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PubMed2002

Permeability profiles of M-alkoxysubstituted pyrrolidinoethylesters of phenylcarbamic acid across caco-2 monolayers and human skin.

PURPOSE: The purpose of the present research was to study 10 m-alkoxysubstituted pyrrolidinoethylesters of phenylcarbamic acid-potential local anesthetics. The relationships between the structure of the molecule, its physicochemical parameters (log D(oct), log k, R(M), solubility) were correlated to the permeability data obtained from permeation experiments in Caco-2 monolayers and excised human skin in vitro. METHODS: The extent and mechanism(s) of permeability of the series were studied through a Caco-2 monolayer in the apical-to-basolateral (a-b) and basolateral-to-apical (b-a) directions. The MTT test was performed to determine cellular damage. In vitro transdermal permeability data were obtained from permeation experiments on excised human skin by using side-by-side chambers. Passive diffusion and iontophoretically enhanced permeability were measured. RESULTS: In Caco-2 monolayers, similar results in the shape of the permeability curves were obtained for the two directions. In the b-a direction, the values of P(app) were approximately 2-6 times greater than in the a-b direction. A plot of drug permeability vs. the number of carbons in the alkoxychain plateaued first, after which the permeability decreased by the increasing lipophilicity of the drug. If the log D(oct) of the ester was > or = 3.4 and the MW > 385 Da, no measurable Caco-2 permeability was found. Cell damage was also higher by the more lipophilic compounds. In excised human skin, the relationship between the passive diffusion of the drugs and the number of carbons in the alkoxychain was parabolic (r2 = 0.95). Introducing low-level electrical current (iontophoresis), transdermal permeability of the more hydrophilic phenylcarbamic acid esters increased clearly. CONCLUSIONS: Lipophilicity and solubility of a compound have crucial roles in the permeation process. A very high lipophilicity has, however, a negative influence on the permeability, both intestinally and transdermally. Iontophoresis significantly increases the diffusion of small and less lipophilic compounds.

Administration, Cutaneous↗
PubMed2003

In vitro permeability of poorly aqueous soluble compounds using different solubilizers in the PAMPA assay with liquid chromatography/mass spectrometry detection.

PURPOSE: This study compares the use of UV-VIS detection with liquid chromatography/mass spectrometry (LC/MS) detection for the PAMPA (Parallel Artificial Membrane Permeability Assay) permeability determination of compounds in the drug discovery stage. LC/MS detection offers a selective and sensitive method for the determination of the PAMPA permeability for compounds that do not contain a UV chromophore or possess a low UV extinction coefficient. To enhance the reliability of our permeability measurements for compounds with low aqueous solubility, we demonstrated the use of LC/MS detection as a means for facilitating the study of solubilizing agents to enhance aqueous solubility that normally would interfere with UV-VIS detection. In doing so, the PAMPA assay can be expanded to study the in vitro permeability of poorly water soluble compounds and evaluate the effects of solubilizers' on the membrane permeability of different compounds. This might be useful in selecting solubilizers for poorly water soluble compounds to be used for further in vivo studies. METHODS: A diverse set of 20 drugs using UV-VIS detection were compared with data using LC/MS detection. A PAMPA screening method was designed which used solubilizers (Brij 35, Cremophor EL, ethanol, and Tween 80) for compounds with low aqueous solubility. The stability of the artificial membrane was determined using various solubilizer concentrations (0.1-5% w/v) to ensure the phospholipid membrane was not disrupted. Two compounds, amiodarone and miconazole, with low aqueous solubility yielding an undetected response in the PAMPA assay using UV-VIS detection were subjected to the different solubilizing agents and their PAMPA permeability was measured using LC/MS detection. RESULTS: Most of the compounds showed similar PAMPA permeability using the two detection systems. However, for compounds lacking a UV chromophore or with a low UV extinction coefficient, LC/MS was the detection method of choice for determination of PAMPA permeability values. LC/MS also gave reliable quantification data for compounds containing impurities, as well as compounds that were not stable during the assay. Although many solubilizers were found to interfere with UV-VIS detection, the LC/MS approach was applicable to determine the permeability values of compounds with normally low aqueous solubility. CONCLUSIONS: LC/MS detection offered greater sensitivity and selectivity as compared with UV-VIS detection for the PAMPA assay. With this added versatility in detection, PAMPA can be used in both discovery and pre-formulation applications, which has not been described before.

