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PubMed2001

Hypercholesterolemia impairs myocardial perfusion and permeability: role of oxidative stress and endogenous scavenging activity.

OBJECTIVES: We intended to study the effect of hypercholesterolemia (HC) on myocardial perfusion and permeability response to increased cardiac demand. BACKGROUND: Hypercholesterolemia is associated with increased incidence of cardiac events and characterized by impaired coronary vascular function, possibly mediated partly through increased pro-oxidative conditions in plasma and tissue. However, it is yet unclear whether HC is also associated with impaired myocardial perfusion and vascular permeability responses in vivo. METHODS: For 12 weeks pigs were fed a normal, HC or HC diet supplemented daily with antioxidants (HC + AO, 100 IU/kg vitamin E and 1 g vitamin C). Myocardial perfusion and vascular permeability were measured in vivo using electron beam computed tomography before and after cardiac challenge with intravenous adenosine. Plasma and tissue oxidative status was determined ex vivo. RESULTS: Plasma cholesterol increased in all cholesterol-fed pigs but was associated with increased markers of oxidative stress only in HC pigs. Myocardial perfusion increased in response to adenosine in normal and HC + AO (+37 +/- 13% and +58 +/- 22%, respectively, p < 0.05 vs. baseline) but not in HC, whereas vascular permeability index increased only in HC pigs (+ 92 +/- 25%, p = 0.002). In HC animals, tissue endogenous oxygen radical scavengers and antioxidant vitamins were depleted and LDL oxidizability enhanced, but both were normalized in HC + AO pigs. Myocardial perfusion response was directly, and permeability inversely, associated with plasma and tissue vitamin concentrations. CONCLUSIONS: This study demonstrates that experimental HC is associated with blunted myocardial perfusion and increased vascular permeability responses in vivo to increased cardiac demand, which may be partly mediated by a shift in oxidative status.

Animals↗

PubMed1995

Inhibition of nitric oxide synthase attenuates primed microvascular permeability in the in vivo microcirculation.

PURPOSE: Changes in microvascular permeability play a critical role in the inflammatory sequence of tissue injury leading to leakage of proteins and subsequent edema. Primed responses induced by topical applications of platelet-activating factor (PAF) and histamine greatly increase microvascular permeability and mimic inflammation. We assessed the role of nitric oxide (NO) by use of 1-NG-monomethyl arginine (1-NMMA, a NO synthase inhibitor), on the primed microvascular permeability. We also explored the role of mast cells and a leukocyte adhesion complex by use of cromolyn sodium and 1B6 (a monoclonal antibody), respectively. METHODS: Forty anesthetized hamsters were separated into five groups: group 1 (n = 5) received no intervention; group 2 (n = 5) received topical 10(-9) mol/L PAF and 10(-6) mol/L histamine at a 5-minute interval; group 3 (n = 5 at each dose) received PAF/histamine and 1-NMMA (at 10(-5) mol/L or 10(-6) mol/L); group 4 (n = 5 at each dose) received cromolyn sodium plus PAF/histamine; group 5 (n = 5) received 1B6 plus PAF/histamine. We examined the cheek pouch with intravital videomicroscopy under fluorescent epiillumination. We quantified microvascular permeability to fluorescein isothiocyanate-dextran 150 with computer-assisted images analysis on the basis of integrated optical intensity (IOI) measurements. RESULTS: The mean (+/- SEM) IOI of the control group was 8.7 +/- 5.2, whereas the group primed with PAF and histamine was 62.4 +/- 10.8. The 1-NMMA (10(-5) mol/L and 10(-6) mol/L) abolished the changes in microvascular permeability (p < 0.05) yielding IOI values of 8.0 +/- 1.6 and 10.9 +/- 2.8, respectively. Cromolyn sodium and 1B6 did not significantly attenuate the primed response to PAF and histamine. CONCLUSION: Inhibition of NO synthase attenuates primed macromolecular extravasation in vivo. Our results indicate that NO is involved in the primed reaction of PAF and histamine, causing increases in microvascular permeability. Our study suggests a role for NO in the microcirculatory changes observed in ischemia-reperfusion injury and shock.

Animals↗

PubMed2003

Paracellular and passive transcellular permeability in immortalized human corneal epithelial cell culture model.

