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J R Pappenheimer

Publications and source records attributed to J R Pappenheimer.

15 recordsLinked to original sources
PubMed1992

Transmucosal impedance of small intestine: correlation with transport of sugars and amino acids.

Transmucosal impedances of isolated perfused segments of jejunum from mice and hamsters were measured at frequencies from 10-100,000 Hz in the presence and absence of sugars and amino acids. Na-coupled transport of organic substrates caused large decreases of transmucosal impedance, reflecting contraction of cytoskeletal proteins controlling permeability of tight junctions, functional surface of basolateral membranes, and width of extracellular pathways. The observed changes of impedance were closely correlated with molar rates of Na-coupled active transport rather than with molecular species. Thus amino acids and sugars having the same molar rates of active transport also have the same effects on transmucosal impedance. It is proposed that a nonspecific increase of intracellular osmotic pressure during active transport is the first step initiating cytoskeletal contraction. Cell volume regulatory responses, including increased basolateral K+ conductance and Ca2+ influx, may be subsequent steps leading to contraction of perijunctional actomyosin, formation of junctional dilatations, and exposure of lateral membranes. Enhancement of oxygen capacity of perfusion fluids (e.g., with fluorocarbon emulsion) is required to maintain viability of isolated intestinal epithelium; in plain oxygenated Ringer-HCO3 solution, the transmucosal impedance is abnormally low and cytoskeletal contractile responses to Na-coupled transport are attenuated. An electrical circuit analog is presented that simulates almost exactly the observed transmucosal impedances and provides quantitative evaluation of the effects of Na-coupled transport of sugars and amino acids on resistances of tight junctions, capacitance of basolateral membranes, and postjunctional resistances of lateral intercellular spaces and villus cores.

Amino Acids↗
PubMed1990

Paracellular intestinal absorption of glucose, creatinine, and mannitol in normal animals: relation to body size.

Mice, rats, or rabbits were provided with a liquid diet of 10-12% glucose (Glc), 0.5-1% creatinine, 1-2% mannitol, and mannitol labeled with 3H on a terminal carbon. Average rates of ingestion of Glc were greater than maximum rates of active, carrier-mediated Glc transport reported for the intestines of these species. The discrepancy was small in mice but increased exponentially with body weight (BW). Ingestion-absorption of Glc increased exponentially with the 0.73 power of BW as expected from metabolic rate, whereas active transport, estimated from the literature, varied exponentially with the 0.50 power of BW. It is estimated that in humans the ingestion-absorption rate of Glc may be 10-20 times greater than active transport. In the presence of Glc, 50-65% of the ingested creatinine was recovered in urine compared with 75-85% recovered after intraperitoneal or subcutaneous injections. The amount of creatinine recovered in urine depended on the amount of ingested Glc, as predicted from the effects of Glc on width and permeability of absorptive cell junctions. Eighty percent or more of the 3H label on mannitol was recovered in urine or other body fluids, although most of the [3H]mannitol was oxidized to [3H]water after being absorbed intact from the intestine. It is concluded that in the presence of Glc, creatinine and mannitol (together with Glc, amino acids, and other small nutrients) are absorbed passively by solvent drag between absorptive cells, as found previously in anesthetized rats (J. R. Pappenheimer and K. Z. Reiss. J. Membr. Biol. 100: 123-136, 1987). The ratio of solvent drag to carrier-mediated transport increases exponentially with BW and may account for the capacity of human intestines to absorb large amounts of Glc during prolonged exercise, Glc tolerance tests, or oral Glc-saline therapy for dehydration.

Animals↗
PubMed1988

Physiological regulation of epithelial junctions in intestinal epithelia.

