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PubMed2004

Spinal disposition and meningeal permeability of local anesthetics.

PURPOSE: To investigate the spinal disposition, the cerebrospinal fluid (CSF) bioavailability, and the ex vivo meningeal permeability of six homologous pipecoloxylidide local anesthetics and to search for correlations with lipophilicity. METHODS: The ex vivo meningeal permeability was studied on fresh specimen of meninges (dura mater and arachnoid mater) removed from lumbar and cervical level of rabbit spine following laminectomy. Spinal disposition and CSF bioavailability were investigated using microdialysis sampling after simultaneous injection of an equimolar dose of the six homologs in the epidural or in the intrathecal spaces. In a first step, intrathecal and epidural microdialysis were performed after epidural administration. In a second step, intrathecal microdialysis was performed after intrathecal administration. RESULTS: Permeability through cervical and lumbar meninges was linearly correlated, and the cervical permeability was around 60% of the lumbar permeability. Apparent permeability data showed a parabolic relationship with the lipophilicity of the derivatives with a marked decrease in permeability for log P above 3. In vivo experiments have shown that the absorption rate constant linearly decreased with lipophilicity of the derivatives (0.171 to 0.125 min(-1)) whereas the intrathecal bioavailability, which was low, increased with lipophilicity (7.2 to 15.9%). CONCLUSIONS: The unexpected increase in CSF bioavailability with a decrease in absorption rate through meninges emphasizes the role of specific competitive clearance and distribution processes in the epidural space.

Anesthetics, Local↗
PubMed2000

Interaction of endothelin-1 with vasoactive factors in mediating glucose-induced increased permeability in endothelial cells.

Alteration of endothelins (ET) and/or their receptors may be important in mediating vascular dysfunction in diabetes. We investigated mechanisms regulating ET-1 expression in human umbilical vein endothelial cells (HUVEC) in response to glucose and the functional significance of these mechanisms. Permeability across HUVEC, grown in medium containing either low (5 mmol/l) or high (25 mmol/l) D-glucose were investigated. L-glucose was used as a control. ET-1, ET(A), and ET(B) mRNA were assessed by semiquantitative RT-PCR. ET-1 immunoreactivity and F-actin microfilament assembly were investigated using confocal microscopy. Increased transendothelial permeability was noted in cells cultured in high glucose or when the cells grown in low (physiologic) glucose were incubated with ET-1, vascular endothelial growth factor (VEGF), or N (G) -nitro-L-arginine methyl ester but not when they were incubated with ET-3, N(G)-nitro-D-arginine methyl ester, or L-glucose. Increased permeability was associated with increased ET-1, ET(A), and ET(B) mRNA expression and augmented ET-1 immunoreactivity. High glucose induced increased permeability, increased ET-1, ET(A), and ET(B) mRNA expression. ET-1 immunoreactivity was blocked by the protein kinase C (PKC) inhibitor chelerythrine, the specific PKC isoform inhibitor 379196, VEGF-neutralizing antibody, or the ET(A) blocker TBC11251, but was not blocked by the specific ET(B) blocker BQ788 or by a VEGF-non-neutralizing antibody. Increased permeability was also associated with deranged F-actin assembly in the endothelial cells and by derangement of endothelial cell junctions as assessed by electron microscopy. Data from this study suggest that high glucose-induced increased permeability may be induced through increased ET-1 expression and disorganization of F-actin assembly. ET-1 expression and increased permeability may occur secondary to PKC isoform activation and may be modulated by VEGF and nitric oxide.

Base Sequence↗
PubMed1975

Permeability to calcium of pigeon erythrocyte 'ghosts' studied by using the calcium-activated luminescent protein, obelin.