Gas Chromatography-Mass Spectrometry↗
PubMed2004

Effects of extracts of commonly consumed food supplements and food fractions on the permeability of drugs across Caco-2 cell monolayers.

PURPOSE: Extracts made from berries, herbs, and various plant materials, which might possess a range of activities, are used as health promoting products. Because little is known about their effects on the absorption of co-administered drugs, the effects of some food supplements, Finnish berries, and herbs were studied on the permeability of some commonly used drugs. METHODS: The permeabilities of verapamil, metoprolol, ketoprofen, paracetamol, and furosemide were studied across Caco-2 cell monolayers with contemporaneously administered extracts from flax seed, purple loosestrife, and Scots pine bark; bilberries, cowberries, and raspberries; oregano, rosemary, and sage. Toxicological tests were conducted to determine cellular damage. RESULTS: The effects of extracts on drug permeabilities were generally minor. Flax seed decreased the permeability of all drugs except verapamil. Purple loosestrife and pine decreased verapamil and metoprolol permeability. Changes caused by berries were mainly pH-related. Rosemary and oregano enhanced furosemide permeability. CONCLUSIONS: Ingestion of extracts of herbs and berries studied are not expected to markedly change the permeabilities of highly permeable drugs. Harmful effects at sites of or during absorption are unlikely. However, if high doses of extracts are administered with low permeable drugs in vitro, effects on drug permeabilities could not be excluded. Use of such extracts should therefore be evaluated during continuous medication.

Biological Transport, Active↗
PubMed1999

Effect of glutamine on the intestinal permeability changes induced by indomethacin in humans.

BACKGROUND: Long-term non-steroidal anti-inflammatory drug (NSAID) intake may induce increased intestinal permeability, eventually resulting in enteropathy. Because increased permeability might be related to cell damage resulting from energy depletion, it was hypothesized that glutamine--the major energy source of the intestinal mucosal cell--might prevent permeability changes. METHODS: The 6-h urinary excretion of 51Cr-EDTA after an oral load of 51Cr-EDTA was used in this study as a measure for intestinal permeability. Healthy volunteers underwent a series of permeability tests: (i) basal test; (ii) test following NSAID (indomethacin); (iii) test following NSAID in combination with glutamine and/or misoprostol. RESULTS: The NSAID induced increased permeability in all volunteers. Pre-treatment with glutamine (3x7 g daily, 1 week before NSAID-dosing) did not prevent the NSAID-induced increase in permeability. Multiple doses of glutamine close in time to NSAID-dosing resulted in significantly lower permeability compared to the NSAID without glutamine. Co-administration of misoprostol with the multiple-dose scheme of glutamine resulted in a further reduction in the NSAID-induced increase in permeability. CONCLUSIONS: Glutamine decreases the permeability changes caused by NSAID-dosing when it is administered close in time, and misoprostol has a synergistic effect.

Adenosine Triphosphate↗
PubMed2000

Increased permeability in dextran sulphate colitis in rats: time course of development and effect of butyrate.

