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PubMed1999

Permeability coefficients from NMR q-space data: models with unevenly spaced semi-permeable parallel membranes.

The NMR "q-space" experiment conducted on water provides information on the sizes of repeated structures on the micrometer-length scale in heterogeneous samples, including cell suspensions or tissues. Under some circumstances these plots display coherence peaks, and it has been implied theoretically that the position of the peaks will vary with the rate of molecular exchange across the membranes. This has been demonstrated (qualitatively) with human erythrocytes in suspension. Thus, in the quest for a quantitative approach to the interpretation of such data, we address here the "inverse problem," namely the estimate of the permeability coefficient of membranes from q-space experiments. The present work describes theoretical predictions of q-space plots from molecules diffusing in a simple system of parallel semi-permeable membranes arranged with separations that alternate between two different values; this was designed to (loosely) mimic the intra- and extracellular compartments in a suspension of cells or a tissue. The development of the theory was facilitated by symbolic computation, and the analysis of synthetic data was shown to be achievable by the use of a three-layer back-propagation artificial neural network.

Cell Membrane↗
PubMed2000

Mean residence time of molecules diffusing in a cell bounded by a semi-permeable membrane: Monte Carlo simulations and an expression relating membrane transition probability to permeability.

The rapid exchange of water across erythrocyte membranes is readily measured using an NMR method that entails doping a suspension of cells with a moderately high concentration of Mn(2-) and measuring the rate of transverse relaxation of the nuclear magnetisation. Analysis of the data yields an estimate of the rate constant for membrane transport, from which the membrane permeability can be determined. It is assumed in the analysis that the efflux rate of the water is solely a function of the rate of membrane permeation and that the time it takes for intracellular water molecules to diffuse to the membrane is relatively insignificant. The limits of this assumption were explored by using random-walk simulations of diffusion in cells modelled as parallel planes, spheres, and biconcave discs. The rate of membrane transport was specified in terms of a transition probability but it was not initially clear what the relationship should be between this parameter and the diffusional membrane permeability P(d). This relationship was derived and used to show that the mean residence time for a water molecule is determined by P(d) when the diffusion coefficient is above a certain threshold value; it is determined by the distance to the membrane below that value.

Animals↗
PubMed1988

Regulation of membrane permeability by vasopressin; activation of the water permeability pathway in toad urinary bladder by N-ethyl-maleimide.

1. Vasopressin induces a rapid increase in water permeability and stimulates net sodium transport in responsive epithelia through the mediation of cAMP. 2. In amphibian urinary bladder, the increase in water permeability is dependent on an intact cytoskeleton and is associated with the exocytotic insertion of tubular vesicles containing particle aggregates (the putative water channels) into the apical membrane of the granular epithelial cells. 3. In the toad bladder, mucosal addition of NEM, 0.1 mM, elicits a slow and irreversible increase in transepithelial water flow, whilst decreasing net sodium transport. 4. The hydrosmotic response to mucosal NEM is inhibited by cellular acidification, by pretreatment with cytoskeleton-disruptive drugs, and by agents that increase cytosolic calcium. 5. Mucosal NEM potentiates the hydrosmotic response to a submaximal, but not a maximal, dose of vasopressin. 6. Mucosal NEM, like vasopressin, induces both vesicle fusion and the appearance of particle aggregates at the granular cell apical surface. 7. NEM, unlike vasopressin, does not increase cellular cAMP content. 8. Mucosal NEM appears to increase transcellular water flow by activating cellular processes normally triggered by vasopressin, at a step beyond cAMP.

Animals↗
PubMed1995

The shortest isoform of human vascular endothelial growth factor/vascular permeability factor (VEGF/VPF121) produced by Saccharomyces cerevisiae promotes both angiogenesis and vascular permeability.

Vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) is a multifunctional cytokine that is expressed as four isoforms having 206, 189, 165, and 121 amino acids in humans. We constructed a system that produces the shortest isoform of human VEGF/VPF in Saccharomyces cerevisiae (yVEGF/VPF121). Active yVEGF/VPF121 was secreted from the yeast cells as a glycosylated dimeric protein. Various biological activities of the purified yVEGF/VPF121 were examined. It bound to cell surface receptor(s) and stimulated the growth of human umbilical vein endothelial cells in culture at a dose similar to that of native VEGF/VPF. Purified yVEGF/VPF121 also induced angiogenesis in mice, and promoted the extravasation of plasma proteins from the blood vessels. These observations demonstrated that the shortest isoform of VEGF/VPF with an amino acid sequence of 121 residues contains enough information necessary to trigger both angiogenesis and the induction of vascular permeability upon binding to its cognate receptor(s).

Animals↗
PubMed2004

Dual effects of morphine on permeability and apoptosis of vascular endothelial cells: morphine potentiates lipopolysaccharide-induced permeability and apoptosis of vascular endothelial cells.

Vascular endothelial cells (VEC) provide an essential protective barrier between the vascular system and underlying tissues. Using VEC barrier models of human coronary artery cells and human and rat brain microvascular endothelial cells, we investigated the mechanism by which morphine affects lipopolysaccharide (LPS)-induced VEC permeability. We demonstrated that co-administration of morphine and LPS induced greater VEC apoptosis and permeability than morphine or LPS alone. The extent of induced apoptosis appeared to be cell-type dependent. Furthermore, RT-PCR analysis revealed that morphine and LPS up-regulated Fas expression. These data suggest potential crosstalk between the signaling pathways that mediate morphine- and LPS-triggered apoptosis in brain VEC.

Apoptosis↗
PubMed1998

Complexes between porin, hexokinase, mitochondrial creatine kinase and adenylate translocator display properties of the permeability transition pore. Implication for regulation of permeability transition by the kinases.

Complexes between hexokinase, outer membrane porin, and the adenylate translocator (ANT) were recently found to establish properties of the mitochondrial permeability transition pore in a reconstituted system. The complex was extracted by 0.5% Triton X-100 from rat brain membranes and separated by anion exchanger chromatography. The molecular weight was approximately 400 kDa suggesting tetramers of hexokinase (monomer 100kDa). By the same method a porin, creatine kinase octamer, ANT complex was isolated and reconstituted in liposomes. Vesicles containing the reconstituted complexes both retained ATP that could be used by either kinase to phosphorylate external creatine or glucose. Atractyloside inhibited this activity indicating that the ANT was involved in this process and was functionally reconstituted. Exclusively from the hexokinase complex containing liposome internal malate or ATP was released by addition of Ca2+ in a N-methylVal-4-cyclosporin sensitive way, suggesting that the hexokinase porin ANT complex might include the permeability transition pore (PTP). The Ca2+ dependent opening of the PTP-like structure was inhibited by ADP (apparent I(50), 8 microM) and ATP (apparent I(50), 84 microM). Also glucose inhibited the PTP-like activity, while glucose-6-phosphate abolished this effect. Although porin and ANT were functionally active in vesicles containing the creatine kinase octamer complex, Ca2+ did not induce a release of internal substrates. However, after dissociation of the creatine kinase octamer, the complex exhibited PTP-like properties and the vesicles liberated internal metabolites upon addition of Ca2+. The latter process was also inhibited by N-methylVal-4-cyclosporin. The activity of peptidyl-prolyl-cis-trans-isomerase (representing cyclophilin) was followed during complex isolation. Cyp D was co-purified with the hexokinase complex, while it was absent in the creatine kinase complex. The inhibitory effect of N-methylVal-4-cyclosporin on the creatine kinase complex may be explained by direct interaction with the creatine kinase dimer that appeared to support octamer formation.

Adenosine Diphosphate↗
PubMed2003

Prediction of human intestinal permeability using artificial membrane permeability.

The purpose of the present study was to examine a correlation between the human intestinal permeability (P(eff)) and the bio-mimetic artificial membrane permeability corrected by the paracellular pathway model based on the Renkin function (P(PAMPA-PP-RF)) and to construct a prediction scheme. The effect of the unstirred water layer was incorporated to the prediction scheme. Eighteen P(eff) values of passively absorbed drugs were employed for the analysis. The correlation coefficient (CC) between the predicted and observed logP(eff) was 0.91. P(eff) of furosemide, hydrochlorothiazide and creatinine were underestimated by P(PAMPA-PP-RF). When these compounds were excluded, CC was 0.97. Without the correction for the paracellular pathway, P(eff) of small, cationic and hydrophilic compounds were underestimated. Therefore, P(PAMPA-PP-RF) was found to be an adequate in vitro surrogate for P(eff).

