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PubMed2003

Prediction of corneal permeability using artificial neural networks.

The purpose of this study was to develop a simple model for prediction of corneal permeability of structurally different drugs as a function of calculated molecular descriptors using artificial neural networks. A set of 45 compounds with experimentally derived values of corneal permeability (log C) was used to develop, test and validate a predictive model. Each compound was encoded with 1194 calculated molecular structure descriptors. A genetic algorithm was used to select a subset of descriptors that best describe corneal permeability coefficient log C and a supervised network with radial basis transfer function (RBF) was used to correlate calculated molecular descriptors with experimentally derived measures of corneal permeability. The best model, with 4 input descriptors and 12 hidden neurones was chosen, and the significance of the selected descriptors to corneal permeability was examined. Strong correlation of predicted with experimentally derived log C values (correlation coefficient greater than 0.87 and 0.83 respectively) was obtained for the training and testing data sets. The developed model could be useful for the rapid prediction of the corneal permeability of candidate drugs based on molecular structure alone as it does not require experimentally derived data.

Chemical Phenomena↗

PubMedDate not supplied

A comparison of gastrointestinal permeability induced by diclofenac-phospholipid complex with diclofenac acid and its sodium salt.

PURPOSE: Gastrointestinal (GI) side effects of the nonsteroidal anti-inflammatory drug (NSAID) diclofenac may be reduced if it is administered as a complex with phospholipid. The upper and lower GI permeability induced by a diclofenac-dipalmitoyl phosphatidyl choline (DPPC) complex were compared with those of diclofenac acid and its sodium salt in rats. METHODS: Pharmacokinetic studies were carried out to assess bioavailability of diclofenac preparations. Adult male Sprague-Dawley rats were dosed orally (equivalent to 15 mg/kg diclofenac sodium) as the acid or its sodium salt as well as diclofenac-DPPC complex. Upper and lower GI permeability, as surrogate markers of toxicity were determined using sucrose and 51Cr-EDTA, respectively. RESULTS: At 1 h post-dose only diclofenac sodium induced a significant increased upper GI permeability. Three h post-dose all formulations significantly increased upper GI permeability although the diclofenac acid had the least effect. In the lower GI tract, the induced increase in permeability was significant at 1 and 3 h post-dose for all formulations with no significant differences between them. CONCLUSION: The induced upper and lower GI toxicity of diclofenac was formulation and time dependent. The lack of effect of diclofenac acid was due to the decreased availability of the drug. In the upper GI tract, up to 1 h post-dose, the diclofenac-DPPC complex demonstrated reduced upper gastroduodenal permeability as measured by sucrose. However, the protective effect of DPPC did not last and was not extended to the lower GI tract due to the systemic effect, contribution from the enterohepatic recirculation and/or dissociation of the complex. In assessing diclofenac GI toxicity, the effect of the different formulations on the entire GI tract at various times after drug administration must be considered.

Animals↗

PubMed2004

[Intestinal permeability in patients with viral and alcoholic liver disease].

BACKGROUND/AIMS: Increased intestinal permeability has been possible contributing factors to the pathogenesis of alcoholic liver disease. Moreover, it can contribute to the development of bacterial infection and intestinal endotoxemia in patients with liver cirrhosis. This study aimed to examine the difference of intestinal barrier dysfunction between alcoholic and viral liver disease patients through the comparison of the intestinal permeabilities of patients with clinical characteristics. METHODS: Intestinal permeabilities were measured in 18 healthy controls, 41 patients with alcoholic liver disease (17 cases of alcoholic liver disease without cirrhosis and 24 cases of alcoholic liver cirrhosis) and 46 patients with viral liver disease (14 cases of chronic viral hepatitis and 32 cases of viral liver cirrhosis) by measuring 24 hour urine excretion of 51Cr-EDTA. RESULTS: The intestinal permeability was significantly increased in the patients with alcoholic liver disease without cirrhosis (5.62 +/- 2.80%), alcoholic liver cirrhosis (5.29 +/- 2.48%) and viral liver cirrhosis (3.15 +/- 1.39%) compared with that in control subjects (1.99 +/- 0.53%). On the contrary, it was not increased in the patients with chronic viral hepatitis (2.05 +/- 0.57%) versus controls. The significant correlation was not found between intestinal permeability and clinical and laboratory findings. CONCLUSIONS: The intestinal permeability was elevated in patients with alcoholic liver disease compared to those with viral liver cirrhosis. The pathophysiology of liver injury secondary to intestinal epithelial damage may be different between alcoholic and viral liver diseases.

Aged↗

PubMed1992

IEC-18, a nontransformed small intestinal cell line for studying epithelial permeability.

Small intestinal epithelium is leaky and allows permeation of hydrophilic molecules of various sizes. Passively absorbed hydrophilic permeability probes have been shown to permeate across intestinal epithelium mainly through the paracellular pathways. In this study we introduce microporous filter-grown IEC-18 epithelial cells, a nontransformed small intestinal cell line, as a in vitro model of intestinal epithelium for the study of epithelial permeability. IEC-18 cells, originally derived from native rat ileal crypts, form confluent epithelium when grown on hydrated collagen-coated Millicell-CM permeable inserts (Millipore Corp., Bedford, Mass.). With scanning and transmission electron microscopy, the presence of tight junctions and desmosomes between cells and the development of microvilli at the apical surface were confirmed. Immunofluorescent labeling of ZO-1 proteins and desmoplakins verified the presence of tight-junctional proteins (ZO-1) and desmosomes in the intercellular junctions of confluent IEC-18 epithelium. The net electrical resistance of IEC-18 epithelium (28 omega-cm2) was similar to resistance values obtained from small intestinal tissue with (50 to 100 omega-cm2) or without (20 to 45 omega-cm2) muscularis and serosal layers. Assessment of mannitol and dextran permeation revealed early "maturation" of paracellular pathway, with increasing restriction of permeation to both probes through day 4. Resistance across IEC-18 epithelium also reached plateau levels between 4 and 7 days. Permeability studies with various probes indicate that cross-sectional diameter rather than molecular weight of the probe is the important determinant of permeation rate. IEC-18 epithelium selectively restricted the permeation of probes proportional to probe size; permeation of larger probes such as albumin was negligible. We conclude that cultured IEC-18 epithelial cells, because of their native crypt origin, similarity in resistance to small intestinal epithelia, retention of ability to differentiate into villus-like enterocytes, and permeability characteristics, are a useful model of intestinal epithelium for the study of permeability and paracellular transport.

