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At least 1,207 records · Page 67Linked to original sources
PubMed1979

Mechanisms involved in differential conduction of potentials at high frequency in a branching axon.

1. The ionic mechanisms involved in block of conduction of action potentials following high frequency stimulation were studied in a branching axon of the lobster Panulirus penicillatus. 2. A 2-3 mM increase in extracellular K concentration (normal concentration 12 mM) produced block of conduction into both daughter branches. 3. While conduction block induced by high frequency stimulation occurs first into the large daughter branch and only later into the smaller one, propagation into both branches is blocked simultaneously by increased extracellular K concentration. 4. Increasing extracellular K by 2-3 mM resulted in membrane depolarization, reduction in membrane resistance and reduced excitability. The latter two effects were larger than expected from the small depolarization. It appears that increase of extracellular K has direct effects on membrane excitability. 5. It is suggested that block of conduction after high frequency stimulation results from accumulation of K in the extracellular space. However, in order to account for differential conduction block in the two branches one must assume differential buildup of extracellular K concentration around the two branches during high frequency stimulation. 6. Ultrastructural studies using La and horseradish peroxidase as extracellular markers show that the space around the two branches is similar and is open to the extracellular space. Therefore differences in periaxonal volume cannot account for differential buildup of K around the two branches. 7. It is demonstrated that the lobster axon has a Na+/K+ electrogenic pump. After blocking this pump with ouabain, stimulation at high frequency resulted in a conduction block in the two branches almost at the same time. 8. Injection of Ca2+ intracellularly into the thick branch prevents or delays the appearance of conduction block after high frequency stimulation. 9. A mechanism based on these findings is suggested to explain the differential conduction block seen after high frequency stimulation in a branching axon with almost ideal impedance matching.

Action Potentials↗
PubMed1988

Adrenergic mechanisms in myocardial infarction: cardiac and systemic catecholamine release.

During myocardial ischemia high amounts of noradrenaline are released from the sympathetic nerve terminals of the heart and accumulate in the extracellular space of the ischemic area. This increase in local catecholamine concentrations within the still viable myocardium may induce further deterioration of myocardial function during the ischemic process, i.e., acceleration of cell damage and induction of arrhythmias. Three different mechanisms of local catecholamine release have been demonstrated to operate subsequently during the course of myocardial ischemia. Correspondingly, three phases of release must be considered. Phase 1 (ischemia up to 10 min): The release of catecholamines occurs by exocytosis and depends on the activity of the efferent cardiac sympathetic nerves. The extracellular accumulation of noradrenaline is limited by the activity of the neuronal reuptake process and by presynaptic inhibitory effects of adenosine. Phase 2 (10-40 min of ischemia): A massive accumulation of noradrenaline is found in the extracellular space of the ischemic myocardium. The release is determined by local energy exhaustion rather than by centrally originating factors. The release mechanism is different from exocytosis and demonstrates the characteristics of a carrier-mediated efflux using the neuronal uptake carrier in reverse of its normal transport direction. Phase 3 (ischemia longer than 40 min): The release occurs in parallel with the development of structural membrane defects within the ischemic area and the sympathetic neurons progressively deplete from noradrenaline. Among these mechanisms, the carrier-mediated release of noradrenaline appears to be of greatest significance since during Phase 2, extracellular noradrenaline concentrations reach micromolar concentrations capable of producing myocardial necrosis even in the nonischemic heart.

Catecholamines↗
PubMed1998

Extracellular Ca2+ regulates the respiratory burst of human neutrophils.

The role of extracellular calcium in the activation of respiratory burst in human neutrophils was studied by using the receptor agonist, N-formyl-methionyl-leucyl-phenylalanine (fMLP), and the activator of protein kinase C phorbol myristate acetate (PMA). The level of intracellular free calcium was measured by using both cell suspensions and single cells in the presence and absence of extracellular calcium. The Ca2+-ATPase inhibitor, thapsigargin, was used to activate higher Ca2+ influx, while a novel calcium channel blocker, panax notoginseng saponins (PNGS) was used to block the Ca2+ entry from extracellular space during the responding period of cells. It was found that about two-thirds of the activation of respiratory burst initiated by the receptor agonist were attributed to the Ca2+ influx under normal physiological conditions. The higher Ca2+ influx resulted in tremendous enhancement of the intensity of respiratory burst initiated by fMLP and marked acceleration of the onset of the respiratory burst stimulated by PMA. It is evident that both intra- and extracellular Ca2+ are required for full activation of the respiratory burst of human neutrophils, and the Ca2+ influx from extracellular space plays an important role either in generation of reactive oxygen metabolites or in activation of protein kinase C.