A cell culture model of human corneal epithelium (HCE-model) was recently introduced [Invest. Ophthalmol. Vis. Sci. 42 (2001) 2942] as a tool for ocular drug permeation studies. In this study, passive permeability and esterase activity of the HCE-model were characterised. Immortalised human corneal epithelial cells were grown on collagen coated filters under air-lift. The sensitivity of transcellular permeability to lipophilicity was tested in studies using nine beta-blockers. The size selectivity of the paracellular route was investigated using 16 polyethylene glycol oligomers (PEG). An effusion-like approach was used to estimate porosity and pore sizes of the paracellular space in HCE membrane. Permeability and degradation of fluorescein diacetate to fluorescein in HCE-cells was used to probe the esterase activity of the HCE-model. Drug concentrations were analyzed using HPLC (beta-blockers), LC-MS (PEGs), and fluorometry (fluorescein). Permeabilities were compared to those in the excised rabbit cornea. Penetration of beta-blockers increased with lipophilicity according to a sigmoidal relationship. This was almost similar to the profile in excised cornea. No apical to basolateral directionality was seen in the permeation of beta-blockers. Paracellular permeability of the HCE-model was generally slightly higher than that of the excised rabbit cornea. The HCE-model has larger paracellular pores, but lower pore density than the excised cornea, but the overall paracellular space was fairly similar in both models. The HCE-model shows significant esterase activity (i.e. fluorescein diacetate was converted to free fluorescein). These data on permeability of 27 compounds demonstrate that the barrier of the HCE-model closely resembles that of the excised rabbit cornea. Therefore, the HCE-model is a promising alternative corneal substitute for ocular drug delivery studies.

Adrenergic beta-Antagonists↗

PubMed1995

Evaluation of peritoneal membrane permeability.

Total removal of fluid and solutes during peritoneal dialysis depends on both the dialysis prescription (ie, the number, length, and timing of the dwells and the volume and contents of the dialysis solution) and the permeability of the peritoneal membrane. Peritoneal membrane permeability determines the rate of solute equilibration between body fluids and the solution within the peritoneal cavity and is, therefore, a significant determinant of the solute removal rate. The relationship between fluid removal during peritoneal dialysis and the properties of the peritoneal membrane is more complex; peritoneal ultrafiltration is inversely related to the permeability of the peritoneal membrane to osmotic solutes but is directly related to the hydraulic conductivity of the peritoneal membrane. The peritoneal equilibration test (PET) is widely used as the standard method for evaluating peritoneal membrane permeability, and results from the PET can be used to determine the type of peritoneal dialysis therapy optimal for the permeability characteristics of the patient's peritoneal membrane. Simple extrapolations from the PET can only provide qualitative estimates of the dialysis dose required for various types of peritoneal dialysis. More accurate estimates of the required dialysis dose can be provided by mathematical models of peritoneal fluid and solute transport, but these models require calculation of the permeability-area product or mass transfer-area coefficient of the peritoneal membrane. Although the latter approach shows promise for improving peritoneal dialysis prescriptions, determination of the delivered dose of peritoneal dialysis can, at present, only be assessed by directly measuring total 24-hour solute and fluid removal.

Evaluation Studies as Topic↗

PubMed1994

Demonstration of differences in vascular permeability in experimental tumors by use of 19F magnetic resonance imaging.

RATIONALE AND OBJECTIVES: In vivo assessment of tumor vascular permeability may provide useful information for chemotherapy treatment planning or for the assessment of treatment effectiveness. We aimed to assess vascular permeability in two tumor sublines as well as changes in vascular permeability with tumor growth by using 19F magnetic resonance imaging. METHODS: An emulsion of perfluorotributylamine was used as a tumor extravascular contrast agent for 19F MRI. The amount of emulsion that leaked into tumor interstitial space was analyzed qualitatively with imaging. A quantitative study of vascular permeability was done with a separate group of tumors by use of Evans blue dye. RESULTS: One tumor type was more permeable to both perfluorotributylamine emulsion and Evans blue than was the second tumor type. The difference was attributed to a difference in surface area for exchange. In larger tumors of both types, pooling of large amounts of perfluorocarbon occurred and was assumed to be attributable to hemorrhage or blood flow stasis or both. CONCLUSION: 19F MRI is capable of demonstrating the permeability of tumor vessels to macromolecular substances.

Adenocarcinoma↗

PubMedDate not supplied

Effect of Staphylococcus aureus bacteria and bacterial toxins on meningeal permeability in vitro.

