 8 ml/min, whereas those for acetaminophen (preformed or generated from phenacetin) were decreased minimally (10 to 11%), and these were generally unchanged for most compounds when flow was altered from 12 to 16 ml/min. The composite findings suggest that a critical flow is required to maintain maximal and constant accessibility into hepatocytes. Flow rates below this critical value affect hepatocyte recruitment differentially, as suggested by drug metabolic data. Below the critical flow rate, the reduction in intracellular space affected mostly metabolic processing of drugs that are mediated by enzymes located in the perihepatic venular region, but the effects are virtually imperceptible for biotransformation of drugs that involve enzyme systems in the periportal region.

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

Kinetics of Rubidium Uptake in the Working Dog Heart

More than 50% of tracer rubidium entering the coronary circulation is actively taken up by the heart muscle cells during a single passage. Rubidium ions must traverse the capillary wall, the interstitial space, and the muscle cell membrane to enter the very large potential rubidium pool within the cells. The aim of this investigation was to determine which, if any, of these steps are rate limiting. The anterior descending branch of the left common coronary artery was perfused at its origin. Pulse injections containing 86Rb+, 22Na+ or 14C-sucrose, and 125I-albumin were made into the perfusion line and timed serial samples of coronary sinus blood were collected and analyzed. A model was designed which incorporates rate constants describing both the exchange of 80Rb+ at the capillary wall and its entry at the muscle cell membrane. Labeled sucrose or 22Na+ was used to determine flow per interstitial fluid volume, a parameter necessary for the application of the model. It was assumed that the interstitial fluid volume available for labeled sucrose or 22Na+ was identical to that available for 86Rb+. The rate constant describing exchange at the capillary wall (the permeability surface product per unit accessible interstitial fluid volume) increased with perfusion, whereas that for uptake by the myocardial cells was relatively constant and independent of flow.

Chronic mesenteric vascular insufficiency with gastric ulceration

Four middle-aged women presented with long histories of severe progressive weight loss and chronic abdominal pain. Endoscopically atypical gastric ulcers were identified in all; the ulcers were multiple and antral in location, with irregular shapes, sloping edges, and whitish sclerotic bases, and were surrounded by mottled and erythematous mucosa containing numerous superficial erosions. They did not heal with conservative therapy. All 4 patients were found to be suffering from chronic mesenteric vascular insufficiency. Balloon dilatation of the superior mesenteric artery in one and surgical revascularization in the others resulted in progressive clinical improvement and healing of the ulcers. The striking feature in these patients with mesenteric ischemia was the finding of gastric ulcers with a morphology different from the ordinary gastric ulcer, which healed only with revascularization. Future observation of similar lesions should suggest the possible diagnosis and expedite early treatment of mesenteric insufficiency in patients with this disorder.

Arctic trichinosis presenting as prolonged diarrhea

We describe an outbreak of trichinosis after the consumption of raw walrus meat in 10 Inuit inhabitants of a northern community. During the presentation of the illness, diarrhea was found in all subjects and was the dominant symptom in 8 of the 10 cases. Myalgia (60%) and muscle weakness (50%) were much less prominent complaints. The diarrhea was characteristically prolonged, lasting up to 14 wk (average 5.8 wk), as opposed to comparatively short episodes of myalgia (average 5.4 days) and muscle weakness (average 4.5 days). Prolonged diarrhea with little or no muscle symptomatology in an epidemic form represents a previously unrecognized clinical presentation of trichinosis. It remains to be determined whether this new clinical presentation is related to variant biological behavior of arctic Trichinella, to previous exposure to the parasite, or to other factors.