This symposium paper is a digest of three full-length manuscripts currently in press with J Membrane Biology (see reference list). The three papers provide evidence that sugars, amino-acids and small peptides are transported through intestinal epithelium primarily by solvent drag through paracellular channels. Active transport of sugars and amino acids plays a necessary but nevertheless secondary role in the mass transport from intestinal lumen to blood at physiological concentrations. Na-coupled solute transport serves two principal functions - a) it inserts relatively small amounts of solutes at high concentration into the intercellular spaces below the occluding junctions thereby providing the force for osmotic flow and solvent drag; b) it triggers contraction of the perijunctional actomyosin ring, thereby widening the occluding junctions and providing optimal conditions for transport of luminal nutrients in bulk by solvent drag. Active transport of glucose reaches its maximum capacity (V max) at luminal concentrations of 10-15 mM whereas transport by solvent drag increases in proportion to luminal concentration; at concentrations normally present in the duodenum and upper jejunum after a meal (50-300 mM) transport through paracellular spaces by solvent drag accounts for 60-90% of total glucose absorbed into blood. Similar considerations apply to other hydrophilic nutrients including amino acids, small saccharides and peptides. As nutrients are removed from the upper intestine by the above mechanisms, their concentrations decrease and the "traditional" role of active transport becomes a greater fraction of total absorption.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Contribution of solvent drag through intercellular junctions to absorption of nutrients by the small intestine of the rat.

The lumen of the small intestine in anesthetized rats was recirculated with 50 ml perfusion fluid containing normal salts, 25 mM glucose and low concentrations of hydrophilic solutes ranging in size from creatinine (mol wt 113) to Inulin (mol wt 5500). Ferrocyanide, a nontoxic, quadrupally charged anion was not absorbed; it could therefore be used as an osmotically active solute with reflection coefficient of 1.0 to adjust rates of fluid absorption, Jv, and to measure the coefficient of osmotic flow, Lp. The clearances from the perfusion fluid of all other test solutes were approximately proportional to Jv. From Lp and rates of clearances as a function of Jv and molecular size we estimate (a) the fraction of fluid absorption which passes paracellularly (approx. 50%), (b) coefficients of solvent drag of various solutes within intercellular junctions, (c) the equivalent pore radius of intercellular junctions (50 A) and their cross sectional area per unit path length (4.3 cm per cm length of intestine). Glucose absorption also varied as a function of Jv. From this relationship and the clearances of inert markers we calculate the rate of active transport of glucose, the amount of glucose carried paracellularly by solvent drag or back-diffusion at any given Jv and luminal glucose concentration and the concentration of glucose in the absorbate. The results indicate that solvent drag through paracellular channels is the principal route for intestinal transport of glucose or amino acids at physiological rates of fluid absorption and concentration. In the absence of luminal glucose the rate of fluid absorption and the clearances of all inert hydrophilic solutes were greatly reduced. It is proposed that Na-coupled transport of organic solutes from lumen to intercellular spaces provides the principal osmotic force for fluid absorption and triggers widening of intercellular junctions, thus promoting bulk absorption of nutrients by solvent drag. Further evidence for regulation of channel width is provided in accompanying papers on changes in electrical impedance and ultrastructure of junctions during Na-coupled solute transport.

Animals↗
PubMed1987

Physiological regulation of transepithelial impedance in the intestinal mucosa of rats and hamsters.

Isolated intestinal segments from rats or hamsters were recirculated with balanced salt solutions containing fluorocarbon emulsion to provide 6 vpc oxygen. The lumen contained an axial Ag-AgCl electrode, and the serosal surface was surrounded by a cylindrical shell of Ag-AgCl. Transmural impedances were measured at frequencies from 0.01-30 kHz before and after removal of the mucosal epithelium. The resistance of intercellular junctions, RJ, the distributed resistance of the lateral spaces, RL, and the distributed membrane capacitance, CM, were computed from the relations between frequency and impedance. Activation of Na-coupled solute transport by addition of glucose, 3-0-methyl glucose, alanine or leucine caused two- to threefold decreases of transepithelial impedance. Typical changes induced by glucose in hamster small intestine were RJ 30----13 omega, RL 23----10 omega, and CM 8----20 microF (per cm length of segment). Half maximal response occurred at a glucose concentration of 2-3 mM. The area per unit path length of the junctions (Ap/delta chi = specific resistance divided by RJ) in glucose activated epithelium was 3.7 cm in hamster midgut and 6.8 cm in rat. These values are close to the 4.3 cm estimated independently from coefficients of solvent drag and hydrodynamic conductance in glucose-activated rat intestine in vivo. The transepithelial impedance response to Na-coupled solute transport was reversibly dependent upon oxygen tension. It is proposed that activation of Na-coupled solute transport triggers contraction of circumferential actomyosin fibers in the terminal web of the microvillar cytoskeletal system, thereby pulling apart junctions and allowing paracellular absorption of nutrients by solvent drag as described in the previous accompanying paper. Anatomical evidence in support of this hypothesis is presented in the following second accompanying paper.