BACKGROUND AND OBJECTIVES: Epidural catheterization is associated with a significant bacterial colonization rate and occasionally frank infection. During epidural space infection, decreased analgesia despite increased epidural opioid doses has been described. One possible explanation for this observation is that bacterial infection decreases meningeal permeability. The purpose of the study was to determine whether Staphylococcus aureus bacteria, the most common organism causing epidural space infection, or S. aureus toxins alter meningeal permeability. METHODS: Spinal meninges of M. nemestrina monkeys were mounted in a previously established in vitro diffusion cell model and exposed to S. aureus toxins A, B, and F. Simultaneous transmeningeal fluxes of mannitol and sufentanil were measured before and after toxin exposure and compared to controls. In a second series of experiments, diffusion cells were inoculated with live S. aureus bacteria in suspension and the permeability of sufentanil was investigated. RESULTS: Staphylococcus aureus toxin-A increased the transmeningeal flux of mannitol but not sufentanil. Toxins B and F did not alter the meningeal permeability of either drug. Inoculation with live S. aureus bacteria increased the transmeningeal flux of sufentanil by 115+/-21% (P = .032). CONCLUSIONS: These data demonstrate that S. aureus alpha-toxin and live S. aureus bacteria can increase meningeal permeability. Thus, clinical observations of decreased epidural analgesia in the face of bacterial infection cannot be explained by decreased meningeal permeability.

Animals↗

PubMed2002

Role of Ca2+ signaling in the regulation of endothelial permeability.

The vascular endothelial cell forms a semipermeable barrier between blood and interstitium. Inflammatory mediators such as thrombin and histamine induce vascular leakage defined as increased endothelial permeability to plasma proteins and other solutes. Increased endothelial permeability is the hallmark of inflammatory vascular edema. Inflammatory mediators that bind to heptahelical G protein-coupled receptors (GPCR) trigger increased endothelial permeability by increasing the intracellular Ca(2+) concentration ([Ca(2+)](i)). The rise in [Ca(2+)](i) activates key signaling pathways, which mediate cytoskeletal reorganization (through myosin light chain (MLC)-dependent contraction) and disassembly of VE-cadherin at the adherens junctions. The Ca(2+)-dependent protein kinase C (PKC) isoform, PKC-alpha, plays a critical role in initiating endothelial cell contraction and disassembly of VE-cadherin junctions. The increase in [Ca(2+)](i) induced by a variety of agonists is achieved by the generation of inositol 1,4,5-trisphosphate (IP3), activation of IP3 receptors (IP3R), release of stored intracellular Ca(2+), and Ca(2+) entry through plasma membrane channels. Recent findings demonstrate that IP3-sensitive Ca(2+) store depletion activates plasma membrane cation channels (i.e., store-operated cation channels (SOC) or Ca(2+) release activated channels) to cause Ca(2+) influx in endothelial cells. This mode of Ca(2+) influx is also known as capacitative Ca(2+) entry (CCE). Store-operated Ca(2+) influx signals increase in permeability and nitric oxide (NO) production and provokes changes in gene expression in endothelial cells. Recent studies have established that the Drosophila transient receptor potential (TRP) gene family of channels expressed in endothelial cells can function as SOC. Deletion of one of the TRP homologues, TRPC4, in mouse caused impairment in store-operated Ca(2+) current and Ca(2+) store release activated Ca(2+) influx in aortic and lung endothelial cells (LEC). In TRPC4 knockout (TRPC4(-/-)) mice, acetylcholine-induced endothelium-dependent smooth muscle relaxation was drastically reduced. In addition, TRPC4(-/-) mice LEC exhibited lack of actin stress fiber formation and cell retraction in response to thrombin activation of proteinase-activated receptor-1 (PAR-1) in endothelial cells. The increase in lung microvascular permeability in response to thrombin receptor activation was inhibited in TRPC4(-/-) mice. These results indicate that endothelial TRP channels such as TRPC1 and TRPC4 play an important role in signaling the increase in endothelial permeability.

Animals↗

PubMed2003

Histamine H3 receptors regulate vascular permeability changes in the skin of mast cell-deficient mice.

