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PubMed1986

Influence of colchicine on the distribution of horseradish peroxidase in the secretory ameloblast layer in vitro.

The distribution of exogenous horseradish peroxidase (HRP) in the secretory ameloblast layer of developing rat molar tooth germs was examined in a culture system with and without colchicine. The secretory ameloblast of cultured tooth germs engulfed HRP added to the medium regardless of the presence of colchicine. The reaction product was localized in various vesicles and granules. Without colchicine in the medium, many small vesicles containing HRP were located in the Tomes' processes, whereas only a few were present with colchicine at concentrations above 5 microM. An intense reaction of HRP also appeared in the distal extracellular spaces beyond the distal junctional complexes of ameloblasts cultured without colchicine, whereas it became almost indiscernible in the tooth germs cultured with colchicine. The lack of HRP in the Tomes' processes and distal extracellular spaces of ameloblasts treated with colchicine might be attributed to the disruption of microtubules. The present study suggests that the secretory ameloblast is able to transport tracer molecules through the intracellular pathway from the proximal and lateral extracellular spaces to the distal extracellular space.

Animals↗

PubMed2001

Kinetics of thyroxine (T(4)) and triiodothyronine (T(3)) transport in the isolated rat heart.

The dynamics and kinetics of thyroid hormone transport in the isolated rat heart were examined using the modified unidirectional paired tracer dilution method. The uptake of (125)I-thyroxine ((125)I-T(4)) and (125)I-triiodothyronine ((125)I-T(3)) from the extracellular space into heart cells was measured relative to the extracellular space marker (3)H-mannitol. The thyroid hormone maximal uptake was 54.4 % for (125)I-T(4) and 52.15 % for (125)I-T(3). The thyroid hormone net uptake was 25.69 % for (125)I-T(4) and 25.49 % for (125)I-T(3). Backflux from the intracellular space was 53.17 % for (125)I-T(4) and 61.59 % for (125)I-T(3). In the presence of unlabelled thyroid hormones, (125)I-T(4) and (125)I-T(3) maximal uptakes were reduced from 10.1 to 59.74 % and from 34.6 to 65.3 %, respectively, depending on the concentration of the unlabelled hormone, suggesting a saturable mechanism of the thyroid hormone uptake by the heart cells, with K(m(T4))= 105.46 microM and the maximal rate of (125)I-thyroid hormone flux from the extracellular space to heart cells (V(max(T4))) = 177.84 nM min(-1) for (125)I-T(4) uptake, and K(m(T3)) = 80.0 microM and V(max(T3)) = 118.5 nM min(-1) for (125)I-T(3) uptake. Experimental Physiology (2001) 86.1, 13-18.

Animals↗

PubMed1998

Functional linkage of Na(+)-Ca2+ exchange and sarcoplasmic reticulum Ca2+ release mediates Ca2+ cycling in vascular smooth muscle.

Ca2+ loss from the sarcoplasmic reticulum (SR) of rabbit inferior vena cava smooth muscle was monitored by measuring the decay of caffeine-induced fura-2 fluorescence transients. Removal of Ca2+ from the extracellular space caused a rapid loss of SR Ca2+ and a decline of cytoplasmic Ca2+ concentration ([Ca2+]i). Simultaneous removal of extracellular Na+ greatly inhibited the rate of this (SR) Ca2+ loss. A rapid loss of SR Ca2+ was induced by 20 microns CPA, regardless of the presence or absence of extracellular Na+ or Ca2+. These effects were not influenced by alterations in membrane potential owing to activity of Ca2(+)-activated K+ channels since 3 mM TEA had no effect on the rate of Ca2+ loss from the SR. These results indicate that when Ca2+ is removed from the extracellular space, it induces Ca2+ release from the SR towards the plasma membrane Na(+)-Ca2+ exchanger which subsequently translocates it from the junctional cytoplasmic space to the extracellular space. When the Na(+)-Ca2+ exchanger is arrested by removal of extracellular Na+ and Ca2+, Ca2+ released from the SR is re-sequestered by the sarco-endo-plasmic reticulum Ca2(+)-ATPase (SERCA). However, when both the Na(+)-Ca2+ exchanger, and, the SERCA are blocked, Ca2+ released from the SR is extruded from the cells by the plasma membrane Ca2(+)-ATPase. These results reveal a hierarchy of interaction between the different Ca2+ transporters in the SR, and cell membranes.