Humans↗
PubMed1988

Enhanced membrane permeability to phenol red by medium-chain glycerides: studies on the membrane permeability and microviscosity.

To clarify the mechanism of the drug absorption enhancement by medium-chain glycerides (MCG), the changes in membrane permeability provoked by MCG were investigated with liposomal uptake experiments. Uptake of phenol red (PR) into liposomes increased with an increase in MCG content in the liposomal membrane, suggesting that PR absorption was enhanced in the "transcellular route." However, the apparent membranous microviscosity obtained in fluorescence depolarization studies tended to increase with the addition of MCG in both the hydrophobic core and the polar head regions of the liposomal membrane. Thus, an enhancement in membrane permeability caused by MCG was not accompanied by a decrease in the apparent membranous microviscosity.

Absorption↗
PubMed1996

Vesiculo-vacuolar organelles and the regulation of venule permeability to macromolecules by vascular permeability factor, histamine, and serotonin.

In contrast to normal microvessels, those that supply tumors are strikingly hyperpermeable to circulating macromolecules such as plasma proteins. This leakiness is largely attributable to a tumor-secreted cytokine, vascular permeability factor (VPF). Tracer studies have shown that macromolecules cross tumor vascular endothelium by way of a recently described cytoplasmic organelle, the vesiculo-vacuolar organelle or VVO (VVOs are grapelike clusters of interconnected, uncoated vesicles and vacuoles). However, equivalent VVOs are also present in the cytoplasm of normal venules that do not leak substantial amounts of plasma protein. To explain these findings, we hypothesized that VPF increased the permeability of tumor blood vessels by increasing VVO function and that the VVOs of normal venules were relatively impermeable in the absence of VPF stimulation. To test this hypothesis, VPF was injected intradermally in normal animals after intravenous injection of a soluble macromolecular tracer, ferritin, whose extravasation could be followed by electron microscopy. VPF caused normal venules to leak ferritin, and, as predicted by our hypothesis, ferritin extravasated by way of VVOs, just as in hyperpermeable tumor microvessels. Ultrathin (14-nm) serial electron microscopic sections and computer-aided three-dimensional reconstructions better defined VVO structure. VVOs occupied 16-18% of endothelial cytoplasm in normal venules. Individual VVOs were clusters of numerous (median, 124) interconnected vesicles and vacuoles that formed complex pathways across venular endothelium with multiple openings to both luminal and abluminal surfaces. Like VPF, histamine and serotonin also stimulated ferritin extravasation across venules by way of VVOs. Together, these data establish VVOs as the major pathway by which soluble plasma proteins exit venules in response to several mediators that increase venular hyperpermeability. These same mediators also increased the extravasation of colloidal carbon, but this large particulate nonphysiological tracer exited venules primarily through endothelial gaps.

Animals↗
PubMed1988

Gastrointestinal permeability to polyethylene glycol: an evaluation of urinary recovery of an oral load of polyethylene glycol as a parameter of intestinal permeability in man.

The permeability of the gastrointestinal tract was investigated by means of polyethylene glycol (PEG), given orally. The PEG solutions contained oligomers with molecular weights from 414 to 1206. The urinary recovery of ingested PEG was determined by high performance liquid chromatography (HPLC). Considerable inter- and intra-individual variations in recovery were found in a reference group of 33 healthy subjects. Intake of food did not change the recovery of PEG, 6.11% (SEM 0.52, n = 13) compared with that for the reference group, 6.45% (SEM 0.39, n = 33). The PEG recovery in a group of ileostomy patients was 5.86% (SEM 0.62, n = 13). No correlation was found between PEG recovery and small bowel transit time. The lipophillic properties of PEG were determined by measuring the partition coefficients in 1-octanol/water and in methylhexanoate/water systems. From these results, correlated with the values for the hydrodynamic volumes of PEG, it was concluded that the intestinal permeation of PEG observed was probably determined by the hydrophillic/hydrophobic properties of the mucosal membrane, rather than by the presence of intercellular junctions or paracellular pores. The PEG molecules with molecular weights from 414 to 1206 were, therefore, not suitable as solitary probes for permeability studies in man.