BACKGROUND: Increased mucosal permeability is an important factor in the genesis of mucosal inflammation in inflammatory bowel disease. This study examined the time course of increased permeability and the effect of butyrate on permeability in experimental colitis in rats. METHODS: Colitis was induced in albino rats by administration of 4% dextran sulphate sodium (DSS) orally for up to 7 days. Rats were killed sequentially after 1-7 days of DSS feeding and compared with control animals. Distal colon sheets, from normal and DSS rats, were mounted in Ussing chambers. Electric resistance and passive permeation of 14C-mannitol were measured over 90 min. In control and 5-day DSS rats additional permeability measurements were made in the presence of butyrate (25 mmol/l) in the bathing solutions. The permeability of the normal distal colon was measured after addition of DSS in vitro. Sections of colon were examined by light microscopy. The viability of colonocytes, from normal and DSS rat colon, was measured by release of lactate dehydrogenase immediately and during a 60-min incubation after isolation. RESULTS: Focal mild inflammation and shedding of epithelium were noted after 2 days of DSS administration; crypt loss with flattened epithelium in adjacent areas after 5 days; and fibrosis after 7 days. Decreased epithelial cell survival after 60 min of incubation was noted after 1 day of DSS administration, whereas decreased viability at the time of isolation was noted after 2 days of DSS administration (viability, 72.7% +/- 1.4%; mean +/- standard error) compared with control (89.3% +/- 0.8%) (P < 0.01). Increased permeability was noted after 1 day of DSS administration. Electric resistance (mu omega/cm2/h) was significantly reduced after 1 day of DSS administration to 85.9 +/- 4.6 (mean +/- standard error) compared with control animals (117.2 +/- 2.2; P < 0.001). Serosa-mucosa flux of mannitol (micromol/cm2/h) was also significantly increased after 1 day of DSS feeding (0.169 +/- 0.01) compared with control (0.061 +/- 0.08) (P < 0.01). Electric resistance and mannitol permeability were significantly returned towards normal by the presence of butyrate. DSS added directly to the bathing solution did not significantly alter the colon permeability in vitro. CONCLUSIONS: Increased mucosal permeability is a very early change in colitis induced by DSS, is accompanied by decreased cell survival, and precedes detectable changes in histology. Reversal of increased mucosal permeability by butyrate may explain its utility in the therapy of inflammatory disease of the colon.

Animals↗
PubMed2003

Effect of pharmacologically induced smooth muscle activation on permeability in murine colitis.

BACKGROUND: Both intestinal permeability and contractility are altered in inflammatory bowel disease. Little is known about their mutual relation. Therefore, an in vitro organ bath technique was developed to investigate the simultaneous effects of inflammation on permeability and smooth muscle contractility in different segments of the colon. METHODS AND MATERIALS: BALB/c mice were exposed to a 10% dextran sulphate sodium drinking water solution for 7 days to induce a mild colitis, while control mice received normal tap water. Intestinal segments were placed in an oxygenated organ bath containing Krebs buffer. Permeability was measured by the transport of the marker molecules 3H-mannitol and 14C-polyethyleneglycol 4000. Contractility was measured through a pressure sensor. Smooth muscle relaxation was obtained by salbutamol and l-phenylephrine, whereas contraction was achieved by carbachol and 1-(3-chlorophenyl)-biguanide. RESULTS: The intensity of mucosal inflammation increased throughout the colon. Also, regional differences were observed in intestinal permeability. In both normal and inflamed distal colon segments, permeability was diminished compared with proximal colon segments and the non-inflamed ileum. Permeability in inflamed distal colon segments was significantly decreased compared with normal distal segments. Pharmacologically induced relaxation of smooth muscles did not affect this diminished permeability, although an increased motility positively affected permeability in inflamed and non-inflamed distal colon. CONCLUSIONS: Inflammation and permeability is inversely related. The use of pro-kinetics could counteract this disturbed permeability and, in turn, could regulate the disturbed production of inflammatory mediators.

Albuterol↗
PubMed2003

Quantitative structure-toxicity relationships using TOPS-MODE. 3. Structural factors influencing the permeability of commercial solvents through living human skin.

