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PubMed1987

Kinetic studies of the tissue binding tendency of the new vasodilator pildralazine.

Studies of the binding and release of the new antihypertensive drug (+/-)-1-[(6-hydrazinopyridazin-3-yl)methylamino]-2-propanol (pildralazine, PD) were performed on isolated perfused guinea pig hearts according to the Langendorff technique. Extensive binding to and accumulation in the tissue were recorded. Even after 30 min of washout considerable PD concentrations were detected both in the myocardium (900 ng/g w.w.) and the effluent (17 ng/ml = 100 ng/min). The calculation of elimination half-life yielded a nearly identical value in the myocardial tissue and the effluent. Coronary vasodilation mediated by PD ran in close parallel to the drug concentrations. As the washout of [3H]-sucrose as an extracellular space marker was half-maximal already after 1.6 min rediffusion of PD originated from tissue sites and not only by dilution of the fluid in the extracellular space. In addition the results indicated that the observed binding of PD to cell structures prevented its normally rapid chemical destruction, already evident in aqueous solutions. The back diffusion of PD from the binding and storage sites into the coronary perfusate was very slow, explaining its long-lasting biological availability and action in vivo. The release kinetics may be described by an exponential function which obeys the criterions of a first order elimination process.

Animals↗
PubMed1982

Sodium balance, fluid homeostasis and the renin-aldosterone system during the prolonged exercise of hill walking.

1. The effect of 5 consecutive days of hill walking on electrolyte balance, fluid homeostasis, plasma renin activity and plasma aldosterone concentration was studied in five male subjects. 2. The 5-day exercise period was preceded by a 4-day control period and followed by a 4-day recovery period. Throughout the 13-day study subjects ate a fixed diet. 3. After 5 days of exercise subjects had retained a mean of 264 mmol (SD 85) of sodium. Plasma sodium concentration remained constant at 142.0 mmol/l (SD 5.4). This indicates an expansion of the extracellular space by 1.84 litres. 4. By the end of the exercise period there was a positive water balance of about 0.9 litre. Thus there was a net movement of 0.94 litre of fluid from the intracellular to the extracellular space. 5. Packed cell volume decreased from a mean of 43.5% to 37.9% after 5 days of exercise, indicating that about 0.9 litre of the extracellular fluid entered the vascular compartment. The remaining fluid may be responsible for the significant increase in lower leg volume. 6. During the exercise period plasma aldosterone concentration and plasma renin activity rose, and there was a highly significant correlation between these values and the sodium retention. There was also a significant correlation between sodium retention and the increase in leg volume, which suggests that oedema may be the result of prolonged exercise of this type.

Adult↗
PubMed1990

The gap junction family: structure, function and chemistry.

Gap junctions are aggregates of transmembranous channels which bypass the extracellular space by transporting messenger molecules and ions from one cytoplasmic source to an adjacent cytoplasmic interior. The channels join the plasma membranes of adjacent cells by bridging the extracellular space between them. Thereby, cellular "compartments" which were once considered to be individual units are, in actuality, interconnected by a system of pathways which form a functional cellular syncytium. The evolutionary importance of a generalized intercellular communication system can be appreciated when one considers the widespread prevalence of gap junctions within animals of all multicellular phyla, and within almost all tissues of vertebrates. Only a few population of cells such as skeletal muscle cells (which are fused to form functional syncytia) and circulating blood cells are not equipped with gap junctions. This paper provides a brief review of the diverse structural, molecular and functional aspects of gap junctions as revealed by current research.

Animals↗
PubMed2003

Modification of elastin by pentosidine is associated with the calcification of aortic media in patients with end-stage renal disease.

