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PubMed1992

Patchy accumulation of apical Na+ transporters allows cross talk between extracellular space and cell nucleus.

Intracellular Na+ activities and local current densities were measured in fused Madin-Darby canine kidney cells using Na+ and voltage-sensing microelectrodes. Na+ that enters the cell across the apical plasma membrane accumulates initially in the nucleoplasm, several seconds ahead of its appearance in the cell cytoplasm. The spatial distribution of Na+ currents, produced by a local superfusion of the cell surface, indicates a nonuniform, patchy accumulation of apical Na+ transporters in the vicinity of the nucleus. Such pathways for direct Na+ flux between extracellular space and cell nucleus could be potentially important for gene activation.

Animals↗

PubMed1987

Intracellular and extracellular spaces of normal adult rat brain determined from the proton nuclear magnetic resonance relaxation times.

The nuclear magnetic resonance method was used to investigate the state of water molecules in normal rat brain tissue in vitro. The transverse magnetization decay curve (TMDC) of the fresh brain tissue of adult rats (8- or 10-weeks-old) was biexponential, which could be interpreted in terms of two distinct transverse relaxation times (T2). Several factors that may affect the TMDC are discussed. It was concluded that the fast and slow components of T2 correspond to those of the water molecules of the intracellular and the extracellular spaces of normal rat brain tissue, respectively.

Animals↗

PubMed1975

The permeability to ions of the neural lamella and the extracellular spaces in the C.N.S. of Anodonta cygnea.

Rapid axonal depolarization follows the elevation of [K+]o in the Ringer bathing the surfaces of the connectives of both intact and desheathed cerebrovisceral connectives of Anodonta cygnea. Potassium movements between the blood or medium bathing the surface of the connectives and the axonal membranes can be accounted for in terms of a first-order diffusion process. No visible structural barriers to prevent free movements of materials through the neural lamella and the extracellular spaces can be detected in electron micrographs of the cerebro-visceral connectives. In desheathed preparations fast action potentials are conducted in sodium-free (dextran) Ringer. Mechanisms of axona .l function and ionic regulation in this and other invertebrate central nervous tissues are discussed in the light of these observations.

Action Potentials↗

PubMed1985

Effect of extracellular space on kallikrein excretion in the rat.

Urinary kallikrein excretion was positively correlated with urine flow and negatively with urinary osmolality, it was also positively correlated with inulin space and its both components, plasma volume and interstitial space. We postulate that increased extracellular fluid increases kallikrein excretion and kallikrein avoids water reabsorption leading to a decrease in the extracellular fluid.

Animals↗

PubMed1996

Dynamic changes in water ADC, energy metabolism, extracellular space volume, and tortuosity in neonatal rat brain during global ischemia.

To obtain a better understanding of the mechanisms underlying early changes in the brain water apparent diffusion coefficient (ADC) observed in cerebral ischemia, dynamic changes in the ADC of water and in the energy status were measured at postnatal day 8 or 9 in neonatal rat brains after cardiac arrest using 1H MRS/MRI and 31P MRS, respectively. The time courses of the MR parameters were compared with changes in the extracellular space (ECS) volume fraction (alpha) and tortuosity (lambda), determined from concentration-time profiles of tetramethylammonium applied by iontophoresis. The data show a decrease of the ADC of tissue water after induction of global ischemia of which the time course strongly correlates with the time course of the decrease in the ECS volume fraction and the increase in ECS tortuosity. This indicates that cell swelling is an important cause for the ADC decrease of water.

Animals↗

PubMed1999

Calcium dynamics in the extracellular space of mammalian neural tissue.

In the brain, hundreds of intracellular processes are known to depend on calcium influx; hence any substantial fluctuation in external calcium ([Ca2+]o) is likely to engender important functional effects. Employing the known scales and parameters of mammalian neural tissue, we introduce and justify a computational approach to the hypothesis that large changes in local [Ca2+]o will be part of normal neural activity. Using this model, we show that the geometry of the extracellular space in combination with the rapid movement of calcium through ionic channels can cause large external calcium fluctuations, up to 100% depletion in many cases. The exact magnitude of a calcium fluctuation will depend on 1) the size of the consumption zone, 2) the local diffusion coefficient of calcium, and 3) the geometrical arrangement of the consuming elements. Once we have shown that using biologically relevant parameters leads to calcium changes, we focus on the signaling capacity of such concentration fluctuations. Given the sensitivity of neurotransmitter release to [Ca2+]o, the exact position and timing of neural activity will delimit the terminals that are able to release neurotransmitter. Our results indicate that mammalian neural tissue is engineered to generate significant changes in external calcium concentrations during normal activity. This design suggests that such changes play a role in neural information processing.