Calcium↗
PubMed1993

Infiltration of hypertrophic esophageal smooth muscle by mast cells and basophils.

Partial obstruction leads to chronic distension and muscular hypertrophy of the opossum esophagus. The smooth muscle cells of the circular muscle layer enlarge, become pleomorphic and are surrounded by an amorphous ground substance in the extracellular space. Here we describe the histological and ultrastructural features of a peculiar cellular infiltrate in the hypertrophic smooth muscle. The infiltrate consisted uniquely of mast cells and basophils. In per unit area, the number of mast cells increased from 0.9 +/- 0.1 cells in controls to 3.7 +/- 0.2 in hypertrophic smooth muscle; the corresponding numbers for basophils were 2.5 +/- 0.2 and 7.2 +/- 0.3 cells. Cells were seen primarily in the septal spaces of the circular muscle layer and at the interface of the circular and longitudinal muscle layer. The cytoplasm of basophils is normally packed with round and oval granules. The granules stain metachromatically and with varying intensity on Wright-Giemsa stains. On transmission electronmicroscopy, granules display a membrane and a great diversity in the structure of their luminal contents. In hypertrophic muscle, most granules were discharging their contents into the cytoplasm or extracellular space. The membranes of adjacent empty granules then fused to form a chain of vacuoles. Similar changes occurred also in the mast cells which differed from the basophil by their lack of nuclear lobulation and by the greater homogeneity of their cytoplasmic granules. It is possible that these inflammatory cells are involved in the reconstruction of the smooth muscle and its connective tissue which occur during esophageal distension and hypertrophy.

Animals↗
PubMed2003

Kinetic modeling of 5-fluorouracil anabolism in colorectal adenocarcinoma: a positron emission tomography study in rats.

Drug uptake and anabolism by tumors are prerequisites of response to 5-fluorouracil (5-FU). Positron emission tomography (PET) with 5-[(18)F]FU (PET/5-[(18)F]FU) is potentially useful for noninvasive measurement of these processes, but is severely hampered by rapid catabolism of 5-[(18)F]FU in vivo. This study explored the combined use of PET/5-[(18)F]FU and eniluracil (5-ethynyluracil), a potent inhibitor of 5-FU catabolism, to measure the pharmacokinetics of 5-FU uptake and metabolism in tumors. Rats bearing a s.c. implanted rat colon tumor were given eniluracil and injected i.v. with 5-[(18)F]FU. Dynamic PET and arterial blood sampling were performed 0-2 h. Tumors (n = 5) were then rapidly excised, frozen, and analyzed for labeled metabolites by high performance liquid chromatography. Tumor TACs were analyzed by compartmental modeling. Compartments were identified with molecular species by comparison with ex vivo assays. Tumor extracellular fluid volume was determined in a separate group of rats. Kinetic analysis indicated partial trapping of (18)F within tumors 0-2 h after injection. Tumor time-activity curves conformed closely to a catenary 3-compartment, 5-parameter model. The model yielded values for 5-FU clearance from plasma into the trap that agreed closely with those reported previously for gastrointestinal tumors from a PET/5-[(18)F]FU + eniluracil study in humans. Tumor extracellular fluid volume as measured with (99m)Tc DTPA [(3.1 +/- 0.2) x 10(-1) ml/g; n = 5] agreed well with the distribution volume for compartment 1 of the 3-compartment, 5-parameter model [(3.7 +/- 0.3) x 10(-1) ml/g; n = 5], thus indicating that compartment 1 corresponds to tumor extracellular space. Compartment 3 closely matched the combined magnitudes of (18)F fluoronucleoside (FN) triphosphates and macromolecules in all of the cases, and compartment 2 was quantitatively consistent with the sum of intracellular 5-FU, FNs, and FN mono- and diphosphates. These observations show that PET/5-[(18)F]FU combined with an inhibitor of 5-FU catabolism and compartmental modeling is capable of quantifying the following for 5-FU in tumors: distribution volume in the extracellular space, cell transport, size and turnover rate of an intermediate intracellular pool, and formation of a long-lived intracellular pool comprising FN triphosphates + macromolecules. Such information could be useful in predicting tumor response to 5-FU, formulating protocols that increase delivery of 5-FU into tumor cells, and modulating 5-FU kinetics to overcome tumor resistance.