BACKGROUND: Calcification of the media of arteries is common in patients with end-stage renal disease (ESRD) undergoing haemodialysis and is a major cause of arteriosclerosis. The aim of this study was to clarify the role of glycoxidative modification of elastin in the calcification of aortic media in this group of patients. METHODS: Samples of tunica media were obtained from non-atherosclerotic areas of the aortas of cadavers of seven non-diabetic patients with ESRD (age 65.5 +/- 10.6 years) and 10 age-matched controls (age 61.1 +/- 10.3 years). The localization of pentosidine, a major glycoxidation product, and calcium deposits in the media were examined using immunohistochemical and von Kossa staining, followed by orcein staining for elastin fibres. Tissue levels of pentosidine and calcium were measured in elastase-digested media using reversed high-performance liquid chromatography and atomic absorption spectrophotometry, respectively. RESULTS: In aortic media, but not intima, immunostained pentosidine was observed along elastin fibres or in the extracellular spaces between them. Early calcification was manifest as small punctate calcified deposits along elastin fibres in the media. Advanced calcification was found as large, confluent calcified deposits in extracellular spaces between elastin fibres. Double staining showed co-localization of pentosidine and calcified deposits in the media. Both the staining density of pentosidine and calcification were more prominent in ESRD patients than in controls. The mean medial contents of both elastin-associated pentosidine and calcium were significantly higher in ESRD patients than in controls. In ESRD patients, the level of calcium in elastase-digested media correlated significantly with pentosidine levels, which increased in parallel with the duration of haemodialysis. CONCLUSIONS: Our results indicate that glycoxidative modification of elastin in aortic media may be involved in the enhancement of medial calcification in ESRD patients on haemodialysis.

Aged↗
PubMed1985

Electron microscopic observations of endothelial junctions in perifocal human brain edema. An interpretative study.

Cortical biopsies of 12 patients with diagnosis of cerebral tumor or complicated brain trauma were studied with the electron microscope to analyse the alterations of endothelial junctions and their probable participation in the pathogenesis of human brain edema. Capillaries with increased vesicular and vacuolar transport from areas with moderate and severe edema were examined. Some endothelial tight junctions were structurally closed and intact while others showed openings and dehiscence of processes. Some accessory mechanisms of bypassing the endothelial junctions were found, such as: a) communicating micropinocytotic vesicles with the extracellular space at the basal segment of endothelial junction; b) chained micropinocytotic vesicles between endothelial luminal membrane and basal segment of endothelial junction and c) tubular structures connecting the extracellular pockets of endothelial junction with the basement membrane bifurcation. In severe brain edema a considerable enlargement of interjunctional pockets of extracellular space was seen, suggesting that in highly increased cerebrovascular permeability the endothelial junctions are partially opened and that an intercellular route through interendothelial clefts for transferring hematogenous edema fluid from blood to the capillary basement membrane is formed.

Astrocytoma↗
PubMed1990

Multiple quantum filtered 23Na NMR spectroscopy in the perfused heart.

It has been proposed that multiple quantum filtered (MQF) 23Na NMR spectroscopy may distinguish between sodium in the intra- and extracellular spaces, in vivo, and without the requirement for toxic shift reagents. We have investigated the origin of such signals in perfused rat hearts, using shift reagents to discriminate between NMR signals from the two compartments. We find that the observed MQF signal arises predominantly from the extracellular space in the normal heart, and from the intracellular space in the ischaemic heart. However, the quenching effect of the shift reagent may hide some of the extracellular MQF signal, especially during ischaemia. Estimates of intracellular and extracellular relaxation times are obtained and possible mechanisms of the interaction discussed.

Animals↗
PubMed2005

Comprehensive analysis of the extracellular proteins from Xanthomonas campestris pv. campestris B100.

The extracellular proteome of Xanthomonas campestris pv. campestris (Xcc) cultivated in minimal medium was isolated from the cell-free culture supernatant and separated by two-dimensional gel electrophoresis. This technique resolved 97 clearly visible protein spots, which were excised, digested with trypsin and identified on the basis of their peptide mass fingerprints generated by matrix assisted laser desorption/ionisation-time of flight-mass spectrometry. Using this approach 87 different proteins could be distinguished. The Signal P software predicted putative signal peptides for 53% of the extracellular proteins. These proteins are probably transported over the inner membrane and are localized in the periplasm, the outer membrane or secreted into the extracellular space. Among the secreted proteins are 11 degradative enzymes, which are involved in pathogenesis of Xcc. The proteins without obvious secretion signals are known to serve functions in the cytosol. How the cytosolic proteins are delivered to the extracellular space remains unclear.