Animals↗

PubMed1992

Structure-activity relationship of the neurotransmitter alpha-bag cell peptide on Aplysia LUQ neurons: implications regarding its inactivation in the extracellular space.

Alpha-bag cell peptide [alpha-BCP (Ala-Pro-Arg-Leu-Arg-Phe-Tyr-Ser-Leu)] is a neurotransmitter that mediates bag cell-induced inhibition of left-upper-quadrant (LUQ) neurons L2, L3, L4, and L6 in the abdominal ganglion of Aplysia. Our recent biochemical studies have shown that alpha-BCP[1-9] is cleaved into alpha-BCP[1-2], [3-9], [1-5], [6-9], and [7-9] by a combination of three distinct peptidase activities located within the extracellular spaces of the CNS: A diaminopeptidase-IV (DAP-IV)-like enzyme cleaves alpha-BCP[1-9] at the 2-3 peptide bond; a neutral metalloendopeptidase (NEP)-like enzyme cleaves either alpha-BCP[1-9] or alpha-BCP[3-9] at the 5-6 bond; an aminopeptidase M-II (APM-II)-like enzyme cleaves alpha-BCP[6-9] at the 6-7 bond, but cleaves neither alpha-BCP[1-9], nor the other ganglionic peptidase products. To further understand the manner in which alpha-BCP is inactivated after release, that is loses its electrophysiological activity, we studied its structure-activity relationship by recording intracellularly from LUQ neurons in isolated abdominal ganglia that were arterially perfused with peptides dissolved in artificial sea water. The effects of alpha-BCP[1-9] and 15 of its fragments ([1-8], [1-7], [1-6], [1-5], [2-9], [3-9], [3-8], [6-9], [7-9], [8-9], [6-7], [6-8], [1-2], Phe, Tyr) indicated that the sequence Phe6-Tyr7 was both necessary and sufficient to produce LUQ inhibitory activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗

PubMed1986

Muscle grafts as entries for blood-borne proteins into the extracellular space of the brain.

Nuchal muscle autografts of two different sizes were transplanted into rat brain parenchyma (intraparenchymal, 1.5 X 1.5 X 1 mm) and onto the surface of the brain stem (intraventricular, 2 X 2 X 1 and 1.5 X 1.5 X 1 mm). The vasculature of the transplants retained its permeability to proteins. Exogenous, intravenously injected horseradish peroxidase (HRP) and endogenous immunoglobulins (IgG) crossed the vessels of the grafts to enter the surrounding brain tissue 1 and 3 months after transplantation. HRP infiltrated about 0.46 to 4.6 mm into the extracellular spaces around the grafts 60 minutes after its intravenous injection. The penetration of HRP depended on the size and age of the graft. Infiltration was greater in 1-month-old rats with slightly larger intraventricular grafts than in those with smaller grafts. There was a tendency for the penetration of HRP to be greater from 1-month-old grafts than from 3-month-old grafts, but the difference was not statistically significant, except for the horizontal vector of spread in the intraparenchymal group. Although endogenous IgG infiltrated the surrounding brain tissue, its penetration was very limited in comparison with that of HRP. The results suggest that muscle grafts could be used as a readily available and accessible means of circumventing the blood-brain barrier selectively and focally.

Animals↗

PubMed1994

Superoxide scavenging activity in the extracellular space of the brain in forming edema.

We carried out a time course study of cerebral superoxide scavenging activity using a modified microdialysis technique. Twelve cats were divided into two groups; six were the reperfusion injury models, and six were cold injury models. In the reperfusion injury model, dialysates were collected during 60 minutes of middle cerebral artery occlusion and at 300 minutes during reperfusion. In the cold injury model, dialysates were collected 240 minutes after the injury. Regional cerebral blood flow on the injured side decreased during occlusion in the reperfusion injury model and 60 minutes after injury in the cold injury model. In the reperfusion model, superoxide scavenging activity, as determined with electron spin resonance, increased in the first 30 minutes and decreased 300 and 330 minutes after occlusion. In the dialysate, albumin increased 180 minutes after cold injury, which may show the progress of vasogenic edema. An increase in water content was observed on the injured side of both models, and a correlation between water content and superoxide scavenging activity was found in the reperfusion injury model. By this technique, a method of detecting the alteration of superoxide scavenging activity in the extracellular space of the brain was established.