The permeability of a series of 12 commercial solvents through living human skin were studied by using a topological sub-structural approach (TOPS-MODE). We first analyzed the influence of several physicochemical parameters used in describing the skin permeability of the solvents. No single significant relationship was found between any of these physicochemical properties and the permeability of the solvents. A QSAR model using TOPS-MODE descriptors was obtained and validated. This model accounted for more than 95% of the variance in the experimental permeability of these solvents. Using the derived model, the structural factors responsible for the permeability of this series of solvents through living human skin were identified. Methyl groups bonded to heteroatoms or to CH2 groups resulted in the greatest contributions to skin permeability and these groups were considered to be "permeability enhancers". In contrast, groups of the type X = O (X = S, C) were found to be "permeability inhibitors" because they possessed negative contributions to the logarithm of permeability in all of the studied solvents. Drawing on the idea of permeability "enhancers" and "inhibitors", we hypothesized that the solvents needed to orientate themselves in front of the stratum corneum layer first before penetrating through the skin.

Chemical Phenomena↗
PubMed2004

Cracks in the palisade cuticle of soybean seed coats correlate with their permeability to water.

BACKGROUND AND AIMS: Soybean (Glycine max) is among the many legumes that are well known for 'hardseededness'. This feature can be beneficial for long-term seed survival, but is undesirable for the food processing industry. There is substantial disagreement concerning the mechanisms and related structures that control the permeability properties of soybean seed coats. In this work, the structural component that controls water entry into the seed is identified. METHODS: Six soybean cultivars were tested for their seed coat permeabilities to water. To identify the structural feature(s) that may contribute to the determination of these permeabilities, fluorescent tracer dyes, and light and electron microscopic techniques were used. KEY RESULTS: The cultivar 'Tachanagaha' has the most permeable seed coat, 'OX 951' the least permeable seed coat, and the permeabilities of the rest ('Harovinton', 'Williams', 'Clark L 67-3469', and 'Harosoy 63') are intermediate. All seeds have surface deposits, depressions, a light line, and a cuticle about 0.2 microm thick overlaying the palisade layer. In permeable cultivars the cuticle tends to break, whereas in impermeable seeds of 'OX 951' it remains intact. In the case of permeable seed coats, the majority of the cracks are from 1 to 5 micro m wide and from 20 to 200 micro m long, and occur more frequently on the dorsal side than in other regions of the seed coat, a position that correlates with the site of initial water uptake. CONCLUSIONS: The cuticle of the palisade layer is the key factor that determines the permeability property of a soybean seed coat. The cuticle of a permeable seed coat is mechanically weak and develops small cracks through which water can pass. The cuticle of an impermeable seed coat is mechanically strong and does not crack under normal circumstances.

Cell Membrane Permeability↗
PubMed1981

Inhibition of the anion permeability of sarcoplasmic reticulum vesicles by some stilbene derivatives.

This paper concerns a study of the inhibition of sulfate permeability of sarcoplasmic reticulum vesicles by stilbene derivatives, such as 4-acetoamido-4'-isothiocyano-2,2'-stilbene-disulfonic acid (SITS), 4,4'-diisothiocyano-stilbene-2,2'-disulfonic acid (DIDS), and diisothiocyano-1,2-diphenyl-ethane-2,2'-disulfonic acid (H2DIDS). The level of sulfate permeability was measured by using a radioactive tracer. The sulfate efflux curves comprise two phases. This is explained by the existence of two types of vesicles with different permeability. The permeability of the rapidly permeated vesicles was at least 100 times higher than that of the slowly permeated vesicles. The permeability of both types of vesicles was inhibited by the above inhibitors. Apparent dissociation constants for the inhibitors of sulfate permeability were 5 mu M, 6 mu M, and 40 mu M for DIDS, H2DIDS, and SITS, respectively. The relation between sulfate permeability and the amount of the bound inhibitors was studied. To effect complete inhibition of permeation by sulfate in both vesicles, the binding of 5 mu mol of inhibitors/g protein was required. However, kinetic analysis of the sulfate efflux of the rapidly permeated vesicles suggested that the amount of the anion transport system is much smaller than 5 mu mol/g protein. Permeability for Na+ and choline was not affected by the same concentration of inhibitors. However, Ca2+ permeability was increased by the inhibitors, and at the same time Ca2+ uptake was reduced. This inhibition of Ca2+ uptake was explained by the increase of Ca2+ permeability.