Administration, Oral↗
PubMed1990

Neurogenic inflammation, vascular permeability, and mast cells. Capsaicin desensitization fails to influence IgE-anti-DNP induced vascular permeability in rat airways.

Mast cells and neuropeptide-containing nerves occur in close proximity throughout the mucosa. The vasodilation that characteristically occurs after mast cell mediator release in skin is dependent upon sensory nerve activation with neuropeptide release. It was therefore of interest to examine the relationship between antigen-induced mast cell activation, vascular permeability, and the influence of capsaicin-sensitive sensory nerves in the airways. To examine this question, capsaicin was administered systemically and the "desensitization" of the animals to topical capsaicin confirmed. Thereafer, capsaicin-desensitized animals were studied to see if mast cell mediator-induced vascular permeability was affected. Plasma protein extravasation (PPE) was induced in Sprague-Dawley rats by intratracheal infusion of capsaicin or by intratracheal infusion of mouse serum albumin-dinitrophenol (MSA-DNP) after passive sensitization with IgE-anti-DNP. Leaking vessels in the airways were localized by using Monastral blue B, a macromolecular tracer. In the trachea, leaking vessels were predominantly located in the anterior wall after capsaicin challenge and in the posterior wall after antigen challenge. PPE was quantified by preinjecting animals with 125I-labeled BSA and expressed as microliter of plasma deposited in the trachea, bronchi, lungs, and tracheobronchial lavage (TBL). Within one minute after challenge, concentrations of capsaicin greater than 10(-7) M significantly increased PPE in trachea and bronchial wall (+ 160% and + 175% above control, respectively, with 10(-5) M). PPE was also observed in the trachea and bronchi after antigen challenge in animals passively sensitized with IgE-anti-DNP (+ 200% and + 153%, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1981

Use of 125I-labeled human serum albumin for quantitation of microvascular permeability in rat skin: reevaluation of an old method for studies on substances with an enhancing effect on microvascular permeability.

A method of determining the leakage of 125I-labeled human serum albumin in the plasma into a standardized area of rat skin to study the effects of intracutaneous application of vasoactive substances on microvascular permeability, was reevaluated. The effect is expressed as a quotient (Q) between the amount of labeled albumin in the test area and that in an area injected with buffer. This calculation is simple and as reliable as more complicated expressions of activity. Within a limited dose range, linear/log dose-response curves can be obtained after application of histamine or bradykinin. Locally injected 125I-labeled human serum albumin is eliminated very slowly from rat skin and determination of the amount of radiolabeled albumin in skin after an intravenous injection therefore represents leakage from the vascular compartments. The potentialities and advantages of this method in pharmacological studies are stressed.

Adenosine↗
PubMed2005

Single-bottle adhesives behave as permeable membranes after polymerisation. II. Differential permeability reduction with an oxalate desensitiser.

OBJECTIVES: This study examined the changes in hydraulic conductance and ultrastructure of dentine bonded with simplified etch-and-rinse adhesives to oxalate desensitiser pre-treated acid-etched dentine. METHODS: Human dentine disks were acid-etched, treated with an oxalate desensitiser (BisBlock, Bisco), and bonded with One-Step (OS), Single Bond (SB), OptiBond Solo Plus (OB) or Prime and Bond NT (PB). Similar disks from each group were acid-etched, and bonded without oxalate pre-treatment. Hydraulic conductance of the specimens was measured at 20 cm of water pressure and analysed with nonparametric statistical methods. Epoxy resin replicas of the smear layer-covered dentine and bonded dentine were examined with SEM for the extent of fluid transudation. Specimens bonded under perfusion were examined with TEM after tracer immersion. RESULTS: OB and PB exhibited a highly significant reversal of the reduced hydraulic conductance obtained with BisBlock on unbonded acid-etched dentine. Profuse water transudation across the bonded dentine was observed from the replicas. Adhesive interfaces were covered with spherical globules that interfered with dentine hybridization. Conversely, no significant difference in hydraulic conductance was observed in SB, between Bisblock pre-treated, unbonded and bonded acid-etched dentine. Significantly lower hydraulic conductance was shown on application of OS to Bisblock-treated acid-etched dentine. Water transudation was sparse, interfering surface globular structures were absent, and only angular subsurface crystals were seen in the dentinal tubules. CONCLUSIONS: Convective water fluxes through dentine may be reduced by applying Bisblock to acid-etched dentine before bonding with One-Step or Single Bond. However, reducing adhesive permeability with the use of oxalate desensitiser is not applicable to low acidity adhesives such as OptiBond Solo Plus and Prime and Bond NT.