Bacterial Proteins↗
PubMed2001

Increases in renal epsilon-(gamma-glutamyl)-lysine crosslinks result from compartment-specific changes in tissue transglutaminase in early experimental diabetic nephropathy: pathologic implications.

Diabetic nephropathy (DN) is characterized by an early, progressive expansion and sclerosis of the glomerular mesangium leading to glomerulosclerosis. This is associated with parallel fibrosis of the renal interstitium. In experimental renal scarring, the protein cross-linking enzyme, tissue transglutaminase (tTg), is up-regulated and externalized causing an increase in its crosslink product, epsilon-(gamma-glutamyl)-lysine, in the extracellular space. This potentially contributes to the extracellular matrix (ECM) accumulation central to tissue fibrosis by increasing deposition and inhibiting breakdown. We investigated if a similar mechanism may contribute to the ECM expansion characteristic of DN using the rat streptozotocin model over 120 days. Whole kidney epsilon-(gamma-glutamyl)-lysine (HPLC analysis) was significantly increased from Day 90 (+337%) and peaked at Day 120 (+650%) (p < 0.05). Immunofluorescence showed this increase to be predominantly extracellular in the peritubular interstitial space, but also in individual glomeruli. Total kidney transglutaminase (Tg) was not elevated. However, using a Tg in situ activity assay, increased Tg was detected in both the extracellular interstitial space and glomeruli by Day 60, with a maximal 53% increase at Day 120 (p < 0.05). Using a specific anti-tTg antibody, immunohistochemistry showed a similar increase in extracellular enzyme in the interstitium and glomeruli. To biochemically characterize glomerular changes, glomeruli were isolated by selective sieving. In line with whole kidney measurement, there was an increase in glomerular epsilon-(gamma-glutamyl) lysine (+361%); however, in the glomeruli this was associated with increases in Tg activity (+228%) and tTg antigen by Western blotting (+215%). Importantly, the ratio of glomerular epsilon-(gamma-glutamyl) lysine to hydroxyproline increased by 2.2-fold. In DN, changes in the kidney result in increased translocation of tTg to the extracellular environment where high Ca(2+) and low GTP levels allow its activation. In the tubulointerstitium this is independent of increased tTg production, but dependent in the glomerulus. This leads to excessive ECM cross-linking, contributing to the renal fibrosis characteristic of progressive DN.

Animals↗
PubMed1979

A fine structural analysis of the myelin sheath in rat spinal roots.

The present study is concerned with the fine structure of the myelin sheath in rat and monkey spinal roots. Pictures are obtained that show that the intraperiod gap of the myelin sheath is continuous and opens into both the internal and external mesaxons, which in turn open into the periaxonal and endoneurial extracellular spaces. These results are compatible with the idea that the intraperiod gap is a cleft that traverses the thickness of the myelin sheath and links the periaxonal and endoneurial extracellular spaces.

Animals↗
PubMed2000

The effect of cyclophosphamide on brainstem remyelination following local ethidium bromide injection in Wistar rats.

Long-term cyclophosphamide (CY) treatment was used in male Wistar rats submitted to ethidium bromide (EB) demyelinating model to investigate ultrastructurally the drug effects on remyelination and on central nervous system (CNS) tissue repair. Demyelination was induced by a single 10 microl intracisternal injection of 0.1% EB solution and the rats anaesthetized and perfused through the heart from the 15th to the 31st day after injection. Brainstem sections were collected and processed for light and transmission electron microscopy studies. At different times after EB injection, it was observed the presence of macrophages in phagocytic activity and non-degraded myelin debris in the extracellular space, as well as remyelinated and demyelinated axons. Remyelination was carried out by both oligodendrocytes and Schwann cells, the latter notably around blood vessels and in areas of expanded extracellular space. It was also noted groups of infiltrating meningeal cells and astrocytes showing hypertrophic processes with numerous bundles of glial filaments. The rats treated with CY showed greater amounts of myelin-derived membranes than non-treated rats, suggesting a delay in the macrophage activity of removing myelin debris. Additionally oligodendrocyte remyelinating activity showed an incipient and restricted pattern, with clear predominance of naked axons. Rare lymphocytes were also found, as well as decreased neovascularization.