Animals↗
PubMed1995

The permeability of fibrin network developed in human plasma.

Fibrin network permeability has an important role in thrombosis and inflammation since it influences the rate of transport of macromolecules through the network by convection. The conditions of polymerization of fibrin determine the network permeability and this has been attributed to variability in fibrin fibre thickness. Inconsistencies between values for fibrin fibre thickness derived from turbidity and permeability were examined. Networks were developed from human plasma by the addition of thrombin and network polymerization was modified pharmacologically. Dextran (MW 70,000) and poloxamer 188 both increased, and lauryl sulphate decreased, network permeability and network turbidity. Network fibre thickness was consistently higher when derived from permeability than from turbidity. Network permeability was significantly more susceptible to pharmacological manipulation by these agents than network turbidity. These inconsistencies were attributed to variation in the arrangement of the network fibres such as inhomogeneity of network fibre distribution and to fibre aggregation or alignment. Collectively these factors prohibit the derivation of fibrin fibre thickness from permeability. The dimensionless permeability (network permeability/(fibre radius)2) was used as an index of network fibre arrangement and found to be readily modified pharmacologically. Physiological and pharmacological regulation of fibrin network permeability may be predominantly mediated through modification of fibre arrangement and not through fibre thickness.

Biopolymers↗
PubMed2004

Low-dose prostacyclin restores an increased protein permeability after trauma in cat skeletal muscle.

BACKGROUND: Increased microvascular permeability inducing leakage of plasma from the intravascular to the extravascular space after trauma is a pathophysiologic event of great clinical significance. A substance reducing an increased microvascular permeability, and especially an increased protein permeability, therefore could be of value to maintain normovolemia and to reduce the need for plasma substitution. Prostacyclin is suggested to have permeability-reducing properties as shown for fluid permeability, but its effects on protein permeability, which may be controlled by partly different mechanisms, are unclear. The present study evaluates whether prostacyclin at a low, clinically relevant, nonvasodilating dose can reestablish an increased protein permeability after trauma. METHODS: The study was randomized, blinded, and performed on surgically traumatized, autoperfused, and denervated cat calf muscle. Relative changes in the osmotic reflection coefficient for albumin after 1.5 hours of prostacyclin (1 ng/min/kg) (n = 7) or vehicle (n = 7) treatment were used as a measure of altered protein permeability from a state of increased permeability after trauma. RESULTS: We found that the osmotic reflection coefficient for albumin was increased by about 35% in the prostacyclin group compared with the vehicle-treated group (p < 0.001). CONCLUSION: If applicable to humans, prostacyclin is a potential therapy for reducing plasma leakage in the critically ill trauma patient by restoring permeability from an increased level.

Animals↗
PubMed1991

Permeability of normal versus carious dentin.

Although a number of reports have been published demonstrating that carious dentin is less permeable than normal dentin, these reports have been qualitative rather than quantitative. The purpose of this in vitro study was to apply a quantitative technique to the study of the permeability of carious human teeth before and after excavation, before and after removal of the smear layer and before and after preparation of a control cavity of similar size and depth in normal dentin subjected to the same measurements, for comparative purposes. Dentin permeability was measured as a hydraulic conductance. The permeability values measured at each step in the protocol were expressed as a percent of the maximum permeability of both cavities, permitting each tooth the serve as its own control. Carious lesions exhibited a slight degree of permeability (2.3 +/- 0.6% of controls) which remained unchanged after excavation of the lesions. Removal of the smear layer in the excavated carious lesions increased the permeability significantly to 6.9 +/- 3.2%. Preparation of a control cavity of the same area and depth increased the permeability slightly. Removal of its smear layer increased the permeability of the dentin 91%. These results confirm previous qualitative studies that carious dentin, even after excavation and removal of the smear layer has a very low permeability.