Animals↗

PubMed1990

Morphological changes in acute cerebral ischemia after occlusion and reperfusion in the rat.

Blood-brain barrier permeability was investigated in acute focal ischemia after MCA occlusion and reperfusion. Four kind of tracers were used: sodium fluorescein and ionic lanthanum as a small molecular tracer, and Evans blue and HRP as a macromolecular tracer. BBB permeability to the tracers was observed macroscopically and studied by electron microscopy. The MCA was dissected free and occluded by ligation with 10-0 monofilament nylon suture. In the reperfusion model, the nylon suture was cut and the occluded MCA was reopened. Diffuse fluorescein staining was noted in the ipsilateral cortex; however, there was no extravasation of Evans blue or HRP in the occlusion model. Ionic lanthanum was demonstrated in the interendothelial space, basement membrane, and extracellular space. In the reperfusion model, intense fluorescein staining and hemorrhagic infarction were observed. Remarkable extravasation of Evans blue and HRP was also revealed in the ischemic lesion. HRP was demonstrated in the basement membrane and around the neuropils. Ultrastructural findings suggested that small molecules such as sodium fluorescein and ionic lanthanum may pass through the entire interendothelial cleft into the extracellular space before leakage of the macromolecules in the acute ischemic stage. Between 30 to 60 min after MCA occlusion, cerebral edema may begin with an escape of water and ions through the tight junctions. Reperfusion of MCA in the acute stage of ischemia may lead to abnormal vascular permeability to macromolecules as a manifestation of severe damage to the BBB.

Acute Disease↗

PubMed2002

Manganese influences the levels of neurotransmitters in synapses in rat brain.

54Mn previously taken up by the amygdala is released along with known neurotransmitters into the extracellular space during stimulation with 100 mM KCl. The possibility of manganese release from neuron terminals in a calcium- and impulse-dependent manner was examined by using the in vivo microdialysis method in the present study. The increase of (54)Mn release into the amygdalar extracellular space during stimulation with high K(+) was inhibited by addition of 1 microM tetrodotoxin. This increase of (54)Mn release into the extracellular space by stimulation with high K(+) was also observed in the hippocampus, but not in the substantia nigra. The increment of glutamate in the extracellular space during stimulation with high K(+) was highly correlated with that of (54)Mn, suggesting that manganese is concurrently released with glutamate from neuron terminals. The level of (54)Mn in the extracellular space in the hippocampus was increased with that of glutamate, but not with those of GABA and glycine, during stimulation with 100 mM KCl in the presence of 30 microM kainate. This increase was more marked than during stimulation with 30 microM kainate alone. It is likely that manganese is released from glutamatergic neuron terminals. When the rat hippocampus was perfused with artificial cerebrospinal fluid containing 20 or 200 nM MnCl(2), the levels of glutamate, aspartate and GABA in the perfusate were dose-dependently decreased during perfusion with manganese. The present findings demonstrate that manganese released into the synaptic cleft may influence synaptic neurotransmission.

Animals↗

PubMed1986

An upper limit for the electrogenic Na-K pump contribution to maximum diastolic potential in feline cardiac Purkinje fibers in steady state.

We have estimated an upper limit for the electrogenic contribution of the Na-K pump to diastolic transmembrane potential. We simultaneously monitored the maximum diastolic potential and the extracellular space potassium activity during exposure to a very high concentration of ouabain. Exposure to ouabain caused a depolarization of approximately 3 mV (n = 33 experiments) over 34 +/- 3 s (mean +/- standard error) prior to any change in extracellular K activity. In four experiments, we monitored intracellular sodium activity and observed it to rise with approximately the same temporal lag (delay = 26 +/- 7 s). We also measured relative membrane conductance in one series of experiments and observed it to decrease to 91 +/- 2% of its control value by the time extracellular space K began to rise. Following the initial increase in extracellular space K activity the subsequent membrane depolarization is shown to be accurately predicted solely from the measured increase in extracellular space K activity as calculated from the Goldman equation. Limitations of the method and possible interpretations of the data are discussed. We interpret this ouabain-induced depolarization that occurs prior to the rise in external K to be an upper limit to the Na-K pump's electrogenic contribution to steady-state membrane potential.