Animals↗
PubMed2002

Water compartmentalization and spread of ischemic injury in thick-slice ischemia model.

Water compartmentalization was studied in a thick-slice (1000 microm) model of ischemia by combining water-content measurements with extracellular diffusion analysis. Thick slices bathed in artificial cerebrospinal fluid continually gained water. Total tissue water content was increased by 67% after 6 hours of the incubation. Diffusion measurements using the tetramethylammonium method showed that the extracellular space, typically occupying 20% of brain tissue in vivo, was decreased to 10% at 30 minutes and 15% at 6 hours in both deep and superficial layers of thick slices. Quantification of water compartmentalization revealed that water moved initially from the extracellular space into the cells. Later, however, both compartments gained water. The initial cell swelling was accompanied by dramatic shifts in potassium. An initial rise of extracellular potassium to about 50 mmol/L was measured with a potassium-selective microelectrode positioned in the center of the thick slice; the concentration decreased slowly afterwards. Potassium content analysis revealed a 63% loss of tissue potassium within two hours of the incubation. In thick slices, ionic shifts, water redistribution, and a loss of synaptic transmission occur in both deep and superficial layers, indicating the spread of ischemic conditions even to areas with an unrestricted supply of nutrients.

Animals↗
PubMed1989

Effect of endothelium on basal and on stimulated accumulation and efflux of cyclic GMP in rat isolated aorta.

1. The aim of this study was to examine the possible role of the release of guanosine 3':5'-cyclic monophosphate (cyclic GMP) into the extracellular space in the regulation of rat aortic cyclic GMP content. 2. Rat aortic segments incubated in physiological solution released cyclic GMP into the medium in a time-dependent manner. This release was greatly enhanced when intact instead of tissues without endothelium were used. After 120 min of observation, a maximal 33 fold difference in extracellular cyclic GMP content was detected. 3. Treatment of rat aortic preparations with either a Ca2+-free solution or methylene blue, both conditions known to inhibit endothelium-derived relaxing factor (EDRF)-mediated responses, markedly reduced the extracellular accumulation of cyclic GMP from tissues with but not without endothelium. 4. Endothelium-dependent vasodilators such as acetylcholine (10 microM) and carbachol (10 microM) greatly increased tissue cyclic GMP content, in a time-dependent manner in rat aortic preparations with endothelium, but only slightly in tissues without. Maximal increases in intact tissues were obtained after about 1 min of agonist contact and amounted to about 35 and 15 fold respectively, thereafter tissue cyclic GMP content rapidly declined. Histamine (10 microM) elicited only minor effects on tissue cyclic GMP content of both intact preparations and those without endothelium. 5. Acetylcholine (10 microM), carbachol (10 microM) and histamine (10 microM) stimulated a time-dependent release of the cyclic nucleotide into the incubation medium from tissues with endothelium. After 120 min of observation, extracellular accumulation of cyclic GMP from intact tissues was increased by about 2.6, 6.6 and 1.7 fold respectively. Carbachol and histamine induced only minor effects on release from tissues without endothelium. 6. Sodium nitroprusside (0.3 and 10 microM), a direct activator of soluble guanylate cyclase, induced a concentration-dependent accumulation of cyclic GMP in tissues with and without endothelium that was associated with a concentration-dependent accumulation of cyclic GMP in the extracellular space. Peak tissue cyclic GMP content reached similar levels in preparations with and without endothelium, while extracellular cyclic GMP levels were about two times greater when experiments were performed with intact compared to endothelium-denuded tissues. 7. Atriopeptin II, an activator of particulate guanylate cyclase, increased tissue cyclic GMP content by about 8 and 18 fold respectively in tissues with and without endothelium. As was the case with sodium nitroprusside, atriopeptin II-stimulated release was markedly enhanced from intact tissues compared with those without endothelium. After 120 min of observation, there was a 16 fold difference in the amount of extracellular cyclic GMP.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1986

A model for receptor-regulated calcium entry.