Acid Etching, Dental↗
PubMed1992

Alveolar epithelial permeability in baboons: histamine and capsaicin.

1. We investigated if changes in alveolar epithelial permeability could be initiated by various doses of the irritant capsaicin through stimulation of pulmonary afferent nerves either directly, or indirectly through the release of an intermediate cell mediator, and whether mediation of permeability involved histamine H1 and/or H2 receptors. 2. Alveolar epithelial permeability was indicated by the clearance of peripherally deposited 99mTc-DTPA (technetium-99m-diethylenetriamine pentaacetate) aerosol in baboons. Aerosol challenge experiments were performed twice with histamine (32 mg/ml), once each with capsaicin (10(-6), 10(-5), 10(-4) and 10(-3) M), and once each with histamine (32 mg/ml) preceded by H1 (terfenadine) and H2 (ranitidine) antagonists alone and combined. 3. Mean half-time for 99mTc-DTPA clearance was 66 +/- 4 min. After histamine, it decreased to 41 +/- 5 min (P < 0.05), and after capsaicin it was 70 +/- 5 min (combined doses). Pretreatment with the H1 and H2 antagonists, either separately or in combination, did not consistently inhibit increases in 99mTc-DTPA permeability. 4. Capsaicin caused tachypnoea only at 10(-3) M (P < 0.05). Inhibition of histamine-induced tachypnoea required both antagonists (P < 0.05) suggesting the existence of a population of peripheral sensory neurons possessing H1 and H2 receptors. Changes in permeability were unrelated to the changes in respiratory frequency. Thus, neither the mechanisms that stimulate respiratory frequency, nor the respiratory frequency per se, were responsible for increased alveolar epithelial permeability. 5. Capsaicin did not change epithelial permeability at doses that cause capsaicin-sensitive C fibre stimulation as delineated by increases in respiratory frequency. Nor does C fibre stimulation, induced by mediators released from pulmonary cells activated by low doses of capsaicin, increase epithelial permeability. These data suggest that in the primate, histamine increases epithelial permeability to small solutes by a mechanism independent of the activation of capsaicin-sensitive C fibres and capsaicin-initiated release of cell mediators. 6. These findings do not support a role for C fibre activation in regulating epithelial permeability of small solutes.

Animals↗
PubMed1999

Different intestinal permeability patterns in relatives and spouses of patients with Crohn's disease: an inherited defect in mucosal defence?

BACKGROUND: A familial defect in intestinal barrier function has been found in Crohn's disease. AIM: To investigate possible genetic and environmental influences on this barrier defect by studying intestinal permeability in both relatives and spouses of patients with Crohn's disease. SUBJECTS: The study included 39 patients with Crohn's disease, 34 healthy first degree relatives, and 22 spouses. Twenty nine healthy volunteers served as controls. METHODS: Intestinal permeability was assessed as the lactulose:mannitol ratio in five hour urinary excretion after oral load, both before (baseline) and after ingestion of acetylsalicylic acid. The permeability response represents the difference between the two tests. A ratio above the 95th percentile for controls was classified as abnormal. RESULTS: Baseline permeability was higher in patients and spouses than in controls. An abnormal baseline permeability was seen in 36% of the patients, 23% of the spouses, 18% of the relatives, and 3% of the controls. After ingestion of acetylsalicylic acid, permeability increased significantly in all groups. Relatives were similar to patients with regard to permeability after exposure to acetylsalicylic acid, whereas spouses were similar to controls. The proportions with an abnormal permeability response to acetylsalicylic acid were 32% in patients, 14% in spouses, 41% in relatives, and 3% in controls. CONCLUSION The findings suggest that baseline permeability is determined by environmental factors, whereas permeability provoked by acetylsalicylic acid is a function of the genetically determined state of the mucosal barrier, and support the notion that environmental and hereditary factors interact in the pathogenesis of Crohn's disease.

