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PubMed2000

Extracellular diffusion parameters in spinal cord and filum terminale of the frog.

Extracellular space (ECS) diffusion parameters were studied in isolated frog spinal cord grey matter and filum terminale (FT), that is predominantly composed of glial cells and axons. We compared the cell swelling induced by K(+) application, hypotonic stress and tetanic stimulation of afferent input. The ECS diffusion parameters, volume fraction alpha (alpha = ECS volume/total tissue volume), tortuosity lambda (lambda(2) = free/apparent diffusion coefficient in the tissue) and non-specific cellular uptake k', were determined by the real-time iontophoretic method using TMA(+)-selective microelectrodes. Stimulation-evoked changes in extracellular K(+) concentration ([K(+)](e)) were measured by K(+)-selective microelectrodes. Histological analysis revealed that in the central region of the FT, the cell density was lower than in SC, neurons and oligodendrocytes were scarce, GFAP-positive astrocytes were abundant, and they showed thicker and more densely stained processes than in spinal cord. In the FT, alpha was 58% higher and lambda significantly lower than in the spinal cord. In 50 mM K(+), alpha in spinal cord decreased from about 0.19 to 0.09, i.e., by 53%, whereas in FT from about 0.32 to 0.20, i.e., by only 38%; lambda increased significantly more in FT than in spinal cord. Hypotonic solution (175 mmol/kg(-1)) resulted in similar decreases in alpha, and there were no changes in lambda in either spinal cord or FT. Stimulation of VIII or IX dorsal root (DR) by 30 Hz evoked an increase in [K(+)](e) from 3 to 11-12 mM in spinal cord, but to only 4-5 mM in FT. In the spinal cord this stimulation led to a 30% decrease in alpha and a small increase in lambda whereas in the FT the decrease in alpha was only about 10% and no increase in lambda was found. We conclude that in spinal cord, a complex tissue with a higher density of cellular elements than the FT, 50 mM K(+), hypotonic stress as well as DR stimulation evoked a greater decrease in ECS volume than in FT. Nevertheless, the K(+)-induced increase in tortuosity was higher in FT, suggesting that a substantial part of the K(+)-evoked increase in lambda was due to astrocytic swelling.

Animals↗
PubMed2000

Accumulation of zinc in degenerating hippocampal neurons of ZnT3-null mice after seizures: evidence against synaptic vesicle origin.

In several brain injury models, zinc accumulates in degenerating neuronal somata. Suggesting that such zinc accumulation may play a causal role in neurodegeneration, zinc chelation attenuates neuronal death. Because histochemically reactive zinc is present in and released from synaptic vesicles of glutamatergic neurons in the forebrain, it was proposed that zinc translocation from presynaptic terminals to postsynaptic neurons may be the mechanism of toxic zinc accumulation. To test this hypothesis, kainate seizure-induced neuronal death was examined in zinc transporter 3 gene (ZnT3)-null mice, a strain that completely lacks histochemically reactive zinc in synaptic vesicles. Intraperitoneal injection of kainate induced seizures to a similar degree in wild type and ZnT3-null mice. Staining of hippocampal sections with a zinc-specific fluorescent dye, N-(6-methoxy-8-quinolyl)-p-carboxybenzoylsulfonamide, revealed that zinc accumulated in degenerating CA1 and CA3 neurons in both groups, indicating that zinc originated from sources other than synaptic vesicles. Injection of CaEDTA into the cerebral ventricle almost completely blocked zinc accumulation in ZnT3-null mice, suggesting that increases in extracellular zinc concentrations may be a critical event for zinc accumulation. Arguing against the possibility that zinc accumulation results from nonspecific breakdown of zinc-containing proteins, injection of kainate into the cerebellum did not induce zinc accumulation in degenerating granule neurons. Taken together, these results support the existing idea that zinc is released into extracellular space and then enters neurons to exert a cytotoxic effect. However, the origin of zinc is not likely to be synaptic vesicles, because zinc accumulation robustly occurs in ZnT3-null mice lacking synaptic vesicle zinc.

Animals↗
PubMed2003

Natriuresis and the extracellular volume expansion by hypertonic saline.