Animals↗
PubMed1987

Structural basis for physiological regulation of paracellular pathways in intestinal epithelia.

Isolated segments of hamster small intestine were perfused with oxygenated salt-fluorocarbon emulsions with or without 10-25 mM glucose, alanine or leucine. Resistances of intercellular occluding junctions and of lateral spaces and the distributed capacitance of epithelial plasma membranes were estimated from steady-state transepithelial impedances at frequencies from 0.01-10 kHz. The segments were then fixed in situ with isorheic 2.5% glutaraldehyde while continuing to measure impedance. This method of fixation increased the resistance of lateral spaces but had little effect on the resistance of occluding junctions or on membrane capacitance. The large decreases of impedance induced by glucose or amino acids were preserved in fixed tissue and could therefore be correlated with changes in structure. The observed changes of impedance were interpreted as decreased resistance of occluding junctions and lateral spaces together with increased exposed surface of lateral membranes (capacitance). Glucose, alanine or leucine induced expansion of lateral intercellular spaces as seen by light and electron microscopy. Large dilatations within absorptive cell occluding junctions were revealed by electron microscopy. Freeze-fracture analysis revealed that these dilatations consisted of expansions of compartments bounded by strands/grooves. These solute-induced structural alterations were also associated with condensation of microfilaments in the zone of the perijunctional actomyosin ring, typical of enhanced ring tension. Similar anatomical changes were found in epithelia fixed in situ at 38 degrees C during luminal perfusion with glucose in blood-circulated intestinal segments of anesthetized animals. These structural changes support the hypothesis that Na-coupled solute transport triggers contraction of perijunctional actomyosin, thereby increasing junctional permeability and enhancing absorption of nutrients by solvent drag as described in the two accompanying papers.

Actomyosin↗
PubMed1987

A silver spoon.

Explore the source record for details and available documents.

Animals↗
PubMed1979

"Nature's soft nurse": a sleep-promoting factor isolated from brain.

A sleep promoting factor has been extracted and purified from cerebrospinal fluid of sleep-deprived goats, from whole brains of sleep-deprived rabbits and from brainstems of slaughterhouse cattle. Intraventricular infusion of the purified material into rats, cats, rabbits or squirrel monkeys induces excess slow-wave sleep in the recipients for several hours following the infusion. The excess sleep appears similar to the deep slow-wave sleep which normally follows sleep deprivation; it is characterized by EEG slow waves of greater than normal amplitude and an increase in both the number and duration of sleep episodes. The sleep factor appears to be a small peptide of molecular weight 350--500 daltons and the effective dose is of the order of a few picomols per gram brain. A similar, perhaps identical, factor is present in human urine.

Animals↗
PubMed1978

Sleep-promoting factor S: purification and properties.

Sleep-promoting factor was purified from acid/acetone extracts of whole brains of rabbits and from brainstems of slaughterhouse cattle. Intraventricular infusion of extracts purified by means of ion exchange and gel filtration induced excess slow-wave sleep in rabbits for 5-10 hr. The procedure is simple and provides material suitable for physiological studies. Further treatment by partition chromatography and electrophoresis yielded an active product that was purified at least 1 million-fold. This product was inactivated by incubation with mixed carboxypeptidases A and B. Amino acid analysis of acid hydrolysates indicated that the effective dose was less than 150 pmol per rabbit and the original concentration in brain tissue was of the order of 30 pmol/g of brain.

Animals↗
PubMed1977

Sleep and respiration of rats during hypoxia.