Adenocarcinoma↗
PubMed2005

A novel L-glutamate transporter inhibitor reveals endogenous D-aspartate homeostasis in rat pheochromocytoma MPT1 cells.

We previously reported for the first time that D-aspartate (D-Asp) is biosynthesized by cultured mammalian cells such as pheochromocytoma (PC)12 cells and its subclone MPT1 (FEBS Lett. 434 (1998) 231, Arch. Biochem. Biophys. 404 (2002) 92). We speculated that D-Asp levels in the intra- and extracellular spaces of the cultured cells are maintained in a dynamic state of homeostasis. To test this here, we utilized a novel and potent L-Glu transporter inhibitor, TFB-TBOA. This inhibitor proved to be a genuine nontransportable blocker of the transporter even during long periods of culture. Use of this inhibitor with MPT1 cells confirmed that D-Asp levels are in a dynamic steady state where it is constantly released into the extracellular space by a yet undefined mechanism as well as being constantly and intensively taken up by the cells via the L-Glu transporter. We estimated the rate with which D-Asp is constitutively released from MPT1 cells is approx. 3.8 pmol/h/1x10(5) cells.

Amino Acid Transport System X-AG↗
PubMed1988

L-929 cells under hyperosmotic conditions. Water, Na+, and K+.

Changes in cell water content resulting from sorbitol addition to the environment of L-929 cells were evaluated gravimetrically using 14C-labeled polyethylene glycol as a probe of extracellular space. Reductions in cell water were proportional to sorbitol supplements up to 0.6 molal, above which no further measurable decrease occurred. No volume regulation occurred for at least 1 h but the percentage of cell water lost was quickly regained when physiological conditions were restored. The amount of cell water lost because of a given hyperosmotic exposure was found to exceed the loss of cell volume. That discrepancy could be the result of an overestimation of extracellular space and/or an underestimation of cell volume reduction as a result of in-folding of the cell surface. Na+ and K+ were also measured in cells of variable water content and volume: no significant change occurred in the amounts of these ions per cell, but large increases in total cell concentration resulted from hyperosmotic exposure. The sum of Na+ and K+ concentrations exceeds the total osmotic pressure of the medium indicating that an appreciable fraction of Na+ and K+ must be bound to fixed charges within the cells. The results are evaluated in the context of intracellular organization.

Animals↗
PubMed2002

Perturbation of free oligosaccharide trafficking in endoplasmic reticulum glucosidase I-deficient and castanospermine-treated cells.

Free oligosaccharides (FOS) are generated both in the endoplasmic reticulum (ER) and in the cytosol during glycoprotein biosynthesis. ER lumenal FOS possessing the di-N-acetylchitobiose moiety at their reducing termini (FOSGN2) are exported into the cytosol where they, along with their cytosolically generated counterparts possessing a single N-acetylglucosamine residue at their reducing termini (FOSGN1), are trimmed in order to be imported into lysosomes for final degradation. Both the ER and lysosomal FOS transport processes are unable to translocate triglucosylated FOS across membranes. In the present study, we have examined FOS trafficking in HepG2 cells treated with the glucosidase inhibitor castanospermine. We have shown that triglucosylated FOSGN2 generated in the ER are transported to the Golgi apparatus where they are deglucosylated by endomannosidase and acquire complex, sialic acid-containing structures before being secreted into the extracellular space by a Brefeldin A-sensitive pathway. FOSGN2 are also secreted from glucosidase I-deficient Lec23 cells and from the castanospermine-treated parental Chinese-hamster ovary cell line. Despite the secretion of FOSGN2 from Lec23 cells, we noted a transient intracellular accumulation (60 nmol/g cells) of triglucosylated FOSGN1 in these cells. Finally, in glucosidase I-compromised cells, FOS trafficking was severely perturbed leading to both the secretion of FOSGN2 into the extracellular space and a growth-dependent pile up of triglucosylated FOSGN1 in the cytosol. The possibility that these abnormalities contributed to the severe and rapidly progressive pathology in a patient with congenital disorders of glycosylation type IIb (glucosidase I deficiency) is discussed.