1. Obelin, the Ca(2+)-activated luminescent protein from the hydroid Obelia geniculata, was sealed inside pigeon erythrocyte ;ghosts' in order to investigate effects on their permeability of different methods of preparation and of the bivalent cation ionophore A23187. 2. Changes in free Ca(2+) within the ;ghosts' were studied by following the rate of luminescence of obelin. The possibility that the obelin might have been released from the ;ghosts' during an experiment was investigated by studying the release of inulin and pyruvate kinase from the ;ghosts'. Less than 10% of the inulin or pyruvate kinase sealed within the ;ghosts' was released under any of the experimental conditions. 3. Triton X-100 (0.1-10%, v/v) made the ;ghosts' highly permeable to Ca(2+). In the presence of 1mm-Ca(2+) and Triton, 95-100% of the obelin was utilized within 10-20s. 4. A time-course of resealing ;ghosts' at 37 degrees C showed that over a period of 90min, the ;ghosts' became gradually less permeable to Ca(2+). ;Ghosts' which remained at 0 degrees C retained only a small concentration of obelin and ATP, and were highly permeable to Ca(2+). 5. Erythrocyte ;ghosts' resealed for 30min at 20 degrees C rather than 37 degrees C were more permeable to Ca(2+), as shown by the fact that 92% of the obelin in the ;ghosts' was utilized during the first 60s after the addition of 1mm-Ca(2+), as opposed to 44% for ;ghosts' resealed at 37 degrees C. 6. Haemolysis at pH6.0 rather than 7.0 resulted in ;ghosts' which were highly permeable to Ca(2+) after resealing for 60min at 37 degrees C. Of the obelin in the ;ghosts', produced by haemolysis at pH6.0, 90% was utilized in the first 60s after the addition of 1mm-Ca(2+) compared with 23% for ;ghosts' produced at pH7.0. 7. The bivalent cation ionophore A23187 increased the permeability of the ;ghosts' to Ca(2+). Maximum effects of the ionophore (16mug/ml) were obtained by preincubating the ;ghosts' with the ionophore A23187 (16mug/ml) in the presence of a low concentration of Mg(2+) and in the absence of Ca(2+).

Adenosine Triphosphate↗
PubMed2006

Lipid raft components cholesterol and sphingomyelin increase H+/OH- permeability of phosphatidylcholine membranes.

H+/OH- permeation through lipid bilayers occurs at anomalously high rates and the determinants of proton flux through membranes are poorly understood. Since all life depends on proton gradients, it is important to develop a greater understanding of proton leak phenomena. We have used stopped-flow fluorimetry to probe the influence of two lipid raft components, chol (cholesterol) and SM (sphingomyelin), on H+/OH- and water permeability. Increasing the concentrations of both lipids in POPC (palmitoyl-2-oleoyl phosphatidylcholine) liposomes decreased water permeability in a concentration-dependent manner, an effect that correlated with increased lipid order. Surprisingly, proton flux was increased by increasing the concentration of chol and SM. The chol effect was complex with molar concentrations of 17.9, 33 and 45.7% giving 2.8-fold (P<0.01), 2.2-fold (P<0.001) and 5.1-fold (P<0.001) increases in H+/OH- permeability from a baseline of 2.4x10(-2) cm/s. SM at 10 mole% effected a 2.8-fold increase (P<0.01), whereas 20 and 30 mole% enhanced permeability by 3.6-fold (P<0.05) and 4.1-fold respectively (P<0.05). Supplementing membranes containing chol with SM did not enhance H+/OH- permeability. Of interest was the finding that chol addition to soya-bean lipids decreased H+/OH- permeability, consistent with an earlier report [Ira and Krishnamoorthy (2001) J. Phys. Chem. B 105, 1484-1488]. We speculate that the presence of proton carriers in crude lipid extracts might contribute to this result. We conclude that (i) chol and SM specifically and independently increase rates of proton permeation in POPC bilayers, (ii) domains enriched in these lipids or domain interfaces may represent regions with high H+/OH- conductivity, (iii) H+/OH- fluxes are not governed by lipid order and (iv) chol can inhibit or promote H+/OH- permeability depending on the total lipid environment. Theories of proton permeation are discussed in the light of these results.