A model is proposed for the mechanism by which activation of surface membrane receptors causes sustained Ca2+ entry into cells from the extracellular space. Reassessment of previously published findings on the behavior of receptor-regulated intracellular Ca2+ pools leads to the conclusion that when such pools are empty, a pathway from the extracellular space to the pool is opened; conversely when the pool is filled, the pathway is closed and it becomes relatively stable to depletion by low Ca2+ media or chelating agents. The biphasic nature of agonist-activated Ca2+-mobilization is thus seen as an initial emptying of the intracellular Ca2+ pool by inositol (1,4,5) trisphosphate, followed by rapid entry of Ca2+ into the pool and, in the continued presence of inositol (1,4,5) trisphosphate, into the cytosol. On withdrawal of agonist, inositol (1,4,5) trisphosphate is then rapidly degraded, the pathway from the pool to the cytosol is closed, and rapid entry from the outside continues until the Ca2+ content of the pool reaches a level that inactivates Ca2+ entry. This capacitative model allows for Ca2+ release and Ca2+ entry to be controlled by a single messenger, inositol (1,4,5) trisphosphate.

Animals↗
PubMed1991

The light-induced increase of carbohydrate metabolism in glial cells of the honeybee retina is not mediated by K+ movement nor by cAMP.

The retina of the honeybee drone is a nervous tissue in which glial cells and photoreceptor neurons constitute two distinct metabolic compartments. The phosphorylation of glucose and its subsequent incorporation into glycogen occur essentially in glia, whereas O2 consumption occurs in the photoreceptors. After [3H] glucose loading of superfused retinal slices, light stimulation induced a significant rise in [3H] glycogen turnover in the glia. This occurs without a concomitant covalent modification of glycogen enzymes. Probably only an increase or a decrease of the availability of [3H] glycosyls that are incorporated into glycogen is necessary. As only photoreceptors are directly excitable by light, we searched for a signal that stimulates glycogen metabolism in the glia. Although K+ in extracellular space and glia increases after repetitive light stimulation, increasing bath K+ in the dark did not mimic the metabolic effects of light, despite an equivalent increase of K+ in the extracellular space and glia. We subsequently explored the role of cAMP, a universal intracellular second messenger. Exposure of retinal slices to the adenylate-cyclase activator forskolin induced an expected increase in the rate of formation of cAMP, but only partially mimicked the metabolic effects of light. Furthermore, light stimulation failed to induce a rise in the rate of formation of cAMP. We conclude that in this nervous system, without synapses, neither K+ nor cAMP mediates the effect of light stimulation on intraglial glucose metabolism.

Animals↗
PubMed2005

A compartmental capillary, convolution integration model to investigate nutrient transport and metabolism in vivo from paired indicator/nutrient dilution curves.

Thirty-three paired indicator/nutrient dilution curves across the mammary glands of four cows were obtained after rapid injection of para-aminohippuric acid (PAH) plus glucose into the external iliac artery. For the measurement of extracellular volume and kinetics of nutrient uptake from indicator dilution curves, several models of solute dispersion and disappearance have been proposed. The Crone-Renkin models of exchange in a single capillary assume negligible washout of solutes from the extracellular space and do not describe entire dilution curves. The Goresky models include a distribution of capillary transit times to generate whole system outflow profiles but require two indicators to parametize extracellular behavior. A compartmental capillary, convolution integration model is proposed that uses one indicator to account for the extracellular behavior of the nutrient after a paired indicator/nutrient injection. With the use of an iterative approach to least squares, unique solutions for nonexchanging vessel transit time t(mu) and its variance sigma were obtained from all 33 PAH curves. The average of heterogeneous vascular transit times was approximated as 2sigma = 8.5 s. The remainder of indicator dispersion was considered to be due to washout from a well-mixed compartment representing extracellular space that had an estimated volume of 5.5 liters or 24% of mammary gland weight. More than 99% of the variation in the time course of venous PAH concentration after rapid injection into the arterial supply of the mammary glands was explained in an unbiased manner by partitioning the organ into a heterogeneous nonexchanging vessel subsystem and a well-mixed compartmental capillary subsystem.