Adult↗
PubMed1994

Permeability properties of the mammalian bladder apical membrane.

The luminal surface of mammalian bladder is exposed to urine with a composition widely different from that of plasma that bathes the basolateral surface of epithelium. Therefore we predict that the bladder permeability barrier, which is likely located in the apical membrane (AM), will exhibit low permeabilities to water, urea, NH3, H+, and small nonelectrolytes. AM surface area increases as the bladder fills with urine and decreases during emptying, a process that involves cyclical endocytosis and reinsertion of membrane from a pool of AM endosomes (AME). Rigid-appearing plaques composed of three proteins, uroplakins, have been identified and occupy 70-90% of AM surface area. To determine permeability properties of the AM permeability barrier, we purified AME and measured their permeabilities. Rabbit urinary bladders were removed, and their apical surface was exposed to carboxyfluorescein (CF) or horseradish peroxidase (HRP). Exposure to hypotonic and then isotonic basolateral solutions induced endocytosis of luminal CF or HRP into AME. Electron microscopy of bladders after this treatment revealed HRP entrapped within AME bordered by plaques. AME were purified by differential and sucrose-gradient centrifugation, and CF-containing AME were purified 17.0 +/- 3-fold (SD) with respect to homogenate. Analysis of purified AME by flow cytometry showed that > 95% of vesicles contained CF entrapped from luminal solution and were selectively labeled with anti-uroplakin antibody. AME osmotic water permeability averaged 2.3 +/- 0.66 x 10(-4) cm/s and exhibited a high activation energy, indicating that AM contains no water channels. Permeability to urea and NH3 averaged 7.8 +/- 3.7 x 10(-7) and 1.5 +/- 0.3 x 10(-3) cm/s, respectively, which are exceptionally low and similar to permeabilities of other water-tight membranes, including toad urinary bladder and gastric mucosa. AME behaved as a single population in all permeability studies, which will permit future characterization of protein and lipid structure responsible for these unique permeability properties.

Ammonia↗
PubMed1997

Low-dose prostacyclin has potent capillary permeability-reducing effect in cat skeletal muscle in vivo.

The dose-response effects of intravenous infusion of prostacyclin on capillary permeability (the capillary filtration coefficient technique), hydrostatic capillary pressure, transcapillary filtration, and vascular tone were analyzed in vivo on cat skeletal muscle from a normal and an increased permeability level. Increased permeability was accomplished by intra-arterial infusion of tumor necrosis factor-alpha or histamine. Permeability effects of bradykinin were also analyzed. Prostacyclin decreased capillary permeability by 8% at a dose of 0.1 ng.kg-1.min-1 and at most by 30% below control attained at 2 ng.kg-1.min-1, also with no effect on vascular tone and hydrostatic capillary pressure. The permeability increase by tumor necrosis factor-alpha and histamine (by 54 and 73%) was more than counteracted by the simultaneous infusion of prostacyclin at 2 ng.kg-1.min-1. The vasodilator effect of tumor necrosis factor-alpha was also restituted. Indomethacin (prostacyclin inhibitor)-induced increase in capillary permeability (25%) was more than restituted by prostacyclin at 2 ng.kg-1.min-1. Surprisingly, bradykinin decreased capillary permeability. We conclude that endogenous prostacyclin may be a physiological regulator of capillary permeability and that low-dose prostacyclin infusion may have clinical relevance in states of increased permeability.

Animals↗
PubMed1995

Fibronectin attenuates increased endothelial monolayer permeability after RGD peptide, anti-alpha 5 beta 1, or TNF-alpha exposure.