Adhesives↗
PubMed2002

Cyclodextrins and drug permeability through semi-permeable cellophane membranes.

Determinations of drug fluxes through semi-permeable cellophane membranes are used to evaluate cyclodextrin complexes and cyclodextrin containing drug formulations. In the present study we investigated how the cyclodextrin concentration, the membrane thickness and the molecular weight cut off (MWCO) of the membrane influence drug fluxes. The cyclodextrin used was 2-hydroxypropyl-beta-cyclodextrin (HPbetaCD) and the sample drug was hydrocortisone. The MWCO of the membranes ranged from 500 to 14,000 and the HPbetaCD concentration ranged from 0 to 25% (w/v). The hydrocortisone flux from saturated solutions through the MWCO 500 membrane was unaffected by the cyclodextrin concentration. When MWCO of the membrane was greater than the molecular weight of the complex the flux from solutions saturated with hydrocortisone increased with increasing HPbetaCD concentration. This increase showed negative deviation from linearity. When the flux was corrected for the viscosity increase with increasing HPbetaCD concentration then the flux pattern could be described on the basis of Fick's first law and Stokes-Einstein equation. However, the flux did not correlate with the viscosity when it was increased by adding polymer to the saturated drug solutions. It was shown that the observed flux pattern was consistent with self-association of cyclodextrin complexes in the aqueous donor phase.

Chromatography, High Pressure Liquid↗
PubMed1995

The standard peritoneal permeability analysis: a tool for the assessment of peritoneal permeability characteristics in CAPD patients.

Peritoneal transport characteristics in CAPD patients are often assessed by the peritoneal equilibration test (PET), which uses a four hour dwell with glucose 2.27% dialysate. From the test, the dialysate/plasma ratio of creatinine (D/PCr), the dialysate/initial dialysate ratio of glucose (D/Do) and net ultrafiltration (NUF, drained minus instilled volume) are calculated. The standard peritoneal permeability analysis (SPA) is a modification and extension of the PET: glucose 1.36% dialysate is used, to which dextran 70 (1 g/liter) is added for the calculation of fluid kinetics. Mass transfer area coefficients (MTAC's) of low molecular weight solutes, clearances of proteins and the change in intraperitoneal volume (delta IPV) can be assessed. In this study the SPA was analyzed, and a comparison with the PET was made. A total number of 138 SPA's was analyzed in 86 different clinically stable patients. Normal values were calculated for both SPA and PET parameters in the same tests. Median (ranges) of comparable transport parameters from SPA and PET were: MTACCr, 10.4 ml/min (5.7 to 19.3); glucose absorption, 61% (35 to 87); delta IPV, 9.5 ml (-761 to 310); D/PCr, 0.76 (0.53 to 1.14); D/D0, 0.37 (0.13 to 0.56); NUF, -75 ml (-675 to 450). The agreement between SPA and PET was analyzed using the method of Bland and Altman. A fairly good agreement was present between NUF and delta IPV. Systematic errors were found when D/PCr and MTACCr were compared: D/P overestimated MTAC mainly in the low range, whereas in the high range values were underestimated. A similar pattern was seen for the transport parameters of glucose. In 40 patients negative net ultrafiltration was present, and possible reasons for this were assessed. In 9 patients no reason could be identified. It can be concluded that the SPA provides useful and extensive information on peritoneal transport parameters. Compared to the PET, the SPA has better discriminative power for the transport of glucose and creatinine.

Adult↗
PubMed1993

Permeability properties of peroxisomes in digitonin-permeabilized rat hepatocytes. Evidence for free permeability towards a variety of substrates.