Cholesterol↗
PubMed1988

Changes in jejunal permeability and passive permeation of sugars in intestinal biopsies in coeliac disease and Crohn's disease.

1. The relative effects of changes in mucosal surface area and mucosal permeability on the passive uptakes of mannitol and raffinose have been studied in vitro using jejunal biopsies from 48 controls, 32 patients with coeliac disease and 11 patients with Crohn's disease. Total mucosal permeation was corrected for surface area measured morphometrically to provide an index of mucosal permeability. 2. In untreated coeliac disease, permeation of mannitol was reduced by 35% (P = 0.006) and that of raffinose was increased by 66% (P = 0.0095) compared with controls, whereas mucosal permeability to mannitol was increased twofold (P = 0.009) and to raffinose fivefold (P = 0.0001). Mucosal permeability was similar for each sugar. 3. In treated coeliac disease, permeation and permeability for mannitol were normal, but remained elevated for raffinose by 23% (P = 0.036) and 41% (P = 0.024), respectively. 4. In Crohn's disease, permeation of mannitol was reduced by 21%, but that of raffinose and mucosal permeability to both sugars were normal. 5. These findings suggest that surface area is quantitatively more important than mucosal permeability in determining the total permeation of mannitol, while the converse is true for raffinose. The findings are compatible with paracellular uptake of raffinose, but with both paracellular and transcellular uptake of mannitol. Both pathways are affected in coeliac disease, whereas only transcellular uptake is affected in Crohn's disease.

Adolescent↗
PubMed1999

Aquaporin Nt-TIPa can account for the high permeability of tobacco cell vacuolar membrane to small neutral solutes.

Members of the major intrinsic protein (MIP) family, described in plants as water-selective channels (aquaporins), can also transport small neutral solutes in other organisms. In the present work, we characterize the permeability of plant vacuolar membrane (tonoplast; TP) and plasma membrane (PM) to non-electrolytes and evaluate the contribution of MIP homologues to such transport. PM and TP vesicles were purified from tobacco suspension cells by free-flow electrophoresis, and membrane permeabilities for a wide range of neutral solutes including urea, polyols of different molecular size, and amino acids were investigated by stopped-flow spectrofluorimetry. For all solutes tested, TP vesicles were found to be more permeable than their PM counterparts, with for instance urea permeabilities from influx experiments of 74.9 +/- 9.6 x 10(-6) and 1.0 +/- 0.3 x 10(-6) cm sec-1, respectively. Glycerol and urea transport in TP vesicles exhibited features of a facilitated diffusion process. This and the high channel-mediated permeability of the same TP vesicles to water suggested a common role for MIP proteins in water and solute transport. A cDNA encoding a novel tonoplast intrinsic protein (TIP) homologue named Nicotiana tabacum TIPa (Nt-TIPa) was isolated from tobacco cells. Immunodetection of Nt-TIPa in purified membrane fractions confirmed that the protein is localized in the TP. Functional expression of Nt-TIPa in Xenopus oocytes showed this protein to be permeable to water and solutes such as urea and glycerol. These features could account for the transport selectivity profile determined in purified TP vesicles. These results support the idea that plant aquaporins have a dual function in water and solute transport. Because Nt-TIPa diverges in sequence from solute permeable aquaporins characterized in other organisms, its identification also provides a novel tool for investigating the molecular determinants of aquaporin transport selectivity.

Amino Acid Sequence↗
PubMed1999

Subpopulations of GABAergic and non-GABAergic rat dorsal horn neurons express Ca2+-permeable AMPA receptors.