Action Potentials↗

PubMed1976

Oral administration of radioactive sulfate to measure extracellular fluid space in man.

Radioactive sulfate-35 (35S) was administered to eight human subjects intravenously and orally, to compare respective kinetics of distribution. Intravenously administered 35S attained equilibration within 60-90 min. Orally administered 35S attained equilibration within 60-105 min and thereafter achieved plasma activity equivalent to the intravenously administered tracer. Eighty percent or greater of the 35S dose was recovered in the 24-h urine, following either intravenous or oral administration. The mean extracellular fluid space demonstrated less than 9% mean difference between routes of administration. It is concluded that 35S is completely absorbed at tracer doses, and may be administered orally as a reliable substitute for intravenously administered 35S for measuring extracellular fluid space.

Administration, Oral↗

PubMed1990

Cryo-electron microscopy of vitrified nerve myelin.

The ultrastructure of rat optic and trigeminal nerve myelin was studied using different cryotechniques. Replicas of rapid cryofixed and deep-etched material were compared with cryosections of chemically unfixed specimens and also of glutaraldehyde-fixed specimens. Hydrated cryosections were analysed in a cryotransfer device. The data reported here show discrepancies with the current descriptions of myelin structure based on osmium-fixed and resin-embedded material. The structures called the major line (as a fusion of the cytoplasmic surfaces of the glial cells) in conventional electron microscopy and the intraperiod line (as a fusion of the outer surfaces) are seen in the present material to represent actually aqueous spaces. The extracellular space (E-space) is most sensitive to chemical fixation and other preparation procedures, and probably also expands under pathological conditions. The virtual C-space (cytoplasmic space = major line) is more stable. The cytoplasmic surfaces are most probably joined by globular proteins (myelin basic protein). The most compact organization of myelin is seen in fresh, unfixed nerves. A continuous bilayer could not be observed and the bilayer membrane showed particulate subunits.

Animals↗

PubMed1979

Evaluation of one dimensional profile scans with a whole body counter--82bromide space in liver cirrhosis: concise communication.

One dimensional profile scans with a whole body counter are refocused with a linear space invariant filter in the frequency domain, 'Hanning' window and inverse system transfer function. Artifacts are eliminated in a way that a clinically applicable method is developed. Topographic information is achieved with the highly energetic nuclide 82bromide. The bromide space (extracellular volume) in patients with liver cirrhosis (n = 9) compared to normal subjects (n = 10) is increased most in the upper abdominal thoracic region.

Adult↗

PubMed1991

Hypertrophic smooth muscle in the partially obstructed opossum esophagus. The model: histological and ultrastructural observations.

Obstruction is a complication of many esophageal diseases, but the morphological changes occurring in the obstructed esophagus are poorly understood. We developed a model of esophageal obstruction in the American opossum, Didelphis virginiana. A nonconstricting band around the gastroesophageal junction led to esophageal distention and tortuosity in the weeks following its placement. Despite a marked increase of the esophageal circumference, the esophageal wall was not thinned, and the circular muscle layer had actually increased its thickness. This was due to an increase in the size of individual smooth muscle cells with proportional increases in the cell surface area and volume. The electron density of hypertrophic smooth muscle cells varied much more than that of normal esophageal smooth muscle cells. As cell size increased, the tissue became more compact and the size of the extracellular space decreased. Also, the extracellular space was filled by an amorphous electron-dense material. Additional changes in the structure of hypertrophic smooth muscle cells included prominent intermediate filaments in the vicinity of thick filaments. There was no difference in the structure of the hypertrophic smooth muscle at 4 weeks and at 8 weeks after placement of the band. The morphological features described here resemble those seen in human esophageal spasm and achalasia of humans and could affect esophageal smooth muscle function.

Animals↗

PubMedDate not supplied

Compartmentalization and movement of calcium in the thyroid.