Animals↗
PubMed1989

Orientation of proteolipid protein in myelin: comparison of models with X-ray diffraction measurements.

Three models have been proposed for the arrangement of proteolipid protein (PLP) in the myelin membrane. We have tested these models by determining to what extent each is consistent with the membrane-membrane interactions and electron density profile of central nervous system myelin obtained from X-ray diffraction. Equilibrium periods and membrane separations were calculated from the proposed organization of lipids and proteins in the membrane, and compared with values obtained experimentally as a function of pH and ionic strength. The orientation of the proteins was also used to calculate electron density levels in the cytoplasmic and extracellular spaces. We found that the Stoffel and Hudson models for PLP were more consistent than the Laursen model with the range of pH over which the intermembrane separation at the extracellular apposition is a minimum. The Hudson model also fits better the swollen periods observed at alkaline pH. The Hudson PLP model has many more residues in the extracellular side of the membrane than does either of the other models, resulting in higher electron density in the extracellular space compared to the cytoplasmic space. Such an asymmetric distribution of electron density is offset by the electron density of myelin basic protein which is localized in the cytoplasmic space. The resulting similar levels of electron density at the two appositions are like those in profiles calculated from the X-ray data.

Animals↗
PubMed1985

Effect of chronic prazosin treatment on the cardiac function and electrolytes in failing heart due to chronic mitral insufficiency.

The effect of three months of prazosin treatment on the hemodynamics, cardiac extracellular space; plasma, tissue and intra-cellular Na+, K+, and Ca++ were investigated in dogs with left ventricular failure due to chronic mitral insufficiency. Mitral insufficiency of 6 months duration significantly decreased the LV systolic pressure, LV dp/dt, LV (dp/dt)/IIP, LVWI, CI, and increased the LVEDP, mean right atrial pressure, heart rate and systemic vascular resistance. Associated with these hemodynamic changes were an increase in the extra-cellular space, tissue and intracellular K+; and a decrease in the tissue and intracellular Ca++. Prazosin treatment produced an improvement in the hemodynamics which was associated with a decreased in the extracellular space, and intracellular K+, and an increase in the intracellular Ca++. Plasma Na+ and Ca++ increased with 6 months of M.I. Prazosin treatment brought back the plasma Na+ and K+ to control level. However, plasma Ca+ decreased significantly with prazosin treatment. The changes in right ventricular hemodynamics and electrolytes were not consistent with the right ventricular failure. These results indicate that decrease in the myocardial contractility in chronic heart failure due to mitral insufficiency might be due to a decrease in the intracellular Ca++. Prazosin treatment was able to reverse the hemodynamic and electrolyte changes induced by failing heart due to mitral insufficiency.

Animals↗
PubMed1982

Brain edema and gliopathy induced by 6-aminonicotinamide intoxication in the central nervous system of rats.

Brain edema was produced by 6-aminonicotinamide (6-AN) in the rat with accompanying metabolic disturbance due to the accumulation of an antimetabolite of nicotinamide in the CNS. Twenty-four hours after intraperitoneal administration of 6-AN, significant (P less than 0.01) increases of sodium and water in the medulla oblongata were observed. By electron microscopy, the lesion was characterized by swelling of the perivascular neuroglial processes, producing disturbances of the active transport in the cell membrane and increased pinocytosis in the endothelial cells, especially of the arterioles and venules. The metabolic inhibitor was shown to produce not only an increased water and sodium uptake in neuroglias, which is characteristic of cytotoxic brain edema, but also produced protein-rich edema in the extracellular space, ie, vasogenic brain edema. The protein transport in the metabolic disturbance caused by 6-AN was traced, using horseradish peroxidase, revealing that it occurred from the vasculature into the extracellular spaces via pinocytotic vesicles due to the change in the cerebrovascular permeability.

6-Aminonicotinamide↗