Subpopulations of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors that are either permeable or impermeable to Ca2+ are expressed on dorsal horn neurons in culture. While both mediate synaptic transmission, the Ca2+ -permeable AMPA receptors provide a Ca2+ signal that may result in a transient change in synaptic strength [Gu, J.G., Albuquerque, C., Lee, C.J. & MacDermott, A.B. (1996) Nature, 381, 793]. To appreciate the relevance of these receptors to dorsal horn physiology, we have investigated whether they show selective expression in identified subpopulations of dorsal horn neurons. Expression of Ca2+-permeable AMPA receptors was assayed using the kainate-induced cobalt loading technique first developed by Pruss et al. [Pruss, R.M., Akeson, R.L., Racke, M.M. & Wilburn, J.L. (1991) Neuron, 7, 509]. Subpopulations of dorsal horn neurons were identified using immunocytochemistry for gamma-aminobutyric acid (GABA), glycine, substance P receptor (NK1 receptor) and the Ca2+-binding proteins, calretinin and calbindin D28K. We demonstrate that, in dorsal horn neurons in culture, kainate-induced cobalt uptake is selectively mediated by Ca2+-permeable AMPA receptors, and that a majority of GABA and NK1 receptor-expressing neurons express Ca2+-permeable AMPA receptors. GABAergic dorsal horn neurons are important in local inhibition as well as in the regulation of transmitter release from primary afferent terminals. NK1 receptor-expressing dorsal horn neurons include many of the projection neurons in the nociceptive spino-thalamic pathway. Thus, we have identified two populations of dorsal horn neurons representing important components of dorsal horn function that express Ca2+-permeable AMPA receptors. Furthermore, we show that several subpopulations of putative excitatory interneurons defined by calretinin and calbindin expression do not express Ca2+-permeable AMPA receptors.

Aging↗
PubMed2002

Intercommunications between brain capillary endothelial cells and glial cells increase the transcellular permeability of the blood-brain barrier during ischaemia.

Increased cerebrovascular permeability is an important factor in the development of cerebral oedema after stroke, implicating the blood-brain barrier (BBB). To investigate the effect of hypoxia on the permeability changes, we used a cell culture model of the BBB consisting of a co-culture of brain capillary endothelial cells and glial cells. When endothelial cells from this co-culture model were submitted alone to hypoxic conditions, long exposures (48 h) were necessary to result in an increase in endothelial cell monolayer permeability to [3H]inulin. When endothelial cells were incubated in presence of glial cells, a huge increase in permeability occurred after 9 h of hypoxic conditions. Oxygen glucose deprivation (OGD) resulted in a much shorter time (i.e. 2 h) required for an increase in permeability. We have demonstrated that this OGD-induced permeability increase involves a transcellular rather than a paracellular pathway. Conditioned medium experiments showed that glial cells secrete soluble permeability factors during OGD. However, endothelial cells have to be made sensitive by OGD in order to respond to these glial soluble factors. This work shows that an early cross-talk between glial and endothelial cells occurs during ischaemic stroke and alters BBB transcellular transport by means of glial factor secretions.

Animals↗
PubMed1999

Inhibition of water permeability in the rat collecting duct: effect of imidazoline and alpha-2 compounds.