BACKGROUND: The mechanisms governing the duration of the extracellular fluid volume (ECF) expansion as a result of intravenous infusion of hypertonic saline solution are poorly understood. We hypothesized that the duration is closely related to the sodium excretion. MATERIALS AND METHODS: Six conscious splenectomized ewes with a mean body weight of 30 kg were given an intravenous infusion of 4 ml x kg(-1) of 7.5% saline solution on two occasions, one over a period of 5 min and another over a period of 20 min. Mass balance and volume kinetic calculations of the distribution and elimination of fluid were performed after repeated sampling of the plasma sodium concentration and the urinary excretion of water and sodium during 3 h. RESULTS: On considering the addition of sodium to and its excretion from the body, the plasma sodium concentration indicated a 10% dilution of the extracellular space. The volume expansion decayed at an average rate of 20% of the volume expansion per hour, which, however, varied greatly in the animals, depending on their capacity to excrete sodium. After 1 h, increasing natriuresis promoted translocation of water into the cells, which amounted to 25-35% of the total elimination. Computer simulations indicated that tripled natriuresis (up to approximately 750 mmol l(-1)) would increase the rate of elimination to 45% of the volume expansion per hour. CONCLUSION: The sodium excretion was inversely proportional to the duration of the extracellular volume expansion by 7.5% saline.

Animals↗
PubMed1977

'Disk shedding' in the cone outer segments of the teleost, Poecilia reticulata P.

Electron microscopical observations show that the cones in the retina of the diurnal Poecilia reticulata shed their membranous outer segment disks. This occurs at the side of the disk which is open to the extracellular space. Shedding is observed in single and twin cones and occurs at any level of the outer segment. The disks are not discarded in packages or as single disks, but are shed in small vesicular portions. This mode of 'disk shedding' may explain why in cone outer segments radioactively labelled replacement protein is diffusely distributed.

Animals↗
PubMed1978

Intracellular and intramitochondrial binding of lanthanum in dark degenerating midgut cells of a collembolan (insect).

Lanthanum is known to be a marker of extracellular spaces. Intracellular organelles are always devoid of stain. But dark and damaged cells may be entered by the marker, as studied at the cellular level, using the electron probe X-ray microanalyser. The technique may be used to detect increased permeability at a stage when no fine structural abnormality is discernible.

Animals↗
PubMed1985

Effects of osmotic shocks on the ultrastructure of different tissues and cell types.

This study deals with the effects of hyper- and hypo-osmotic media on the ultrastructure of four different types of cells and tissues: rat pheochromocytoma cells of line PC12, mouse Ehrlich ascites tumor cells, rat kidney cortex and intestine. Application of hyper-osmotic conditions induces in the nuclear compartment of the tested cell types a condensation of chromatin, a ruffling of the nuclear envelope with loosening of condensed chromatin from the lamina, and an apparent loss of nucleolar fibrillar component which disappears in a background of diffuse granular material. In hypo-osmotic media, there is a marked decondensation of chromatin and a fragmentation of the granular material of the nucleolus. As far as the cytoplasmic compartment is concerned, the electron density of the cytosol is markedly increasing when going from hypo- to hyper-osmotic conditions and there is no vacuolization in hypo-osmotic media. In kidney cortex slices, application of hypo-osmotic shocks further results in a marked reduction of the extracellular space delimited by the infoldings of the tubular cells plasma membranes. These modifications are discussed in relation to the volume regulation process and the changes in ion concentration that occur in cells submitted to anisosmotic media.

Animals↗
PubMed1987

A model study of the effects of the discrete cellular structure on electrical propagation in cardiac tissue.

The effects of the discrete cellular structure on propagation of electrical excitation in cardiac muscle were studied in a one-dimensional fiber model containing a periodic intercalated disk structure. Globally, the macroscopic velocity of propagation follows the behavior associated with propagation in a continuous tissue (except for high values of disk resistance). In addition, the computed spatial extracellular potential along the fiber is a smooth biphasic waveform and does not reflect the underlying discrete cellular structure of the tissue. Other results of the simulations demonstrate the discontinuous nature of propagation and the importance of the structure in arrhythmogenesis. Vmax displays a biphasic behavior as a function of increasing intercalated disk resistance. An initial "paradoxical" increase in Vmax (with a simultaneous decrease in conduction velocity) is followed by a decrease that leads to decremental propagation and conduction block. The time constant of the foot of the action potential (tau foot) increases monotonically with increasing intercalated disk resistance. An increase in the leakage current to extracellular space brings about a significant decrease in the action potential duration and a loss of the plateau. This major effect is accompanied by a relatively smaller decrease in conduction velocity. Collision of two activation wavefronts results in a significant (100%) increase in Vmax and a very small (0.6%) decrease in tau foot.

Action Potentials↗
PubMed1990

Endocytosis in odontoclasts and osteoclasts using microperoxidase as a tracer.