In order to investigate the permeability properties of rat-liver peroxisomes in situ, we selectively permeabilized hepatocytes with digitonin in a medium mimicking the cytosol. This system permitted us to study the latency of peroxisomal oxidases by means of measurement of their activities in permeabilized compared to disrupted hepatocytes. The activity of peroxisomal oxidases was studied using three different methods: (1) measurement of the oxidase-mediated production of H2O2 in a system containing homovanillic acid, horseradish peroxidase and azide; (2) measurement of the rate of substrate utilization or product formation; (3) measurement of the production of H2O2 via the peroxidative action of catalase in the presence of an excess of methanol. The results obtained depended on which system was used to measure the activity of the different oxidases. Our observations lead us to conclude that method 1 cannot be used for latency studies, whereas methods 2 and 3 are suitable under defined circumstances. Based on the results of methods 2 and 3, we conclude that urate oxidase, L-alpha-hydroxyacid oxidase A and D-amino acid oxidase show no structure-linked latency in digitonin-permeabilized hepatocytes, suggesting that the substrates for these enzymes permeate freely through the peroxisomal membrane.

Alcohol Oxidoreductases↗
PubMed1997

In-vitro permeability of the human nail and of a keratin membrane from bovine hooves: influence of the partition coefficient octanol/water and the water solubility of drugs on their permeability and maximum flux.

Penetration of homologous nicotinic acid esters through the human nail and a keratin membrane from bovine hooves was investigated by modified Franz diffusion cells in-vitro to study the transport mechanism. The partition coefficient octanol/water PCOct/W of the esters was over the range 7 to > 51,000. The permeability coefficient P of the nail plate as well as the hoof membrane did not increase with increasing partition coefficient or lipophilicity of the penetrating substance. This indicates that both barriers behave like hydrophilic gel membranes rather than lipophilic partition membranes as in the case of the stratum corneum. Penetration studies with the model compounds paracetamol and phenacetin showed that the maximum flux was first a function of the drug solubility in water or in the swollen keratin matrix. Dissociation hindered the diffusion of benzoic acid and pyridine through the hoof membrane. Since keratin, a protein with an isoelectric point of about 5, is also charged, this reduction can be attributed to an exclusion of the dissociating substance due to the Donnan equilibrium. Nevertheless, the simultaneous enhancement of the water solubility makes a distinct increase of the maximum flux possible. In order to screen drugs for potential topical application to the nail plate, attention has to be paid mainly to the water solubility of the compound. The bovine hoof membrane may serve as an appropriate model for the nail.

Adult↗
PubMed2000

[Changes in myopic refractive errors after 9 months of extensive wear of hydrogel lenses with high oxygen permeability and compared with those with low permeability].

BACKGROUND: A small but significant increase in myopia after extended wear of low oxygen permeability (Dk) hydrogel lenses has been previously reported; however, the specific impact of hypoxia on refractive status and corneal curvature with extended wear are not well documented. THE PURPOSE of this study was to compare the refractive changes induced over a period of 9 months' extended wear with high-Dk fluorosiloxane hydrogel lenses and low-Dk hydrogel lenses. METHODS: Adapted daily wear contact lens wearers were randomly assigned to one of two groups. The low-Dk group wore etafilcon A (Dk = 28) for up to 7 days and 6 nights and the high-Dk group wore lotrafilcon A (Dk = 140) for up to 30 days and nights. Refractive error and corneal curvature were measured at 3-month intervals over 9 month of extended wear. RESULTS: The etafilcon A group demonstrated an average increase in myopia of 0.30 D over the 9 months period; however, no change in spherical myopic correction was measured in the lotrafilcon A group. The cylindrical component did not change in either group. A stratified analysis revealed a greater increase in myopia for low myopes than moderate myopes in the etafilcon A group but no difference in the lotrafilcon A group. Keratometric analysis revealed no change in the etafilcon A group and a small degree of central corneal flattering in both major meridians of 0.35 D in the lotrafilcon A group. CONCLUSIONS: Nine months of extended wear of low-Dk lenses is associated with a small degree of myopic progression in adult myopes that appears to be reversible. Wearing fluorosiloxane-hydrogel lenses of high-Dk had no impact on refractive error and may be associated with a small degree of central corneal flattering.

Adult↗