Arginine vasopressin (AVP) increases water permeability in the collecting duct of the nephron via activation of adenylyl cyclase. Alpha-2 (alpha2) agonists inhibit AVP-stimulated water permeability via binding to alpha2 adrenoceptors that have been divided into 3 subtypes- alpha2A, alpha2B, and alpha2C. Some biological effects mediated by alpha2 agonists result from nonadrenergic imidazoline receptors that exist in the rat kidney. Thus, alpha2-inhibition of AVP-stimulated water permeability in the rat collecting duct could be caused by imidazoline receptors. The purpose of this study was to test agonists and antagonists selective for alpha2 and imidazoline receptors on AVP-stimulated water permeability in the rat inner medullary collecting duct (IMCD). Some experiments were conducted where water permeability was stimulated by a nonhydrolyzable analog of adenosine 3', 5'-cyclic monophosphate (cAMP). Agonists included dexmedetomidine, clonidine, oxymetazoline, agmatine and rilmenidine. The latter two are selective imidazoline agonists. Antagonists included yohimbine, RX821002, atipamezole, prazosin, WB4101, idazoxan, and BU239. Prazosin and WB4101 demonstrate selectivity for the alpha2B and alpha2C subtypes, respectively, and oxymetazoline and RX821002 are selective for the alpha2A subtype. BU239 is selective for imidazoline receptors. Wistar rat terminal IMCDs were isolated and perfused to determine the osmotic water permeability coefficient (Pf). All agonists except agmatine inhibited AVP-stimulated Pf. Inhibition by rilmenidine indicated a different mechanism of action from other agonists. Dose-response data show dexmedetomidine to be the most potent inhibitor. Oxymetazoline and clonidine inhibited cAMP-stimulated Pf indicating that the mechanism involves postcAMP cellular events. It was reported previously that dexmedetomidine inhibits cAMP-stimulated Pf (1). All antagonists except prazosin and WB4101 reversed alpha2-inhibition of AVP-stimulated Pf. BU239 was effective at 1 microM but not at 100 nM. Results suggest that alpha2A adrenoceptors modulate water permeability in the IMCD. The involvement of imidazoline receptors is inconclusive.

Adrenergic alpha-2 Receptor Agonists↗
PubMed1996

Intestinal permeability changes in response to acetylsalicylic acid in relatives of patients with Crohn's disease.

BACKGROUND & AIMS: Presence of a familial intestinal permeability defect in Crohn's disease remains controversial despite numerous studies. The purpose of this study was to determine whether detection of a permeability defect in first-degree relatives of patients with Crohn's disease can be enhanced using an acetylsalicylic acid provocation test. METHODS: Lactulose-mannitol ratio, a measure of intestinal permeability, and total sucrose excretion, a measure of gastroduodenal permeability, were determined before and after ingestion of acetylsalicylic acid in healthy controls, in patients with Crohn's disease, and in the first-degree relatives of patients with Crohn's disease. Subjects were classified as hyperresponders if their results were above the mean of + 2SD of the controls. RESULTS: First-degree relatives had a 110% increase in intestinal permeability after acetylsalicylic acid compared with an increase of 57% in controls (P = 0.001). Thirty-five percent of relatives were classified as hyperresponders. There was no significant difference in the change in sucrose excretion between relatives and controls (259% vs 198%; P < 0.05). CONCLUSIONS: First-degree relatives of patients with Crohn's disease have an exaggerated increase in intestinal but not gastroduodenal permeability in response to acetylsalicylic acid. This study supports a familial permeability defect in Crohn's disease, which may not be present in all families.

Adult↗
PubMed2000

Environmental stress-induced gastrointestinal permeability is mediated by endogenous glucocorticoids in the rat.

BACKGROUND & AIMS: Abnormal presentation of luminal constituents to the mucosal immune system, caused by dysfunction of the intestinal epithelial barrier, is a candidate theory for the cause of Crohn's disease. Increased epithelial permeability is found in subgroups of patients at high risk for the development of Crohn's disease and has been found to precede disease recurrence. Clinical observations have suggested that disease recurrence can follow times of increased psychological stress, although the underlying mechanism remains obscure. We hypothesized that environmental stress increases gastrointestinal permeability. METHODS: We evaluated site-specific gastrointestinal permeability after application of graded levels of stress in rats. RESULTS: Increased epithelial permeability after stress was shown in all regions of the gastrointestinal tract and seemed to be mediated by adrenal corticosteroids. Stress-induced increases in epithelial permeability disappeared after adrenalectomy or pharmacologic blockade of glucocorticoid receptors. Dexamethasone treatment of control animals increased gastrointestinal permeability and mimicked the effects of stress. CONCLUSIONS: Psychological stress may increase gastrointestinal permeability, allowing luminal constituents access to the mucosal immune system. This provides a potential mechanism for the observation of stress-induced disease recurrence in Crohn's disease.