Animals↗

PubMed2002

Release of cytokeratin-18 and -19 fragments (TPS and CYFRA 21-1) into the extracellular space during apoptosis.

Serum fragments of cytokeratins-18 and -19 (measured as TPS and CYFRA 21-1, respectively) have traditionally been considered as markers of tumor proliferation, although the evidence is scarce for a causative relationship between proliferation and levels of TPS and CYFRA 21-1. We examined whether apoptosis might produce TPS and CYFRA 21-1 fragments. MCF-7 breast cancer cells were treated with mitomycin C or agonistic anti-CD95 antibody, and levels of TPS and CYFRA 21-1 in tissue culture supernatants were compared with the frequency of cells exhibiting the following markers of cell death: intracellular cytokeratin-18 cleavage, surface staining with annexin-V, propidium iodide uptake, DNA fragmentation. Twenty-four hours after inducing apoptosis, levels of TPS and CYFRA 21-1 were elevated > or = 4-fold in culture supernatants. Elevations in TPS and CYFRA 21-1 coincided with apoptosis measured by the first three cell death markers but preceded DNA fragmentation. These mitomycin C- and CD95-mediated elevations were completely inhibited by co-incubation with the caspase inhibitors Z-VAD.fmk and Z-IETD.fmk, respectively. We conclude that TPS and CYFRA 21-1 can be abundantly released into the extracellular space during the intermediate stage of epithelial cell apoptosis.

Antigens, Neoplasm↗

PubMed2003

Meprin proteolytic complexes at the cell surface and in extracellular spaces.

Meprins are metalloproteinases of the astacin family and metzincin superfamily that are composed of evolutionarily related alpha and beta subunits, which exist as homo- and hetero-oligomeric complexes. These complexes are abundant at the brush border membranes of kidney proximal tubule cells and epithelial cells of the intestine, and are also expressed in certain leucocytes and cancer cells. Meprins cleave bioactive peptides such as gastrin, cholecystokinin and parathyroid hormone, cytokines such as osteopontin and monocyte chemotactic peptide-1, as well as proteins such as gelatin, collagen IV, fibronectin and casein. Database predictions and initial data indicate that meprins are also capable of shedding proteins, including itself, from the cell surface. Membrane-bound meprin subunits are composed of dimeric meprin beta subunits or tetrameric hetero-oligomeric alpha beta complexes of approx. 200-400 kDa, and can be activated at the cell surface; secreted forms of homo-oligomeric meprin alpha are zymogens that form high-molecular-mass complexes of 1-6 MDa. These are among the largest extracellular proteases identified thus far. The latent (self-associating) homo-oligomeric complexes can move through extracellular spaces in a non-destructive manner, and deliver a concentrated form of the metalloproteinase to sites that have activating proteases, such as sites of inflammation, infection or cancerous growth. Meprins provide examples of novel ways of concentrating proteolytic activity at the cell surface and in the extracellular milieu, which may be critical to proteolytic function.

Amino Acid Sequence↗

PubMed1985

Contribution of restricted extracellular space to the inactivation of calcium current in the snail neuron.

The mechanisms underlying the inactivation of calcium current (ICa) were investigated in isolated nerve cell bodies of Helix aspersa using a suction pipette technique that allowed voltage clamp and internal perfusion at the same time. ICa was recorded after eliminating the Na and K currents by removing Na+ and K+ both in external and internal solutions, and ICa inactivation due to intracellular Ca2+ accumulation was blocked by 5-25 mM EGTA. The inactivation rates of ICa, IBa and ISr corresponded to two exponential processes. The inactivation rates of the inward currents (IMn, ICd and IZn) less than 1/5 of ICa fitted a single exponential. However, when neurons were superfused with hypertonic external solution by adding 100 mM sucrose together with internal EGTA, the steady-state inactivation of ICa, IBa and ISr was reduced, and the inactivation processes changed to a single exponential similar to that of IMn, ICd and IZn. In contrast, internal perfusion with the hypertonic solution had no effect on the inactivation of ICa, IBa and ISr. Therefore, it was concluded that the inactivation process of ICa is dependent not only on the membrane voltage and the intracellular Ca2+ accumulation as described previously, but is also affected by the rapid fall in the concentration of Ca2+ in the restricted extracellular spaces (RES) which gets enlarged by the hypertonic external solution. The same is also true for IBa and ISr.