Microperoxidase (MP, a peptide tracer) was intravenously injected into rats after six days of tooth movement by the Waldo method. Bone resorption was seen along the distal bone surface of the inter-radicular septum of the upper first molar, and tooth root resorption occurred along the mesial and distal surfaces of the distal root of the same molar. Odontoclasts were smaller in size and numbers than osteoclasts, but had the same organelles [multiple nuclei, ruffled borders (RB), clear zones, vacuoles, mitochondria, and specific granules] as osteoclasts. MP was deposited on the resorbed area through the clear zone and was transported into the vacuoles along the channels of the RB. The uptake of MP by odontoclasts was small, compared with that by osteoclasts. Collagen fibrils were found in the channels of the RB but were not detected in the vacuoles. Instead, filament-like structures were seen in the vacuoles and were located very near the collagen fibrils in the channels. Fibroblasts outside the resorbed lacunae had endocytosed collagen. In contrast, some cells close to odontoclasts (osteoclasts) in the dentin (bone)-resorbed lacunae had not endocytosed any collagen fibrils. These findings suggest (1) that odontoclasts resorb the dentin or cementum just as osteoclasts do in bone resorption, (2) that the resorbed area connects with the extracellular spaces of the odontoclasts or osteoclasts, and (3) that the organic components (e.g., collagen fibrils) of dentin or cementum are endocytosed through the channels of the RB in the same manner as that for MP. However, the endocytotic ability of odontoclasts appears inferior to that of osteoclasts.

Animals↗
PubMed1984

Acute and chronic experimental optic neuritis. Alteration in the blood-optic nerve barrier.

Horseradish peroxidase (HRP) tracer studies in experimental allergic optic neuritis showed alterations in the blood-optic nerve barrier. Light and electron microscopic examination of the optic disc disclosed intense leakage of HRP at the lamina scleralis, with extracellular staining of both axonal and glial columns, despite the lack of inflammation at this region. The intraorbital optic nerve showed leakage of HRP at the sites of both acute and chronic demyelination. Ultrastructurally, leakage of HRP was confined to the perivascular and extracellular spaces. The mechanism of leakage seems to be by diffusion through the endothelial cell junctions or vesicular transport across the endothelial cells. The high predilection for involvement of the optic nerve in chronic demyelinating disorders may be due to the inherent weakness of the blood-brain barrier at the optic nerve head.

Animals↗
PubMed2006

[Matrix metalloproteinases. Part I].

Metalloproteinases (MMPs) are the extracellular matrix enzymes indispensable in physiological and pathological matrix remodeling. They are produced intracellulary as endopeptidases and secreted to the extracellular space. Under normal conditions MMPs are present in tissues at low levels which increases dramatically during any changes. To date 28 enzymes have been identified and 23 in humans. This paper is a review of metalloproteinases structure, their natural and artificial inhibitors and regulation mechanisms. Function and distribution are critical for pathogenesis and therapy of diseases.

Extracellular Space↗
PubMed1998

Localization and translocation of MMP-2 during aggregation of human platelets.

We have previously shown that human platelets express matrix metalloproteinase-2 (MMP-2) and that the release of this enzyme during platelet activation mediates the ADP- and thromboxane-independent part of aggregation. We have now used immunogold electron microscopy, flow cytometry. Western blot analysis and zymography methods to study the ultrastructural localization of MMP-2 in human washed platelets. Platelet aggregation was stimulated by collagen and the MMP-2 immunoreactivity of platelets was followed during various stages of aggregation. In resting platelets, MMP-2 was randomly distributed in the platelet cytosol without detectable association with platelet granules. Platelet aggregation caused the translocation of MMP-2 from the cytosol to the extracellular space. During the early stages of aggregation, MMP-2 remained in close association with the platelet plasma membrane. We conclude that the interactions of MMP-2 with platelet surface membranes mediate the aggregatory response induced by this enzyme.

Adenosine Diphosphate↗
PubMed1997

Mechanism of angiotensin II-induced arachidonic acid metabolite release in aortic smooth muscle cells: involvement of phospholipase D.