Adrenal Cortex Hormones↗
PubMed1997

K(+)-permeability in diabetics and nondiabetics with and without renal insufficiency.

Looking for causes or consequences of primary hypertension much attention is drawn to the ion transport systems of the cellular membrane. The existence of endogeneous digitalis-like factors, that lower the activity of Na+/K(+)-ATPase and result in a complex change of electrolyte balance of cells are discussed as a reaction of the organism to salt and volume retention. The measurement of passive permeability of erythrocyte membranes for potassium is an easy and useful method for the detection of disturbances of Na+/K(+)-transport, especially for extensive screening investigations. We examined the potassium permeability of erythrocytes in healthy individuals (GR1, n = 48), patients with compensated renal insufficiency (GR2, n = 36) and diabetics (GR3, n = 25) as well as a group of diabetics with renal failure (GR4, n = 47). The relative change of potassium concentration in the whole blood, based on the efflux of potassium during a 4-hour-incubation at 37 degrees C, is defined as a measure for K(+)-permeability. K(+)-concentrations are determined every 60 minutes with ion sensitive electrodes. K(+)-permeability was significantly increased in patients with compensated renal insufficiency compared to the control group and to diabetics. Diabetics differed markedly in their erythrocyte reaction regarding K(+)-permeability. Whereas patients with renal insufficiency show an efflux of potassium during investigation there is a decrease of potassium in plasma in diabetics. The K(+)-permeability results of patients with both diseases are intermediate between the GR2- and GR3 results and are significantly different from the control group. When g-strophanthin is added to inhibit the sodium pump, the differences between the groups are abolished. The decreased K+permeability in diabetics compared to the control group could be explained by the increased supply of energy-rich substrates for the Na+/K(+)-ATPase.

Adult↗
PubMed2001

Microvascular permeability is increased in both types of diabetes and correlates differentially with serum levels of insulin-like growth factor I (IGF-I) and vascular endothelial growth factor (VEGF).

Vascular endothelial growth factor (VEGF) and insulin-like growth factor-I (IGF-I) both play a pivotal role in diabetic microangiopathy. This study assessed the relationship between capillary permeability as a marker of endothelial dysfunction and serum VEGF and IGF-I levels in normotensive diabetics. Subjects were 10 Type 1 (6/4, male/female, age: 30 [mean] +/- 5 [SD] years, HbA1c: 7.5 +/- 1.1 %), 13 Type 2 diabetics (9/4, m/f; 63 +/- 7 years, 8.3 +/- 1.8 %), and 24 age- and sex-matched control subjects. We determined nailfold capillary permeability by intravital fluorescence videomicroscopy after intravenous injection of sodium-fluorescein. Serum VEGF, free and total IGF-I, IGF binding protein (IGFBP)-1, IGFBP-3, and insulin levels were measured by specific immunoassays. Capillary permeability was increased in both types of diabetes patients compared to age- and sex-matched controls. In Type 1 diabetics, fluorescence light intensities increased over time, reaching significance 30 minutes after dye injection. Type 2 diabetics already revealed an early onset of elevated fluorescence light intensities after one minute. Capillary permeability showed a significant positive correlation with VEGF levels in Type 1 diabetics, (r = 0.76, p < 0.05; 20 min after dye injection) but with free IGF-I levels in type 2 diabetics (r = 0.65, p < 0.05; 5 min after dye injection). IGFBP-3 correlated negatively with capillary permeability in both diabetes types, whereas IGFBP-1 levels correlated positively in Type 2 patients. In conclusion, capillary permeability is increased in both types of diabetes mellitus. However, VEGF and IGF-I may differentially affect microvascular permeability depending on the diabetes type.

Adult↗
PubMed2002

Effects of inflammatory cytokines on the permeability of human lung microvascular endothelial cell monolayers and differential eosinophil transmigration.