Animals↗
PubMed1986

Oral hairy leukoplakia: ultrastructural features.

Ten instances of a white plaque of the lateral tongue unique to homosexual males and referred to as oral hairy leukoplakia were analysed ultrastructurally. The surface epithelial layer exhibited extracellular, intracellular and intranuclear penetration by hyphae of Candida albicans, sometimes accompanied by coccobacilli in the extracellular space. The subcorneal epithelial layer included koilocytoid ballooned cells which had a paucity of cytoplasmic organelles and displayed condensation and emargination of the chromatin. Cells that exhibited these nuclear changes were found to be infected by a herpes-type virus which was visualized by electron microscopy in all ten cases. Clusters of nucleocapsids (86-110 nm in diameter) occurred in the nuclei and enveloped virions (111-175 nm in diameter) occurred in the cytoplasm and extracellular spaces. Virions showed budding from the nuclear envelope. Bundles of tubular structures (20 nm diameter) arranged in parallel occurred in the cytoplasm of some koilocytoid cells. There was no evidence by electron microscopy of the presence of papilloma virus within koilocytotic nuclei.

Candida albicans↗
PubMed1981

Diltiazem and verapamil inhibit norepinephrine-stimulated 45Ca uptake in rabbit aorta.

The effects of two Ca antagonists, diltiazem (DZ) and verapamil (VP), on norepinephrine (NE)-stimulated 45Ca uptake in vascular smooth muscle from New Zealand White rabbit aortas were studied. Data were collected before, at 10, 30, and 60 min after drug addition, and during a simultaneous control period without drug addition. NE alone (6 X 10(-6) M) significantly increased 45Ca uptake from the extracellular space presumably by activating the receptor-operated Ca channel during excitation-contraction coupling. This effect was maximal by 10 min after NE addition and stable through the 60-min time point. Both VP (5 X 10(-5) M) and DZ (2.2 X 10(-7) M) inhibited the NE-stimulated 45Ca uptake at the 10- and 60-min time points, respectively. These data demonstrate that both DZ and VP inhibit 45Ca uptake from the extracellular space during activation of the receptor-operated Ca channel with NE. The effects of DZ and VP to inhibit NE-stimulated 45Ca uptake are demonstrated at concentrations which have been previously shown to cause dilation of vascular smooth muscle.

Animals↗
PubMed1975

An ultrastructural study of normal and injured hypoglossal nuclei after injection of horseradish peroxidase.

The left hypoglossal nuclei of normal rats, and rats which had received left hypoglossal nerve axotomies 7-21 days previously, were studied by electron microscopy after injection of horseradish peroxidase as a marker of extracellular space and pinocytosis. Quantitative analysis showed that the number of pinocytotically-derived structures in presynaptic boutons was significantly increased in rats at 7, 14, and 21 days after axotomy when compared with normal rats. It was suggested that presynaptic boutons which became detached from injured neurones retracted by a membrane cycling mechanism involving pinocytotic uptake of bouton plasmalemma, without compensatory membrane production elsewhere. It was confirmed that the channels in the microglial cells communicated with the extracellular space.

Animals↗
PubMed1989

Serosal bicarbonate protects against acid injury to rabbit esophagus.

The role of serosal bicarbonate ions (HCO3-) in protection against acid injury was investigated in rabbit esophageal mucosa mounted in Ussing chambers. Luminal acidification reduced potential difference and resistance in tissues exposed serosally to HCO3- or (unbuffered) HCO3-free solution. Whereas resistance declined similarly in both groups, potential difference declined less in HCO3- solution. After washout, HCO3-bathed tissues also had a greater increase in resistance, lower permeability to mannitol, and less histologic damage. Furthermore, as protection by HCO3- was not blocked by pretreatment with either the anion exchange blocker, 4 acetamido-4'-isothiocyanatostilbene 2-2'-disulfonic acid, or the carbonic anhydrase inhibitor, acetazolamide, and replacement of HCO3- with N-2-hydroxyethylpiperazine-N'-2-ethane sulfonic acid, a buffer impermeant to cells, was protective, an extracellular site for protection by HCO3- was likely. Where in the extracellular space HCO3- buffers H+ is unclear, but the absence of change in luminal pH and the inability to prevent the acid-induced increase in permeability in HCO3-bathed tissues argue against a luminal (preepithelial) site. Also, rapid repair was not demonstrated, indicating that a luminal site for protection after surface cell damage was unlikely. We conclude that serosal HCO3- is important in esophageal protection against acid damage by buffering H+ within the intercellular compartment of the extracellular space.