The present work suggests that in dog thyroid tissue Ca2+ is distributed at least in two compartments (A) and (B). Compartment (A) could be the extracellular space, and extracellular binding sites for Ca2+. The uptake of Ca2+ in this compartment is increased and the release is decreased at 0 degrees C. The release is not influenced by the ionophore A23187 or by metabolic inhibitors (NaF, iodoacetate, dinitrophenol) or by thyrotropin (TSH). Compartment (B) is defined functionally as a slowly exchangeable store of Ca2+. Uptake and release from this compartment are temperature dependent. The release is accelerated by A23187 and by antimycin A, this suggests an intracellular, presumably mitochondrial, location. TSH stimulates the efflux of Ca2+ originating from the cellular compartment (B). Our data are compatible with the hypothesis that, as in other tissues, the translocations of stored intracellular calcium may be a crucial step in the activation of the thyroid cell.

Animals↗

PubMed2005

Interaction of stress proteins with misfolded keratins.

Misfolded and aggregated proteins are a characteristic feature of a variety of chronic diseases. Examples include neurofibrillary tangles in Alzheimer disease, Lewy bodies in Parkinson disease and Mallory bodies (MBs) in chronic liver diseases, particularly alcoholic and non-alcoholic steatohepatitis (ASH and NASH). MB formation is at least in part the result of chronic oxidative cell stress in hepatocytes and can be induced in mice by long-term intoxication with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). Proteomic analysis revealed that MBs consist of ubiquitinated keratins and the stress proteins Hsp70, Hsp25, and p62. Furthermore, marked overexpression of clusterin, which shares functional properties with small heat shock proteins, was identified by gene expression profiling of DDC-treated mice livers. To investigate whether clusterin has a function in the stress response to misfolded keratins, we performed transfection studies utilizing expression constructs encoding ubiquitin, p62, Hsp27, clusterin, keratin 8, and keratin 18. Ubiquitin was found in a strong and constant association with keratin aggregates, whereas binding of p62 to keratin was variable. Hsp27 did not colocalize with keratin aggregates under these experimental conditions. In contrast, clusterin associated with misfolded keratin only if its signal peptide was deleted and its secretion inhibited. This suggests that clusterin has ability to bind misfolded proteins, including keratins but its physiological function is restricted to the extracellular space. The extracellular localization of clusterin was underlined by immunohistochemical studies in Alzheimer disease brains, where clusterin was constantly found in association with amyloid plaques; in contrast, cytoplasmic inclusions such as neurofibrillary tangles as well as MBs in ASH were negative. Furthermore, we found clusterin in association with elastic fibers in the extracellular matrix in several chronic liver diseases, including ASH and alpha1-antitrypsin deficiency, implying a possible role of clusterin in liver fibrosis.

Adaptor Proteins, Signal Transducing↗

PubMed1999

Prostaglandin D2 and sleep regulation.

Prostaglandin (PG) D2 is recognized as the most potent endogenous sleep-promoting substance whose action mechanism is the best characterized among the various sleep-substances thus far reported. The PGD2 concentration in rat cerebrospinal fluid (CSF) shows a circadian change coupled to the sleep-wake cycle and elevates with an increase in sleep propensity during sleep deprivation. Lipocalin-type PGD synthase is dominantly produced in the arachnoid membrane and choroid plexus of the brain, and is secreted into the CSF to become beta-trace, a major protein component of the CSF. The PGD synthase as well as the PGD2 thus produced circulates in the ventricular system, subarachnoidal space, and extracellular space in the brain system. PGD2 then interacts with DP receptors in the chemosensory region of the ventro-medial surface of the rostral basal forebrain to initiate the signal to promote sleep probably via the activation of adenosine A2A receptive neurons. The activation of DP receptors in the PGD2-sensitive chemosensory region results in activation of a cluster of neurons within the ventrolateral preoptic area, which may promote sleep by inhibiting tuberomammillary nucleus, the source of the ascending histaminergic arousal system.

Animals↗

PubMed1973

Fetal rat intestinal absorption of horseradish peroxidase from swallowed amniotic fluid.