In a previous study, we have shown that angiotensin II (Ang II) activates phosphatidylcholine-hydrolyzing phospholipase D due to Ang II-induced Ca2+ influx from extracellular space in subcultured rat aortic smooth muscle cells. In the present study, we have investigated the role of phospholipase D in Ang II-induced arachidonic acid (AA) metabolite release and prostacyclin synthesis in subcultured rat aortic smooth muscle cells. Ang II significantly stimulated AA metabolite release in a concentration-dependent manner in the range between 1 nmol/I and 0.1 mumol/I. D.L.-Propranolol hydrochloride (propranolol), an inhibitor of phosphatidic acid phosphohydrolase, significantly inhibited the Ang II-induced release of AA metabolites. The Ang II-induced AA metabolite release was reduced by chelating extracellular Ca2+ with EGTA. Genistein, an inhibitor of protein tyrosine kinases, significantly suppressed the Ang II-induced AA metabolite release. 1,6-Bis-(cyclohexyloximinocarbonylamino)-hexane (RHC-80267), a potent and selective inhibitor of diacylglycerol lipase, significantly inhibited the Ang II-induced AA metabolite release. Both propranolol and RHC-80267 inhibited the Ang II-induced synthesis of 6-keto-prostaglandin F1 alpha, a stable metabolite of prostacyclin. The synthesis was suppressed by genistein. These results strongly suggest that the AA metabolite release induced by Ang II is mediated, at least in part, through phosphatidylcholine hydrolysis by phospholipase D activation in aortic smooth muscle cells.

Angiotensin II↗
PubMed1980

["Autodesmosomes", desmosomes formed between apposing surface membranes of the same cell, in the human chorion laeve and amnion (author's transl)].

An unusual desmosome formation in the human amnion and chorion laeve is described. The macula adherens, found at the cell surface, forms contact zones between different parts of one and the same cell: autodesmosomes. These zones appear to seal off and trap compartments of various sizes formed by invagination of the extracellular space. Furthermore they are indistinguishable morphologically from intracellular desmosomes. Epithelial cells of the chorion laeve display autodesmosomes along the whole cell surface, however the basal surfaces of these cells are particularly rich in these structures. Amnion epithelial cells exhibit autodesmosomes on their basal surface only. These surfaces are deeply indented and the foldings, in many cases, reach into the nuclear region. In this area semidesmosomes are found. It is suggested that autodemosomes are formed by semidesmosomes which have approached and become adjacent to each other. Moreover, the presence, and relationship of the autodesmosomes to the extracellular compartments, perhaps indicate a novel metabolic regulatory function of the chorionic and amnionic cells.

Amnion↗
PubMed1975

The development of proline-containing extracellular connective tissue fibrils by chick notochordal epithelium in vitro.

Notochords were isolated from Hamburger-Hamilton stages 13-15 chick embryos by trypsinization and microdissection. These were shown by electron microscopy to be completely devoid of extracellular materials or mesenchymal contaminants. Cultivation of notochordal isolates was carried out on a non-collagenous (Falcon Plastic) substratum for 0 to 48 hours. At 12 hours of in vitro incubation, a discontinuous basal lamina could be demonstrated on the surface of notochordal cells. This was followed by the appearance of microfibrils of various sizes and other components of the extracellular matrix. By 48 hours of in vitro incubation, the same extracellular materials which surround the notochord in vivo (notochord sheath) could be demonstrated in vitro. Autoradiographic studies show that tritiated proline is taken up by notochordal cells and secreted to the extracellular space where label is associated with basal lamina, microfibrils and ground substance. When cis-hydroxyproline, a known collagen-specific inhibitor is added to the system, tritiated proline label is located primarily intracellularly and fewer areas of active fibrillogenesis are noted. This suggests that ultrastructurally recognizable materials produced by notochordal cells in vitro may be at least partially collagenous. Significantly, these materials are produced in vivo at the same time (following stage 10) that notochordal tissues actively induce somite differentiation and cartilage formation. It seems reasonable that a biochemically or ultrastructurally identifiable component of the extracellular matrix may possibly mediate such induction.

Animals↗
PubMed2001

Glial diffusion barriers during aging and pathological states.