1. The effects of hypoxia on slow-wave sleep (SWS) and of SWS on respiratory responses to hypoxia were investigated on rats provided with chronically implanted cortical electrodes. 2. During the daytime (5-7 hr periods) the proportion of time spent in SWS was 45% (S.E. +/- 1.0%) when the rats breathed air. Exposure to 10% O2 (equivalent to 18,000 ft.) reduced this proportion to 27% (S.E. +/- 2.5%). During hypoxia the intensity of e.e.g. activity in SWS (mean, rectified slow-wave voltage) rarely equalled the normal values characteristic of the same rats in fully developed SWS breathing air. The normal pattern of 5-15 min episodes of SWS was changed by hypoxia to a series of brief (2-3 min) incompletely developed episodes. 3. Addition of CO2 to inspired gas failed to prevent the reduction of SWS during hypoxia. CO2 in normal O2 did not alter sleep significantly. The effects of hypoxia on sleep therefore depend upon changes in O2 pressure rather than upon changes in CO2. 4. The effect of SWS on respiration of rats breathing air was to decrease frequency and minute volume by 10-20%. In hypoxia, however, the frequency increased markedly when the animals entered SWS ; minute volume was not significantly changed. It follows that stimulation of breathing by hypoxia is greater during SWS than during wakefulness. 5. The anomalous increase of respiratory frequency when hypoxic rats entered SWS was abolished by addition of CO2 to the hypoxic gas mixture. 6. Steady-state gaseous metabolism (Vo2 Vco2) was decreased 18 +/- 3% during hypoxia and was increased 31 +/- 4% during exposure to 5% CO2. The implications of these changes for interpretation of respiratory responses to O2 and CO2 are discussed.

Animals↗
PubMed1975

Extraction of sleep-promoting factor S from cerebrospinal fluid and from brains of sleep-deprived animals.

Sleep-promoting factor (factor S) was extracted, partially purified, and concentrated from cerebrospinal fluid and from acid-acetone extracts of brain stem anc cortex of sleep-deprived goats and sheep. 2. Solutes greater than 500 daltons were largely removed by serial ultrafiltrations through molecular sieves (Amicon membranes UM10 and UM05); solutes less than 350 daltons were largely eliminated by gel filtration through Sephadex G10 columns. Sleep-promoting activity was found in a fraction eluted prior to [14C] sucrose marker. 3. Concentrated fraction were infused intraventricularly in rats (0.1 ml in 30 min just prior to 12-h dark cycle) and in rabbits (0.3 ml in 90 min in morning). Sleep-promoting activity was assayed by decrease in nocturnal locomotor activity of rats and by duration and amplitude of slow-wave cortical EEG in rabbits.

Animals↗
PubMed1971

Factors in cerebrospinal fluid from goats that affect sleep and activity in rats.

1. Intraventricular infusion in the rat of 0.1 ml. cerebrospinal fluid (c.s.f.) from sleep-deprived goats increases the duration of sleep (measured by e.e.g.) and decreases locomotor activity (measured photo-electrically) for at least 6 hr subsequent to the infusion. Subarachnoid infusions are ineffective.2. C.s.f. from control and sleep-deprived goats was fractionated by ultrafiltration through molecular sieves. The sleep-promoting Factor S is found in the low molecular weight fraction (mol. wt. < 500) of c.s.f. from sleep-deprived but not from control goats.3. The concentration of Factor S in c.s.f. increases progressively during the first 48 hr of sleep deprivation.4. The sleep promoting effects of Factor S cannot be duplicated by serotonin, 4-OH-butyrate, butyrolactone, GABA (gamma-amino butyric acid), glutamic acid or 3',5'-cyclic AMP when these substances are added to control fluids in concentrations up to 10 times greater than those found in normal c.s.f.5. Intraventricular or subarchnoid infusion in the rat of 0.1 ml. proteinfree c.s.f. containing molecules in the mol. wt. range of 500-10,000 at 10-30 x normal concentration causes hyperactivity which persists for several days and nights following the infusion. The excitatory material, probably a peptide, is present in c.s.f. from both control and sleep-deprived goats.6. The properties of Factor S suggest that it may play a role in the normal regulation of sleep and wakefulness.

Aminobutyrates↗