4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfo↗
PubMed2001

Efficacy of background GABA uptake in rat hippocampal slices.

GABA uptake is crucial for the termination of inhibitory synaptic events. In addition, GABA transporters may also control the level of diffusely distributed GABA in the extracellular space. We analysed this function by superfusing rat hippocampal slices with different concentrations of GABA. Whole-cell patch clamp recordings of CA1 pyramidal cells revealed small increases in chloride conductance at 5-10 microM GABA which increased dramatically upon addition of the GABA uptake blocker tiagabine. Tiagabine alone induced a significant chloride conductance indicating that spontaneous release of GABA in hippocampal slices is neutralized by GAT-1, the main hippocampal GABA transporter. Thus, GAT-1 clears the extracellular space in the hippocampus from diffusely distributed GABA with high efficacy.

Animals↗
PubMed2000

Liver hyperplasia and paradoxical regulation of glycogen metabolism and glucose-sensitive gene expression in GLUT2-null hepatocytes. Further evidence for the existence of a membrane-based glucose release pathway.

We investigated the impact of GLUT2 gene inactivation on the regulation of hepatic glucose metabolism during the fed to fast transition. In control and GLUT2-null mice, fasting was accompanied by a approximately 10-fold increase in plasma glucagon to insulin ratio, a similar activation of liver glycogen phosphorylase and inhibition of glycogen synthase and the same elevation in phosphoenolpyruvate carboxykinase and glucose-6-phosphatase mRNAs. In GLUT2-null mice, mobilization of glycogen stores was, however, strongly impaired. This was correlated with glucose-6-phosphate (G6P) levels, which remained at the fed values, indicating an important allosteric stimulation of glycogen synthase by G6P. These G6P levels were also accompanied by a paradoxical elevation of the mRNAs for L-pyruvate kinase. Re-expression of GLUT2 in liver corrected the abnormal regulation of glycogen and L-pyruvate kinase gene expression. Interestingly, GLUT2-null livers were hyperplasic, as revealed by a 40% increase in liver mass and 30% increase in liver DNA content. Together, these data indicate that in the absence of GLUT2, the G6P levels cannot decrease during a fasting period. This may be due to neosynthesized glucose entering the cytosol, being unable to diffuse into the extracellular space, and being phosphorylated back to G6P. Because hepatic glucose production is nevertheless quantitatively normal, glucose produced in the endoplasmic reticulum may also be exported out of the cell through an alternative, membrane traffic-based pathway, as previously reported (Guillam, M.-T., Burcelin, R., and Thorens, B. (1998) Proc. Natl. Acad. Sci. U. S. A. 95, 12317-12321). Therefore, in fasting, GLUT2 is not required for quantitative normal glucose output but is necessary to equilibrate cytosolic glucose with the extracellular space. In the absence of this equilibration, the control of hepatic glucose metabolism by G6P is dominant over that by plasma hormone concentrations.

Animals↗
PubMedDate not supplied

Release of endogenous Zn2+ from brain tissue during activity.

The role of divalent transition metal ions in neural function is poorly understood. In excess, these ions are associated with neurological disorders such as Wilson's disease, Pick's disease and epileptic seizures. We suggest that zinc ions, which are contained in nerve terminals, are extruded into the extracellular space during neuronal activity. Excessive levels of zinc may be released during intense neuronal activation, and contribute to the paroxysm and toxic damage observed. Zinc ions are contained in high concentrations in mossy fibres of the hippocampal formation, and it is the postsynaptic neurones of these fibres which are most susceptible to the toxic effects of kainic acid, a potent convulsant, or to chronic exposure to organometallic compounds. Here we demonstrate for the first time that Zn2+ is released into the extracellular space during excitation of hippocampal slices.