Horseradish peroxidase (HRP) injected into amniotic fluid is swallowed by rat fetuses and within 3-6 h reaches the gut lumen. This macromolecular protein is then absorbed by the columnar lining cells via a system of apical cytoplasmic tubules formed by invaginations of the plasma membrane. From cytoplasm subjacent to the brush border HRP is transported, within vacuoles, to the supranuclear region, where some is retained for at least 18 h, and to interepithelial spaces. Extracellular enzyme is then found throughout the epithelial basement membrane and between connective tissue cells of the mucosal and submucosal layers Finally, HRP can be detected within lumina of blood and lymphatic capillaries, strongly suggesting that it is transported from the intestine to the circulation.

Acid Phosphatase↗

PubMed1993

Release of nitric oxide from glyceryl trinitrate by captopril but not enalaprilat: in vitro and in vivo studies.

1. The hypotensive effects of glyceryl trinitrate (GTN, 0.5 mg kg-1) but not of 3-morpholino-sydnonimine (SIN-1, 0.125 mg kg-1) in anaesthetized rats were attenuated following a seven day (using a q.i.d. dosing schedule) oral treatment with isosorbide-5-mononitrate (IS-5-MN; 5 mg kg-1) indicative of the induction of tolerance to GTN but not to SIN-1. The hypotensive effects of GTN did not decline when the sulphydryl (SH) containing angiotensin converting enzyme inhibitor (ACE-1), captopril (CPT, 5 mg kg-1) or the structurally unrelated SH-containing, N-acetylcysteine (NAC, 10 mg kg-1) but not the non-SH-containing ACE-I, enalaprilat (ENA, 5 mg kg-1) were given together with IS-5-MN for the seven days treatment. 2. The attenuated hypotensive effects of GTN (0.5 mg kg-1) in rats treated with IS-5-MN were also restored when CPT (1 mg kg-1) or NAC (2.5 mg kg-1) but not ENA (1 mg kg-1) was administered intraperitoneally (i.p.) 30 min before GTN. Furthermore, in control rats, CPT or NAC but not ENA given i.p. 30 min before GTN, potentiated its haemodynamic effects. These effects were blocked by methylene blue (10 mg kg-1). At the same doses, CPT or NAC did not affect the hypotensive effects of SIN-1. 3. The reduced ability of cultured tolerant smooth muscle cells (SMC, 24 x 103 cells) or endothelial cells(EC, 40 x 103 cells) to potentiate the anti-platelet effects of GTN (44 microM) was restored by CPT or NAC but not by ENA or glutathione (all at 0.5 mM). Potentiation of the anti-platelet effects of tolerant SMC or EC by CPT or NAC was abolished by co-incubation with oxyhaemoglobin (Oxy-Hb, 10 microM)indicative of nitric oxide (NO) formation.4. When GTN (150-2400 microM) was incubated with CPT, NAC or glutathione but not ENA (all at 0.1 mM) for 30 min in Krebs buffer at 37 degrees C a concentration-dependent increase in nitrite (NO2-)formation was observed. 5. The antiplatelet effects of GTN (5.5-352 microM) were potentiated by co-incubation with CPT or NAC but not with ENA or glutathione (all at 0.5 mM). The concentration of GTN required to inhibit platelet aggregation by 50% (IC50) was 110 +/- 2 microM for GTN alone, 14 +/- 2 microM for GTN in the presence of NAC and 30 +/- 2 microM for GTN in the presence of CPT. The potentiation of the effects of GTN by CPT or NAC was inhibited by co-incubation with Oxy-Hb (10 microM). By themselves, CPT or NAC did not inhibit platelet aggregation.6. The ability of CPT to restore (a) the haemodynamic effects of GTN in tolerant rats and (b) the reduced capacity of tolerant SMC or EC to potentiate the anti-platelet effects of GTN is not related to its ACE inhibitory activity.7. CPT also potentiated the hypotensive effects of GTN in non-tolerant rats, and in vitro CPT released NO from GTN in the absence of a GTN to NO converting cell, so that it is unlikely that reversal of tolerance by CPT is due to the replenishment of intracellular thiols. Rather it can be explained by the ability of CPT to release NO from GTN in the extracellular space. This extracellular formation of NO from GTN by CPT would then compensate for the impaired enzymic biotransformation of GTN to NO that develops during tolerance as was originally proposed for NAC.