The participation of histamine H(3) receptors in the regulation of skin vascular permeability changes in mast cell-deficient mice was studied. Although intradermal injection of histamine H(3) antagonists, iodophenpropit and clobenpropit, at a dose of 100 nmol/site caused significant increases in skin vascular permeability in both mast cell-deficient (WBB6F1 W/W(v)) and wild-type (WBB6F1 +/+) mice, this response was significantly lower in mast cell-deficient mice than in the wild-type controls. Histamine also caused dose-related increases in skin vascular permeability in both wild-type and mast cell-deficient mice. Significant effects were observed at doses of 10 and 100 nmol/site, and no significant difference in skin vascular permeability was observed between mast cell-deficient and wild-type mice. However, histamine contents of dorsal skin in mast cell-deficient mice were significantly lower than in wild-type mice. In addition, the H(1) antagonists diphenhydramine and chlorpheniramine and the NK(1) antagonists, L-732,138 and L-733,060, were able to antagonize H(3) antagonist-induced skin vascular permeability. These results indicated that blockade of H(3) receptors by H(3) antagonists induce skin vascular permeability through mast cell-dependent mechanisms. In addition, histamine and, to a lesser extent substance P are involved in the reaction.

Animals↗

PubMed2003

Separation methods that are capable of revealing blood-brain barrier permeability.

The objective of this review is to emphasize the application of separation science in evaluating the blood-brain barrier (BBB) permeability to drugs and bioactive agents. Several techniques have been utilized to quantitate the BBB permeability. These methods can be classified into two major categories: in vitro or in vivo. The in vivo methods used include brain homogenization, cerebrospinal fluid (CSF) sampling, voltametry, autoradiography, nuclear magnetic resonance (NMR) spectroscopy, positron emission tomography (PET), intracerebral microdialysis, and brain uptake index (BUI) determination. The in vitro methods include tissue culture and immobilized artificial membrane (IAM) technology. Separation methods have always played an important role as adjunct methods to the methods outlined above for the quantitation of BBB permeability and have been utilized the most with brain homogenization, in situ brain perfusion, CSF sampling, intracerebral microdialysis, in vitro tissue culture and IAM chromatography. However, the literature published to date indicates that the separation method has been used the most in conjunction with intracerebral microdialysis and CSF sampling methods. The major advantages of microdialysis sampling in BBB permeability studies is the possibility of online separation and quantitation as well as the need for only a small sample volume for such an analysis. Separation methods are preferred over non-separation methods in BBB permeability evaluation for two main reasons. First, when the selectivity of a determination method is insufficient, interfering substances must be separated from the analyte of interest prior to determination. Secondly, when large number of analytes is to be detected and quantitated by a single analytical procedure, the mixture must be separated to each individual component prior to determination. Chiral separation in particular can be essential to evaluate the stereo-selective permeation and distribution of agents into the brain. In conclusion, the usefulness of separation methods during BBB permeability evaluation is immense and more application of these methods is foreseen in the future.

Blood-Brain Barrier↗

PubMed1976

Evidence for phase boundary lipid. Permeability of Tempo-choline into dimyristoylphosphatidylcholine vesicles at the phase transition.

The existence of distinct regions of mismatch in molecular packing at the interfaces of the fluid and ordered domains during the phase transition of dimyristoylphosphatidylcholine vesicles has been demonstrated by measuring the temperature dependence of the permeability to a spin-label cation and comparing this with a statistical mechanical calculation of the fraction of interfacial lipid. The kinetics of uptake and release of the 2,2,6,6-tetramethylpiperidinyl-1-oxycholine (Tempo-choline) spin label by single-bilayer dimyristoylphosphatidylcholine vesicles were measured using electron spin resonance spectroscopy to quantitate the amount of spin label present within the vesicles after removal of the external spin-label by ascorbate at 0 degrees C. Both the uptake and release experiments show that the Tempo-choline permeability peaks to a sharp maximum at the lipid-phase transition, the vesicles being almost impermeable to Tempo-choline below the transition and having a much reduced permeability above. The temperature profile of the permeability is in reasonable quantitative agreement with calculations of the fraction of interfacial boundary lipid from the Zimm and Bragg theory of cooperative transitions, which use independent spin-label measurements of the degree of transition to determine the cooperativity parameter. The relatively high intrinsic permeability of the interfacial regions (P approximately 0.2-1.0 X 10(-8) cm/s) is attributed to the mismatch in molecular packing of the lipid molecules at the ordered-fluid boundaries, which could have important implications not only for permeability in natural membranes (e.g., in transmitter release), but also for the function of membrane-bound enzymes and transport proteins.