Animals↗
PubMed1999

Brain temperature modifies glutamate neurotoxicity in vivo.

The purpose of this study was to examine the effects of mild hypothermia and hyperthermia on glutamate excitotoxicity. Glutamate-induced cortical lesions were produced in hypothermic (32 degrees C), normothermic (37 degrees C), and hyperthermic (40 degrees C) rats by perfusion of a 0.5 M glutamate solution via a microdialysis probe. The volume of the lesion 7 days after glutamate perfusion was quantified histologically by image analysis. This histological assessment was performed in two experiments; in one, each of the target temperatures was induced before glutamate perfusion, and in the other, each of the target temperatures was induced after stopping the glutamate perfusion. We also examined the effect of temperature on the diffusion of exogenously delivered material in the extracellular space using autoradiography of the perfused glutamate solution containing 14C-labeled sucrose. In the two experiments in which each of the target temperatures was induced before or after glutamate perfusion, the volume of damage was reduced by mild hypothermia and enlarged by mild hyperthermia. The volume of 14C diffusion also increased as brain temperature increased. These results provide evidence that small variations of brain temperature modify glutamate excitotoxicity. The results also suggest that the change in glutamate diffusion in the extracellular space is one mechanism by which mild hypothermia and hyperthermia exert their protective and harmful effects respectively.

Analysis of Variance↗
PubMed2005

Surface properties, more than size, limiting convective distribution of virus-sized particles and viruses in the central nervous system.

OBJECT: Achieving distribution of gene-carrying vectors is a major barrier to the clinical application of gene therapy. Because of the blood-brain barrier, the distribution of genetic vectors to the central nervous system (CNS) is even more challenging than delivery to other tissues. Direct intraparenchymal microinfusion, a minimally invasive technique, uses bulk flow (convection) to distribute suspensions of macromolecules widely through the extracellular space (convection-enhanced delivery [CED]). Although acute injection into solid tissue is often used for delivery of oligonucleotides, viruses, and liposomes, and there is preliminary evidence that certain of these large particles can spread through the interstitial space of the brain by the use of convection, the use of CED for distribution of viruses in the brain has not been systematically examined. That is the goal of this study. METHODS: Investigators used a rodent model to examine the influence of size, osmolarity of buffering solutions, and surface coating on the volumetric distribution of virus-sized nanoparticles and viruses (adeno-associated viruses and adenoviruses) in the gray matter of the brain. The results demonstrate that channels in the extracellular space of gray matter in the brain are large enough to accommodate virus-sized particles and that the surface characteristics are critical determinants for distribution of viruses in the brain by convection. CONCLUSIONS: These results indicate that convective distribution can be used to distribute therapeutic viral vectors in the CNS.

Adenoviridae↗
PubMed1993

Extracellular matrix 4: the elastic fiber.

The elastic properties of many tissues such as the lung, dermis, and large blood vessels are due to the presence of elastic fibers in the extracellular space. These fibers have been shown by biochemical and ultrastructural analysis to be composed of two distinct components, a more abundant amorphous component and a 10-12 nm microfibrillar component, which is located primarily around the periphery of the amorphous component. The protein elastin makes up the highly insoluble amorphous component and is responsible for the elastic properties. Elastin is found throughout the vertebrate kingdom and possesses an unusual chemical composition rich in glycine, proline, and hydrophobic amino acids, consonant with its characteristic physical properties. The 72-kDa biosynthetic precursor, tropoelastin, is secreted into the extracellular space where it becomes highly cross-linked into a rubber-like network through the activity of the copper-requiring enzyme lysyl oxidase. Analysis of the elastin gene has demonstrated that hydrophobic and cross-linking domains are encoded in separate exons and that there is significant alternative splicing, resulting in multiple isoforms of tropoelastin. The elastin gene promoter contains many potential binding sites for various modulating factors indicative of a complex pattern of transcriptional regulation. The microfibrils contain several proteins, including fibrillin, and probably act as an organizing scaffold in the formation of the elastin network. There appears to be a fibrillin gene family in which each protein contains multiple repeats of a motif previously found in epidermal growth factor and a second motif observed in transforming growth factor beta 1-binding protein. Mutations in the fibrillin gene located on human chromosome 15 have been strongly implicated as the cause of the Marfan syndrome.

Amino Acid Sequence↗