Kupffer cell depletion associated with capillarization of liver sinusoids in carbon tetrachloride-induced rat liver cirrhosis*

Rats were made cirrhotic by carbon tetrachloride inhalation associated with phenobarbital in the drinking water over 10 weeks. After a 1-week recovery period a 99mTc sulphur colloid radioisotope scan of the liver was carried out on each animal following bolus injection into the iliac vein. Kupffer cells were then histologically identified by one of three methods: colloidal carbon uptake, iron staining after ferritin-dextran, or endogenous peroxidase staining. The degree of liver injury was classified into four pathological groups and these were correlated with the phagocytic capacity of each liver as recorded on the isotope scan. All three histological markers demonstrated that in normal liver, Kupffer cells are more plentiful in periportal areas. In cirrhotic liver, there were very few Kupffer cells in nodular regenerative areas, where continuous capillaries are found, but Kupffer cells were present in the remaining more normal trabecular-sinusoidal areas. Morphometric counting of carbon- and ferritin-labelled Kupffer cells demonstrated a significant decrease in cirrhotic livers. A close correlation was also found between increasing degree of liver injury and diminished hepatic phagocytic capacity, as demonstrated by the radioisotope scan. The study demonstrates that where regenerative liver is capillarized, with replacement of fenestrated sinusoids, Kupffer cells are absent.

Labeled catecholamine uptake in the dog heart. Interactions between capillary wall and sympathetic nerve uptake.

The kinetics underlying the uptake of tracer amounts of norepinephrine and isoproterenol by the heart were studied in a pentobarbital-anesthetized dog with the multiple indicator dilution technique. The circumflex coronary artery was perfused with blood from the femoral artery, with a pressure-dependent system. A small bolus containing labeled albumin (a tracer confined to the vascular space), labeled sucrose (which penetrates into the extracellular space in a barrier-limited fashion), and labeled norepinephrine or isoproterenol was injected into the artery and outflow dilution curves were obtained from the coronary sinus. Analysis of data enabled us to assess separately the myocardial capillary permeability for norepinephrine or isoproterenol, and their rate constants for uptake by the interstitial sympathetic fibers (the process is essentially unidirectional over the time of a single passage, because of the highly concentrative nature of the uptake). We found a major resistance to catecholamine transfer at the capillary surface (approximately half of the label emerged at the outflow without leaving the circulation) and a neuronal uptake process beyond the barrier large enough that, after steady infusion, it would be expected to reduce the tracer concentration of norepinephrine to a value the order of one-sixth that in the plasma space. The injection of desmethylimipramine selectively diminished the apparently unidirectional flux of labeled norepinephrine into the neuronal terminals, and this uptake was found to be significantly lower for isoproterenol than for norepinephrine. The capillary-intersti-tium-concentrative uptake mechanism, documented here, partially explains the quantitatively different cardiac responses to infused and locally released catecholamines. Circ Res 47: 329-338, 1980

Kinetics of endothelin-1 binding in the dog liver microcirculation in vivo

Endothelin-1 (ET-1) is a 21-amino acid peptide produced by vascular endothelial cells that acts as a potent constrictor of hepatic sinusoids. Hepatic binding of tracer 125I-labeled ET-1 was investigated in anesthetized dogs with the multiple-indicator dilution technique with simultaneous measurements of unlabeled immunoreactive ET-1 plasma levels. Despite 80% binding to albumin, tracer 125I-ET-1 was avidly extracted by the liver, with only 15 ± 6% of the peptide surviving passage through the organ. Exchange of ET-1 between plasma and binding sites, probably located on the surface of liver cells, was quantitatively described by a barrier-limited, space-distributed variable transit time model. Reversible and irreversible parallel binding sites were found. Reversible and irreversible plasma clearances of unbound 125I-ET-1 were 0.084 ± 0.033 ml ⋅ s-1 ⋅ g liver-1 and 0.17 ± 0.09 ml ⋅ s-1 ⋅ g liver-1, respectively, and the dissociation rate constant for reversible binding was 0.24 ± 0.12 s-1. The specific ETA receptor antagonist BMS-182874 did not modify binding to either site. The nonspecific ETA/ETBantagonist LU-224332 dose-dependently reduced irreversible binding only. ET-1 levels in the hepatic vein were significantly lower than in the portal vein but were not different from those in the hepatic artery. The ratio between hepatic vein and portal vein levels (0.64 ± 0.31) was considerably higher than survival fractions, suggesting a substantial simultaneous release of newly synthesized or stored ET-1 by the liver. These results demonstrate both substantial clearance and production of ET-1 by the intact liver. Hepatic ET-1 clearance is mediated by the ETB receptor, with the presence of reversible, nonspecific ET-1 binding at the liver surface.