Binding Sites↗

PubMed2001

Reduced outer membrane permeability of Escherichia coli O157:H7: suggested role of modified outer membrane porins and theoretical function in resistance to antimicrobial agents.

Outer membrane permeability of Escherichia coli O157:H7 was determined by an in vivo kinetic model with the periplasmic enzyme alkaline phosphatase [Martinez et al. (1996) Biochemistry 35, 1179-1186]. p-Nitrophenyl phosphate (PNPP) substrate, added to intact bacteria, must diffuse through the outer membrane to reach the enzyme. At low substrate concentration the bacterium was in the perfectly reactive state where all molecules that entered the periplasm were captured and converted to product. Transmembrane diffusion was rate limiting, and the permeability of the outer membrane was determined from kinetic properties. The O157:H7 strain grown at 30 degrees C showed one-sixth the permeability of wild-type E. coli grown at 30 degrees C. Wild-type bacteria grown at >/=37 degrees C show a physiological response with a shift in expression of outer membrane porins that lowered permeability to PNPP by approximately 70%. The O157:H7 strain did not display this temperature-sensitive shift in permeability even though a change in porin expression could be visualized by staining intensity of Omp F and Omp C on acrylamide gels. Altered behavior of the O157:H7 membrane was also indicated by a several thousand-fold lower response to transformation relative to wild-type E. coli. Matrix-assisted laser desorption ionization time of flight mass spectrometry and electrospray ionization mass spectrometry confirmed the expression of the Omp F and Omp C variants that are unique to E. coli O157:H7. This reduced outer membrane permeability can contribute to enhanced resistance of O157:H7 to antimicrobial agents.

Amino Acid Sequence↗

PubMed2006

Effect of interfacial permeability on droplet relaxation in biopolymer-based water-in-water emulsions.

In this paper, we show that for aqueous phase-separated biopolymer mixtures (water-in-water emulsions) both interfacial tension and permeability of the interface are important for the relaxation process of deformed droplets. We give an expression for the characteristic relaxation time that contains both contributions. With this description, the interfacial tension and the permeability can be deduced from cessation-of-flow experiments. The results show that for samples that are very close to the critical point the interfacial tension, calculated without taking into account the permeability, are overestimated significantly. For samples close to the critical point, the permeability has to be taken into account in the description for the relaxation time to get a reliable estimation of the interfacial tension. Our experiments show that for these systems the effective permeability is inversely proportional to the interfacial tension, lambda(eff) proportional, variant1/gamma, and proportional to the square of the interfacial thickness, lambda(eff) proportional, variant xi(2). We find that the permeability is related to an effective diffusion coefficient as D(eff) proportional, variant lambdagamma(eff). From this relation, we find that the diffusion coefficient is equal to 0.9.10(-9) m(2)/s, which is close to the self-diffusion coefficient of water; = 2.3.10(-9) m(2)/s. This indicates that only water diffuses through the interface, and the diffusion coefficient is independent of the composition of the system for the concentration regime that is used.

Animals↗

PubMed2001

An approach for estimating the permeability of agricultural films.

Plastic tarps currently used during soil fumigation to control emissions have been shown to be permeable to fumigant vapors, resulting in appreciable losses to the atmosphere. New low-permeability films are being developed to reduce fumigant emissions and increase efficacy. A rapid, reliable, and sensitive method is required to measure the permeability of various films that may be used in new management practices. This manuscript presents an approach for estimating the mass transfer coefficient (h) of fumigant compounds across agricultural films. The h is a measure of the resistance to diffusion which, unlike other measures of permeability, is a property of the film-chemical combination and independent of the concentration gradient across the film. This method uses static sealed cells; fumigant vapor is spiked to one side of the film and the concentrations on both sides of the film are monitored until equilibrium. An analytical model is fitted to the data to obtain h. This model relies on a mass balance approach and includes sorption to and diffusion across the film membrane. The method was tested using two polyethylene films and a very low-permeability film and showed that the method produces a sensitive and reproducible measure of film permeability.

Agriculture↗

PubMed1998

Synergistic effect of iontophoresis and a series of fatty acids on LHRH permeability through porcine skin.