BACKGROUND: Rhinovirus (RV) infections can result in asthma exacerbations in both adults and children. Respiratory epithelium, the primary site of RV replication, responds to the viral infection by generating a variety of cytokines and chemokines capable of promoting airway inflammation and hence might increase asthma severity. Some of these mediators might also affect the permeability of underlying vascular endothelium. OBJECTIVE: We hypothesized that RV infections can promote airway inflammation and thus asthma by enhancing local vascular permeability. METHODS: Confluent human lung microvascular endothelial cell (HMVEC-L) monolayers were used as an in vitro model of vascular endothelium to determine whether cytokines associated with RV-induced infections are capable of modulating endothelial cell permeability as measured by means of transendothelial electrical resistance. Recombinant cytokines and chemokines were added to confluent HMVEC-L monolayers cultured on Transwell filters, and permeability was measured as decreased electrical resistance over time. Eosinophil transendothelial migration was assessed under the same experimental conditions. RESULTS: TNF- alpha, IL-1 beta, and IFN- gamma significantly increased HMVEC-L permeability. In contrast, GM-CSF, G-CSF, IL-8, IL-6, and RANTES had no effect. Although incubation of HMVEC-L monolayers with either TNF-alpha or IL-1beta promoted eosinophil migration, IFN-gamma had no effect, indicating that enhanced permeability alone was not sufficient for eosinophil infiltration. CONCLUSION: Select cytokines, generated in response to RV infection, can increase vascular permeability and might provide a mechanism by which RV infection can lead to edema, cellular infiltration, and inflammation and thus compromised airflow.

Asthma↗
PubMed1975

Structure of tight junctions in epithelia with different permeability.

Freeze-fracture studies have shown a network of intramembrane fibrils in the tight junctions of epithelia. A direct correlation between the number of fibrils and junctional permeability has been suggested by previous studies. However, we have made two groups of observations showing that junctional permeability is not univocally related to the complexity of the network revealed by freeze-fracture. (i) The tight junctions of the rabbit ileum mucosa are permeable to lanthanum, although they have a complex network of fibrils resembling the junctions of toad urinary bladder, which are impermeable to lanthanum. (ii) The tight junctions of the toad urinary bladder are normally of low permeability; however, when the luminal solution is made hypertonic with lysine, junctional permeability markedly increases and lanthanum permeates through the tight junctions. In freeze-fracture replicas, no differences between the fibrils of control and lysine-treated bladders were found. Our results indicate that junctional permeability is controlled not only by the complexity of the fibrilar network, but that some features of the junctions or the fibrils themselves, not yet revealed by electron microscopy, play a central role in regulating epithelial permeability.

Animals↗
PubMed1995

Vasopressin increases water permeability of kidney collecting duct by inducing translocation of aquaporin-CD water channels to plasma membrane.

Water excretion by the kidney is regulated by the peptide hormone vasopressin. Vasopressin increases the water permeability of the renal collecting duct cells, allowing more water to be reabsorbed from collecting duct urine to blood. Despite long-standing interest in this process, the mechanism of the water permeability increase has remained undetermined. Recently, a molecular water channel (AQP-CD) has been cloned whose expression appears to be limited to the collecting duct. Previously, we immunolocalized this water channel to the apical plasma membrane (APM) and to intracellular vesicles (IVs) of collecting duct cells. Here, we test the hypothesis that vasopressin increases cellular water permeability by inducing exocytosis of AQP-CD-laden vesicles, transferring water channels from IVs to APM. Rat collecting ducts were perfused in vitro to determine water permeability and subcellular distribution of AQP-CD in the same tubules. The collecting ducts were fixed for immunoelectron microscopy before, during, and after exposure to vasopressin. Vasopressin exposure induced increases in water permeability and the absolute labeling density of AQP-CD in the APM. In parallel, the APM:IV labeling ratio increased. Furthermore, in response to vasopressin withdrawal, AQP-CD labeling density in the APM and the APM:IV labeling ratio decreased in parallel to a measured decrease in osmotic water permeability. We conclude that vasopressin increases the water permeability of collecting duct cells by inducing a reversible translocation of AQP-CD water channels from IVs to the APM.