In conclusion, glial cells control not only ECS ionic composition, but also ECS size and geometry. Since ECS ionic and volume changes have been shown to play an important role in modulating the complex synaptic and extrasynaptic signal transmission in the CNS, glial cells may thus affect neuronal interaction, synchronization and neuron-glia communication. As shown in Fig. 2, a link between ionic and volume changes and signal transmission has been proposed as a model for the non-specific feedback mechanism suppressing neuronal activity (Syková, 1997; Ransom, 2000). First, neuronal activity results in the accumulation of [K+]e, which in turn depolarizes glial cells, and this depolarization induces an alkaline shift in glial pHi. Second, the glial cells extrude acid and the resulting acid shift causes a decrease in the neuronal excitability. Because ionic transmembrane shifts are always accompanied by water, this feedback mechanism is amplified by activity-related glial swelling compensated for by ECS volume shrinkage and by increased tortuosity, presumably by the crowding of molecules of the ECS matrix and/or by the swelling of fine glial processes. This, in turn, results in a larger accumulation of ions and other neuroactive substances in the brain due to increased diffusion hinderance in the ECS. Astrocyte hypertrophy, proliferation and swelling influence the size of the ECS volume and tortuosity around neurons, slowing diffusion in the ECS. Their organization may also affect diffusion anisotropy, which could be an underlying mechanism for the specificity of extrasynaptic transmission, including 'cross-talk' between distinct synapses (Barbour and Hausser, 1997; Kullmann and Asztely, 1998). An increased concentration of transmitter released into a synapse (e.g. repetitive adequate stimuli or during high frequency electrical stimulation which induces LTP) results in a significant activation of high-affinity receptors at neighboring synapses. The efficacy of such synaptic cross-talk would be dependent on the extracellular space surrounding the synapses, i.e. on intersynaptic geometry and diffusion parameters. Other recent studies have also suggested an important role for proteoglycans, known to participate in multiple cellular processes, such as axonal outgrowth, axonal branching and synaptogenesis (Hardington and Fosang, 1992; Margolis and Margolis, 1993) that are important for the formation of memory traces. Recent observation of a decrease of fibronectin and chondroitin sulfate proteoglycan staining in the hippocampus of behaviorally impaired aged rats (Syková et al., 1998a,b) supports this hypothesis. It is reasonable to assume that besides neuronal and glial processes, macromolecules of the extracellular matrix contribute to diffusion barriers in the ECS. It is therefore apparent that glial cells play an important role in the local architecture of the CNS and they may also be involved in the modulation of signal transmission, in plastic changes, LTP, LTD and in changes of behavior and memory formation.

Aging↗
PubMed1964

AN ANALYSIS OF COLLAGEN SECRETION BY ESTABLISHED MOUSE FIBROBLAST LINES.

In vitro synthesis of collagen by established mouse fibroblast lines has been examined by electron microscopy. During rapid growth (log phase), when collagen could not be detected in the cultures, the cells lacked a well developed granular ergastoplasm and Golgi system. Upon cessation of growth (stationary phase), collagen accumulated in the cultures and the cells demonstrated highly developed granular and smooth ergastoplasm. Collagen appeared to be synthesized in the rough-surfaced endoplasmic reticulum and to be transported as a soluble protein to the cell surface by vesicular elements of the agranular ergastoplasm. Fusion of the limiting membranes of these vesicles with the cell membrane permitted the discharge of the soluble collagen into the extracellular space, where fibrils of two diameter distributions formed. The secretion of collagen is concluded to be of the merocrine type. Alternative theories of collagen secretion are discussed and the data for established lines compared with the results of other in vitro and in vivo studies of collagen fibrillogenesis.

Animals↗
PubMed1975

Size and shape of transverse tubule openings in frog twitch muscle fibers.

The openings of transverse tubules in frog twitch fibers are described. The tubules open to the extracellular space by a narrow neck, with an inner diameter of 20 nm. The most peripheral portion of the tubules is tortuous and has a variable diameter. The similarity in size of the openings of T tubules and caveolae and the meandering path of the tubules are sufficient to account for the paucity of observed openings.

Animals↗
PubMed2003

Long-term potentiation in the dentate gyrus of the anaesthetized rat is accompanied by an increase in extracellular glutamate: real-time measurements using a novel dialysis electrode.

We have used a glutamate-specific dialysis electrode to obtain real-time measurements of changes in the concentration of glutamate in the extracellular space of the hippocampus during low-frequency stimulation and following the induction of long-term potentiation (LTP). In the dentate gyrus, stimulation of the perforant path at 2 Hz for 2 min produced a transient increase in glutamate current relative to the basal value at control rates of stimulation (0.033 Hz). This activity-dependent glutamate current was significantly enhanced 35 and 90 min after the induction of LTP. The maximal 2 Hz signal was obtained during post-tetanic potentiation (PTP). There was also a more gradual increase in the basal level of extracellular glutamate following the induction of LTP. Both the basal and activity-dependent increases in glutamate current induced by tetanic stimulation were blocked by local infusion of the N-methyl-D-aspartate receptor antagonist D-APV. In areas CA1 and CA3 we were unable to detect a 2 Hz glutamate signal either before or after the induction of LTP, possibly owing to a more avid uptake of glutamate in the pyramidal cell fields. These results demonstrate that LTP in the dentate gyrus is associated with a greater concentration of extracellular glutamate following activation of potentiated synapses, either because potentiated synapses release more transmitter per impulse, or because of reduced uptake by glutamate transporters. We present arguments favouring increased release rather than decreased uptake.

Animals↗