The effect of chemical penetration enhancers (e.g., fatty acids) in combination with iontophoresis was examined on the in vitro permeability of luteinizing hormone releasing hormone (LHRH) through porcine skin. Porcine epidermis was pretreated with either ethanol (EtOH) or 10% fatty acid/EtOH. The permeability coefficient of LHRH was significantly (p < 0.05) greater through EtOH, lauric acid/EtOH, palmitic acid/EtOH, oleic acid/EtOH, linoleic acid/EtOH, and linolenic acid/EtOH treated epidermis than the control (untreated epidermis). Iontophoresis further enhanced the permeability of LHRH (p < 0.05) through enhancer-pretreated epidermis in comparison with corresponding passive permeability. Among saturated fatty acids tested, 10% palmitic acid/iontophoresis showed the highest permeability coefficient [(59.52 +/- 2.40) x 10(-4) cm/h], which was approximately 16-fold higher than that of the control [(3.57 +/- 0.41) x 10(-4) cm/h]. Unsaturated cis-octadecenoic acids were more effective penetration enhancers when compared with octadecanoic acid. Among cis-octadecenoic acids in combination with EtOH, the greater iontophoretic permeability coefficient [(59.18 +/- 12.43) x 10(-4) cm/h] was obtained through linolenic acid treated epidermis, which was significantly greater (p < 0.05) than through saturated octadecanoic acid treated epidermis [(29.08 +/- 3.18) x 10(-4) cm/h]. Also, pretreatment of epidermis with 5% linolenic acid/propylene glycol (PG) resulted in greater (p < 0.05) iontophoretic flux of LHRH in comparison to 5% linolenic acid/EtOH. Furthermore, increases in the degree of unsaturation in octadecenoic acids did not produce corresponding increases in the degree of enhancement. Reversibility studies revealed that the postrecovery passive flux of LHRH through 5% linolenic acid in combination with EtOH or PG/iontophoresis treated epidermis was significantly (p < 0.05) reduced than the prerecovery value but could not completely recover to the baseline flux (i.e., flux of LHRH through untreated epidermis).

Animals↗

PubMed1998

Effects of various protease inhibitors on the stability and permeability of [D-Ala2,D-Leu5]enkephalin in the rat intestine: comparison with leucine enkephalin.

The effects of various protease inhibitors on the stability of leucine enkephalin (Leu-Enk) and [D-Ala2,D-Leu5] enkephalin (DADLE) were investigated, and the permeability of these peptides was also examined in an in vitro Ussing chamber. Captopril, thiorphan, bacitracin, bestatin, puromycin, amastatin, and sodium glycocholate (Na-GC) were chosen as protease inhibitors. Regional differences in the stability of Leu-Enk and DADLE were observed, and the rank order of the stability of these peptides was colon > duodenum > ileum > jejunum. Na-GC, amastatin, and puromycin were effective protease inhibitors for improving the stability of these peptides, although captopril and thiorphan did not improve the stability of Leu-Enk. In the transport studies, Leu-Enk did not cross the intestinal membrane in the absence of protease inhibitors, but its transport was improved in the presence of Na-GC. In addition, Na-GC, amastatin, and puromycin improved the permeability of DADLE in both jejunum and colon, while the permeability of DADLE was not improved by the addition of captopril, thiorphan, and bestatin. Furthermore, the permeability of 6-carboxyfluorescein, a poorly absorbable and stable compound, was also improved in the presence of Na-GC and bacitracin at a concentration of 10 mM. These findings indicated that amastatin, puromycin, and Na-GC at a concentration of 0.5 mM might increase the permeability of DADLE due to the improved stability of DADLE in the donor site. However, Na-GC and bacitracin at a concentration of 10 mM had absorption-enhancing activities which might be also related to the enhanced permeability of DADLE across the intestinal membrane.

Animals↗

PubMed2000

Bradykinin and alpha-thrombin increase human umbilical vein endothelial macromolecular permeability by different mechanisms.

Bradykinin and alpha-thrombin both increase endothelial macromolecular permeability, however the mechanism for this effect is unclear. Human umbilical vein endothelial cell (HUVEC) permeability to human serum albumin was increased by 1 microM alpha-thrombin (AT) or bradykinin (BK), but the kinetics of the permeability response were different. Intracellular calcium mobilization of HUVEC by AT was increased, yet BK had no effect on intracellular calcium. Distribution of F-actin and content was increased by AT as early as 10 minutes after administration, yet BK had no affect on F-actin when compared to control. We hypothesized that BK may increase HUVEC permeability by producing matrix metalloproteinase-2 (MMP-2). The AT-treated HUVEC produced an intermediate 64 kDa MMP-2, whereas BK-treated HUVEC increased the intermediate 64 kDa MMP-2 and also an active 62 kDa MMP-2. Pre-treatment of the HUVEC with tissue inhibitor of matrix metalloproteinase-2 slightly decreased the AT-induced increase in macromolecular permeability and completely inhibited the BK-induced increase in macromolecular permeability.