Action Potentials↗

PubMed1994

Superoxide scavenging activity in vitro and in the cerebral extracellular space measured by microdialysis.

Using the electron spin resonance (ESR) spin-trapping method and a high molecular cut-off membrane, we measured the superoxide scavenging activity in dialysates obtained from microdialysis. The activity in the dialysates of the Cu,Zn-superoxide dismutase (SOD) solution and feline serum were measured in vitro, and the recovery rate was calculated to be 12.88 +/- 0.9% in Cu,Zn-SOD solution and 21.52 +/- 4.38 in feline serum, which was significantly different. This difference was believed to originate from the higher osmotic pressure due to proteins in the serum and substances other than Cu,Zn-SOD that acted as antioxidants in the serum. In an in vivo study, microdialysis probes were implanted into the cerebral hemispheres in 6 cats. The sequential changes of superoxide scavenging activity were measured for 16 h and during induced cardiac arrest. No significant difference was observed and the microdialysis technique itself did not seem to cause the significant alteration of the activity in the extracellular space, although at cardiac arrest, the activity varied widely. This method can be used to study the reaction against superoxide injury in further experiments involving brain insult.

Animals↗

PubMed1993

Cellular morphology and extracellular space at rhombomere boundaries in the chick embryo hindbrain.

The chick embryo hindbrain is a segmented region of the CNS characterised by repeated blocks of neuroepithelial cells, known as rhombomeres. Individual rhombomeres are polyclonal compartments, defined both by cell lineage restriction and by the restricted expression of development control genes, that later acquire specific patterns of neuronal differentiation and axon outgrowth. The interfaces between adjacent rhombomeres are defined by boundaries across which cells do not move; the boundaries contain specialised cells and are preferentially colonised at early stages of development by extending axons. In this study, routine electron microscopy and high-pressure cryopreservation, a technique that avoids artifacts of chemical fixation, have been used to examine the morphology of rhombomere boundaries through a staged series of chick embryos. We find that the boundary regions contain enlarged extracellular spaces and that these form conduits for axons subsequently extending in the circumferential plane of the hindbrain. Labeling the ventricular surface of the neuroepithelium with DiI crystals in aqueous suspension revealed the morphology of individual cells in the intact neural tube, and demonstrated unusual fan-shaped arrays of cells at the boundaries. These findings contribute further to the evidence that cells at rhombomere boundaries differ from those in rhombomere centres, and leads to hypotheses about both the mechanism of development of the boundaries, and the role they may play in hindbrain patterning.

Animals↗

PubMed2004

Diffusion of epidermal growth factor in rat brain extracellular space measured by integrative optical imaging.

Epidermal growth factor (EGF) stimulates proliferation, process outgrowth, and survival in the CNS. Understanding the actions of EGF necessitates characterizing its distribution in brain tissue following drug delivery or release from cellular sources. We used the integrative optical imaging (IOI) method to measure diffusion of fluorescently labeled EGF (6,600 Mr; 4 microg/ml) in the presence of excess unlabeled EGF (90 microg/ml) to compete off specific receptor binding and reveal the "true" EGF diffusion coefficient following injection in rat brain slices (400 microm). The effective diffusion coefficient was 5.18 +/- 0.16 x 10(-7) (SE) cm2/s (n = 22) in rat somatosensory cortex and the free diffusion coefficient, determined in dilute agarose gel, was 16.6 +/- 0.12 x 10(-7) cm2/s (n = 27). Tortuosity (lambda), a parameter representing the hindrance imposed on EGF by the convoluted brain extracellular space (ECS), was 1.8, the lowest yet measured by IOI for a protein in brain. Control experiments with fluorescent dextran of similar molecular weight and tetramethylammonium confirmed EGF did not affect local ECS structure. We conclude that transport of smaller growth factors such as EGF through brain ECS is less hindered than that of larger proteins (>10,000 Mr, e.g., nerve growth factor) where typically lambda > 2.1. Modeling was used to predict that low lambda will allow EGF sources in the brain to be further from target cells and still elicit a biological response. High lambda values for larger growth factors imply more constrained local biological effects than with smaller proteins such as EGF.

Amino Acid Sequence↗

PubMedDate not supplied

Effects of dextran on hippocampal brain slice water, extracellular space, calcium kinetics and histology.