Endothelial permeability can be altered by tumor necrosis factor-alpha (TNF-alpha), a cytokine released in association with inflammation-induced tissue injury. In the subendothelial matrix, fibronectin (Fn) influences endothelial cell adhesion by the interaction of integrins with RGD and non-RGD attachment sites in Fn. We compared the effect of TNF-alpha, RGD-containing peptides (GRGDSP), or antibody to alpha 5 beta 1-integrins on the protein permeability of bovine lung endothelial monolayers as assessed by transendothelial 125I-labeled albumin clearance. We also examined the influence of purified human plasma fibronectin (hFn) on this permeability response. TNF-alpha, RGD peptides, and antibodies to alpha 5 beta 1-integrins elicited a dose- and time-dependent increase in protein permeability as well as a reorganization and/or disruption of the endogenous Fn matrix. A control RGE peptide (GRGESP) as well as immunoglobulin G purified from nonimmune rabbit serum did not increase endothelial protein permeability or disrupt the endogenous fibrillar Fn pattern in the matrix. Likewise, a LDV peptide derived from the alternatively spliced type III connecting segment (IIICS) within bovine Fn (bFn) was unable to increase permeability of the bovine endothelial monolayer. Co-incubation of purified soluble hFn (300 or 600 micrograms/ml) with either TNF-alpha, the RGD peptide, or the antibody to alpha 5 beta 1-integrins prevented the increase in endothelial permeability. This protective effect was also observed when the purified hFn (600 micrograms/ml) was added after the TNF-alpha-induced increase in endothelial permeability had taken place. Immunofluorescent analysis confirmed the incorporation of the hFn into the subendothelial matrix and its co-localization with the endogenous bFn. The similar alteration of the subendothelial matrix after exposure to RGD peptides, anti-alpha 5 beta 1-antibodies, or TNF-alpha, coupled with the ability for hFn to attenuate the permeability increase typically elicited by all three agents, suggests that disruption of cell-matrix interactions may be the mechanism by which TNF-alpha alters endothelial permeability.

Animals↗
PubMed1989

Permeability of human endothelial monolayers: effect of vasoactive agonists and cAMP.

Permeability coefficients of human umbilical vein endothelial cell monolayers cultured on polycarbonate filters were determined by monitoring transendothelial albumin transport. Permeability was determined as a function of time in culture and in the presence of vasoactive agonists. Permeability decreased with increasing time in culture. All agonist experiments were performed with 15-day cultures because this time point best modeled the in vivo permeability barrier function. Permeability of endothelial monolayers decreased significantly in the presence of the stable prostacyclin analogue iloprost (6 nM), dibutyryl adenosine 3',5'-cyclic monophosphate (cAMP, 0.5 mM)-3-isobutyl-1-methylxanthine (IBMX, 0.1 mM), 8-bromo cAMP (0.5 mM)-IBMX, dibutyryl cAMP-theophylline (0.5 mM), or IBMX. A 9.6-fold increase in permeability resulting from thrombin [0.15 U/ml (1 nM)] treatment was inhibited by pretreating the monolayers with dibutyryl cAMP-IBMX, 8-bromo cAMP-IBMX, dibutyryl cAMP-theophylline, dibutyryl cAMP, IBMX, iloprost, or D-Phe-Pro-Arg-CH2-alpha-thrombin (1 nM). The thrombin-induced permeability increase was not significantly altered by pretreating monolayers with aspirin (5 microM) or indomethacin (50 microM). Inactivated forms of thrombin, diisopropylflurophosphate-alpha-thrombin (1 nM) and D-Phe-Pro-Arg-CH2-alpha-thrombin, did not significantly affect permeability. Monolayer permeability was not altered in response to bradykinin (1 microM). These results suggest a mediating role for intracellular cAMP in the permeability barrier function of endothelial monolayers.

Bradykinin↗