Animals↗
PubMed2000

Positive effect of rebamipide on gastric permeability in mice after eradication of Helicobacter felis.

BACKGROUND: Despite Helicobacter pylori eradication, gastric inflammation persists for months or years. Preliminary results have indicated that an increase in gastric permeability could be one reason. Our aim was to evaluate the effect of a mucosal protective drug, rebamipide, on gastric permeability in a model of H. felis-infected mice. METHODS: Thirty-three C57/BL6 mice were inoculated with H. felis, and seven controls were kept non-inoculated. After 2 months 20 infected mice were treated with omeprazole, amoxicillin, and clarithromycin for 1 week and then for 4 weeks with either rebamipide (n = 9) or placebo (n = 11). The 13 remaining mice were kept untreated. After cessation of treatment, a fragment of antrum obtained from each mouse was mounted in a small Ussing chamber to study the electric resistance of the tissue (R) and antral permeability. RESULTS: No modification of the paracellular permeability (R, JNa, JMan) was observed in either group. However, the transcellular permeability to horseradish peroxidase (HRP) was significantly increased in H. felis-infected non-treated mice (1131 +/- 463, 948 +/- 339, and 182 +/- 312 ng/h x cm2) as compared with non-infected controls (469 +/- 262, 458 +/- 261, and 10 +/- 6 ng/ h x cm2, for J3H-HRP, JD, and JHRPi, respectively) (P < 0.003). Eradication of the bacteria by antibiotics without subsequent treatment with rebamipide led to a non-significant decrease in the HRP fluxes. However, when rebamipide was used after the antibiotic treatment, a significant (P < 0.01) decrease in HRP fluxes as compared with non-treated mice was observed. CONCLUSIONS: These results confirm that gastric permeability to macromolecules remains increased despite H. felis eradication and show that rebamipide can facilitate the normalization of gastric permeability to macromolecules after bacterial eradication.

Alanine↗
PubMed2000

Relationship between intestinal permeability and calprotectin concentration in gut lavage fluid.

BACKGROUND: Calprotectin is released from neutrophils and monocytes, and increased calprotectin levels in stool may serve as a marker of intestinal inflammation. Intestinal permeability is increased in inflammatory bowel diseases, especially in Crohn disease. We studied the relationship between intestinal permeability and calprotectin concentration in intestinal lavage fluid in patients with known or suspected inflammatory bowel disease (IBD). METHODS: Thirty-eight patients were examined; 17 had Crohn disease; 3, ulcerative colitis; and 18, irritable bowel syndrome. Intestinal lavage was performed by means of a nasojejunal tube positioned by gastroduodenoscopy. By means of a peristaltic pump 2 l isotonic polyethylene glycol solution (MW, 3350) containing 50 microCi 51Cr-labelled ethylenediaminetetraacetic acid (EDTA) were administered through the tube over a period of 40 min. The first clear fluid passed per rectum was collected and analysed for calprotectin levels with an enzyme-linked immunosorbent assay method. Urine was collected for 5 h and analysed for gamma radioactivity. 51Cr-EDTA excretion in urine was expressed as percentage of dose administered (that is, intestinal permeability). RESULTS: Both intestinal permeability and calprotectin concentration were significantly higher in patients with IBD than in patients with functional conditions. In Crohn disease the values depended on disease activity but not on whether the disease was located in the small or in the large bowel. There was a highly significant correlation between calprotectin concentration in gut lavage fluid and intestinal permeability (r=0.79, P<0.0001). CONCLUSION: The significant correlation between calprotectin concentration in gut lavage fluid and intestinal permeability supports the view that increased intestinal permeability in IBD might, at least in part, be a consequence of increased transepithelial migration of neutrophils.

Adult↗