Hippocampal brain slices are valuable models for studying brain function but are compromised by several artifacts, including significant water gain and histologic injury, which occur under certain incubation conditions. Addition of colloid to Krebs-Ringer buffer (K-R) has been shown to eliminate water gain but has not achieved widespread acceptance. We confirm prior observations that dextran and PEG lessen the increase in slice mass during incubation in a dose-dependent manner with no water gain occurring at 4% concentrations. However, we also observe that addition of colloid to standard K-R induces severe neuronal pyknosis. Fortunately, the pyknosis can be eliminated by reduction in buffer osmolarity through adjustment of NaCl, producing markedly improved slice histology in dextran buffer, especially in the CA3 and CA4 regions of the hippocampus which are severely injured when incubated submerged in K-R at 37 degrees C. Extracellular space markers are not affected by either colloid. The volume of distribution for 45Ca is much larger in dextran buffers than in K-R and variability of 45Ca kinetics is also reduced. In the presence of dextran, hypoxia induces significant slice water gain, a relatively selective histologic injury and an alteration of tissue Ca2+ kinetics. Use of dextran buffers may eliminate many troubling brain slice artifacts.

Animals↗

PubMed2004

Extrasynaptic volume transmission and diffusion parameters of the extracellular space.

Extrasynaptic communication between neurons or neurons and glia is mediated by the diffusion of neuroactive substances in the volume of the extracellular space (ECS). The size and irregular geometry of the diffusion channels in the ECS substantially differ not only around individual cells but also in different CNS regions and thus affect and direct the movement of various neuroactive substances in the ECS. Diffusion in the CNS is therefore not only inhomogeneous, but often also anisotropic. The diffusion parameters in adult mammals (including humans), ECS volume fraction alpha (alpha=ECS volume/total tissue volume) and tortuosity lambda (lambda(2)=free/apparent diffusion coefficient), are typically 0.20-0.25 and 1.5-1.6, respectively, and as such hinder the diffusion of neuroactive substances and water. These diffusion parameters modulate neuronal signaling, neuron-glia communication and extrasynaptic "volume" transmission. A significant decrease in ECS volume fraction and an increase in diffusion barriers (tortuosity) occur during neuronal activity and pathological states. The changes are often related to cell swelling, cell loss, astrogliosis, the rearrangement of neuronal and astrocytic processes and changes in the extracellular matrix. They are also altered during physiological states such as development, lactation and aging. Plastic changes in ECS volume, tortuosity and anisotropy significantly affect neuron-glia communication, the spatial relation of glial processes toward synapses, glutamate or GABA "spillover" and synaptic crosstalk. The various changes in tissue diffusivity occurring during many pathological states are important for diagnosis, drug delivery and treatment.

Animals↗

PubMed1996

The effects of halothane on arginine-vasopressin-induced Ca2+ mobilization from the intracellular stores and the receptor-mediated Ca2+ entry from the extracellular space in single cultured smooth muscle cells of rat aorta.

Halothane has a direct action on vascular smooth muscle cells and causes relaxation of these cells, yet neither the mechanism nor the site of its action is completely understood. Using digital imaging microscopy with the Ca2+ indicator fura-2, the effects of halothane on the intracellular [Ca2+] dynamics induced by arginine vasopressin (AVP) in the perinuclear region and cytosol in single cultured smooth muscle cells of rat aorta were studied. Changes in intracellular [Ca2+] were expressed as percent increases in the ratios of fluorescence intensity at 500 nm excited by 340 nm and 380 nm. AVP (10(-7) M) elicited an initial transient increase in [Ca2+] in the perinuclear region higher than that in the cytosol in Ca(2+)-containing solution (346% +/- 21% and 213% +/- 22%, respectively). Halothane, 0.5%, attenuated the [Ca2+] increase induced by AVP in the perinuclear region and cytosol, and halothane, 1.0% and 2.0%, abolished the differential increase. Under the continuous application of AVP (10(-7) M), Ca2+ restoration in the medium after perfusion with Ca(2+)-free solution increased the perinuclear [Ca2+] more than the cytosolic [Ca2+]. Both were significantly attenuated by 2.0% halothane, but not by nicardipine (10(-5) M) or ryanodine (10(-6) M). Our results suggest that halothane may attenuate the Ca2+ release from the intracellular Ca2+ stores more than the receptor-mediated Ca2+ entry from the extracellular space in the AVP-induced response in these cells.

Anesthetics, Inhalation↗