Actins↗

PubMed2000

Ionic permeability of the frog sciatic nerve perineurium: parallel studies of potassium and lanthanum penetration using electrophysiological and electron microscopic techniques.

The isolated sciatic nerve of the frog Rana temporaria was used for a parallel electrophysiological and electron microscopic examination of the ionic permeability of the perineurium, one component of the blood-nerve barrier. Nerves mounted in a grease-gap chamber for electrophysiological recording showed negligible changes in DC potential (Delta DC) or compound action potential on challenge with 100 mM K(+) Ringer, evidence that the perineurium was tight to K(+). In preparations then fixed and exposed to 5 mM lanthanum in the fixative, and examined in the electron microscope, electron-dense lanthanum deposits were seen between perineurial lamellae, but lanthanum was not detectable within the endoneurium, confirming that the perineurium was also tight to lanthanum. Absence of lanthanum penetration was confirmed by X-ray analysis of electron microscopic sections. In nerves exposed to 2 mM sodium deoxycholate (DOC) in the recording chamber, then challenged with high [K(+)], a moderate increase in perineurial K(+) permeability (P(K)) was observed, but lanthanum was still excluded. Exposure of nerves to 4 mM DOC caused a greater increase in perineurial potassium permeability, and the two nerves with the greatest permeability (P(K) > 1 x 10(-5) cm x sec(-1)) also showed detectable lanthanum within the endoneurium. The results indicate that DOC causes a dose-dependent increase in tight junctional permeability in the perineurium, and that the electrophysiological monitoring of K(+) penetration is a more sensitive measure of small ion permeability than electron microscopical analysis using lanthanum as tracer. Vesicular profiles observed in perineurial lamellae did not form open channels for ion flux across the perineurium in control nerves, or in those exposed to DOC. In preparations where lanthanum reached the endoneurium, lanthanum was observed in dense deposits in the extracellular spaces around nodes of Ranvier, and in the outer mesaxon cleft, but did not penetrate the internodal periaxonal space, the myelin intraperiod line, or the Schmidt-Lanterman incisures, in contrast to observations in mammalian nerves. The apparent differences in accessibility of the internodal periaxonal space in frog and mammalian axons are discussed in relation to axonal physiology. The study illustrates the value of parallel electrophysiological and electron microscopic examination in elucidating the properties of extracellular ionic pathways and their role in neural function.

Animals↗

PubMed1998

Human drug absorption kinetics and comparison to Caco-2 monolayer permeabilities.

PURPOSE: This study aims to assess the drug absorption kinetics of three drugs and compare their resulting first-order intestinal permeation rate constants to their Caco-2 monolayer permeabilities. METHODS: In vitro dissolution--in vivo absorption analysis was conducted on four formulations of each ranitidine HCl, metoprolol tartrate, and piroxicam to yield apparent and "true" human clinical permeation rate constants. Drug permeability coefficients through Caco-2 monolayers were also determined. RESULTS: In vitro dissolution--in vivo absorption analysis revealed different relative and absolute contributions of dissolution and intestinal permeation to overall drug absorption kinetics for various drug formulations and yielded estimates of each drug's true and apparent human intestinal permeation rate constant [kp = 0.225 hr-1, 0.609 hr-1, and 9.00 hr-1 for ranitidine, metoprolol, and piroxicam, respectively]. A rank order relationship was observed for both the apparent and true permeation rate constant with Caco-2 monolayer permeability. The decrease in the true permeation rate constant relative to the apparent permeation rate constant was most significant (almost three-fold) for the least permeable compound, ranitidine. CONCLUSIONS: There were marked differences in the permeation kinetics of ranitidine, metoprolol, and piroxicam. The possibility of an association between absorption kinetics from dosage forms in humans and Caco-2 monolayer permeability may allow for a direct kinetic interpretation of human oral absorption from Caco-2 monolayer permeability values.

Anti-Inflammatory Agents, Non-Steroidal↗