Acetylcysteine↗

PubMed1987

Optical recording of electrical activity from parallel fibres and other cell types in skate cerebellar slices in vitro.

1. A reliable and simple fish brain slice preparation was obtained from the cerebellum of the skate, and its properties were described. 2. A potentiometric oxonol dye, RH-482, and multiple site optical recording of transmembrane voltage (MSORTV) were used to reveal the electrophysiological properties of the parallel fibre action potential and to measure its conduction (0.13 m/s). The parallel fibre action potential was blocked in the presence of tetrodotoxin (TTX) and prolonged by tetraethylammonium (TEA), suggesting that the upstroke depends upon sodium entry and the repolarization upon potassium efflux. An after-hyperpolarization results from a calcium-dependent potassium conductance. 3. A second potentiometric dye, RH-155, differing only slightly from RH-482, exhibited a high affinity for glial cell membrane, and could be used to monitor changes in extracellular potassium concentration by detecting changes in glial membrane potential. 4. Calcium channel blockers such as cadmium ions blocked the optical signal that reflected the extracellular accumulation of potassium. 5. Interventions that modified the extracellular volume, and thereby affected the accumulation of potassium, produced large changes in the optical signal that monitored glial depolarization. Hypertonic and hypotonic bathing solutions resulted in decreases and increases, respectively, in the magnitude of the extrinsic absorption change that tracked potassium accumulation. 6. Blocking sodium-potassium pump activity by means of ouabain prolonged the time course of the optical signal that was related to potassium accumulation in the extracellular space. 7. Extracellular potassium accumulation was revealed to be critically dependent upon intracellular calcium ions.

Action Potentials↗

PubMed1977

The effects of glucose and insulin on contraction of the isolated diaphragm.

High glucose concentrations (55 mM) were found to suppress the isometric contraction tension of rat diaphragm. The effect appears to be due to the resulting transmembrane osmotic gradient in spite of the fact that glucose uptake by the diaphragm is fairly rapid. Insulin can reverse the effect of hypertonic glucose to a considerable extent. The problems of estimating intracellular glucose concentration in the isolated muscle are considered. Estimates of intracellular glucose taking into account extracellular space and extracellular diffusion gradients were made using a two-compartment model. Calculations based on the model show that in the presence of insulin, intracellular glucose increases from about 1 to 19 mumol/ml of muscle fibre. The mean transmembrane glucose concentration gradient dcreases from 41 to 18 mumol/ml. With the use of the model it appears possible to relate most of the observed effect of glucose and insulin on isometric contraction to their influence on the osmotic gradient across the muscle fibre membrane. Insulin appears to have some additional effects on muscles suppressed by hypertonic solutions which are not accounted for by this mechanism.

Animals↗

PubMed1976

Transendothelial vesicular transport of protein following compression injury to the spinal cord.

Routes of vascular leakage resulting in trauma-induced edema have not been clarified. To explore the problem we followed the fate of intravascular horseradish peroxidase (HRP) after compression injury to the thoracic cord (cats). At 90 seconds and 15 minutes, HRP was confined to the gray matter, occupying perivascular spaces, unexpanded extracellular channels, and cytoplasmic compartments of injured cells. Adjoining segments contained similar but lesser deposits. At 4 hours, tracer occupied the expanded extracellular spaces of the lesion's white matter; gray matter deposits were present up to 4 cm. distal. Vessels revealed no evidence of rupture. Open interendothelial junctions were not found. Counts of HRP-labeled vesicles in the endothelium of gray matter capillaries revealed a significant intensification of vesicular activity in the lesion and in adjacent areas up to 9 cm. caudal. Morphologically, labeled vesicles exhibited a wide diversity in shape and size. Typical pinocytotic (700A) and tubular forms measured 400 to 700 A in width; vacuolar forms measuring up to 0.7 mum. across were frequently observed. Continuity between the three types was often evident. Where basement membrane and perivascular clefts were not yet inundated with HRP, sites of vesicular emptying of HRP at the tissue front were identified. Serial sections revealed that vesicles may be contiguous from luminal to abluminal surfaces, thus providing facilitated transport pathways. The data suggest that vesicular transport plays a role in the genesis of trauma-induced edema.

Animals↗