Animals↗

PubMed2004

Effect of thrombin on blood brain barrier permeability and its mechanism.

BACKGROUND: Previous studies have indicated that thrombin (TM) may play a major role in brain edema after intracerebral hemorrhages (ICHs). However, the mechanism of TM-induced brain edema is poorly understood. In this study, we explored the effect of TM on the permeability of the blood brain barrier (BBB) and investigated its possible mechanism, aiming at providing a potential target for brain edema therapy after ICHs. METHODS: TM or TM + cathepsin G (CATG) was stereotaxically injected into the right caudate nucleus of Sprague-Dawley rats in vivo. BBB permeability was measured by Evans-Blue extravasation. Brain water content was determined by the dry-wet weight method. Brain microvascular endothelial cells were then cultured in vitro. After TM or TM + CATG was added to the endothelial cell medium, changes in the morphology of cells were dynamically observed by phase-contrast light microscopy, and the expression of matrix metalloproteinase-2 (MMP-2) protein was measured by immunohistochemical method. RESULTS: BBB permeability increased at 6 hours after a TM injection into the ipsilateral caudate nucleus (P < 0.05), peaked between 24 hours (P < 0.01) and 48 hours (P < 0.05) after the injection, and then declined. Brain water content changed in parallel with the changes in BBB permeability. However, at all time points, BBB permeability and brain water content after a TM + CATG injection were not significantly different from the respective parameters in the control group (P > 0.05). TM induced endothelial cell contraction in vitro in a time-dependent manner and enhanced the expression of MMP-2 protein. After incubation with TM + CATG, cell morphology and MMP-2 expression did not change significantly as compared to the control group (P > 0.05). CONCLUSIONS: Increased BBB permeability may be one of the mechanisms behind TM-induced cerebral edema. TM induces endothelial cell contraction and promotes MMP-2 expression by activating protease activated receptor-1 (PAR-1), possibly leading to the opening of the BBB.

Animals↗

PubMed2004

Intestinal permeability assessment before and after ileal pouch-anal anastomosis.

AIM: Intestinal permeability is considered an index of anatomic and functional integrity of the small intestine mucosa. Altered intestinal permeability has been suggested to be a possible cause of pouchitis. Aim of this paper was to assess variations in intestinal permeability during the first year of a pouch reconstruction. METHODS: Intestinal permeability (IP) was investigated in 8 ulcerative colitis patients before and after total proctocolectomy, with ileal pouch-anal anastomosis (IPAA), by means of the cellobiose/mannitol test. To each patient a basal test (before surgery) and 3 more tests during a 1 year follow-up were administered. RESULTS: Individual data were altered despite clinical findings in 9 of 30 IP measured values. An overall pattern of unaffected permeability was however shown and none of our patients, during the first year follow-up, has developed pouchitis. CONCLUSIONS: Six of the 8 investigated patients presented at least 1 altered IP value. A longer follow-up aimed to further investigate patients beyond the first year after IPAA confection as to the occurrence of pouchitis and its possible correlation with a previous permeability alteration of the pouch mucosa is in progress.

Administration, Oral↗

PubMed1979

RNA synthesis in permeable mouse ascites sarcoma cells.

A permeable cell system for studying RNA synthesis was established. Mouse ascites sarcoma cells were made permeable to nucleoside triphosphates and alpha-amanitin by treating with a hypotonic buffer. Separate determinations of endogenous RNA polymerase I, II and III activities in permeable cells were conducted using the different sensitivities of these enzymes to alpha-amanitin. The endogenous activity of RNA polymerase II under optimal conditions was one tenth of total RNA synthetic activity in isolated nuclei, and one third of that in permeable cells. The extremely low ratio of RNA polymerase II activity to total RNA synthetic activity in isolated nuclei was thought to be caused by increase of RNA polymerase I activity and decrease of RNA polymerase II activity. These and other results suggested that RNA synthesis in permeable cells reflects more precisely the in vivo state of RNA synthesis than thatin isolated nuclei. The permeable cell system will provide a useful method for studying the separate activities of RNA polymerases I, II and III in situ.

Amanitins↗

PubMed1992

[Changes in pulmonary epithelial permeability due to thoracic irradiation].

The changes in pulmonary epithelial permeability during and following radiation therapy were studied in 10 patients with malignant diseases of the chest; 9 patients with bronchogenic carcinoma and one with thymoma. 99mTc-DTPA aerosol was inhaled during tidal breathing with the patient in supine position, and radioactivity was measured anteriorly by a gamma camera and recorded on a computer. Half time clearance (t1/2) was calculated from exponential fitting of time activity curves by regression analysis in various regions of interest in the initial 7 min following completion of aerosol inhalation. Studies were made every two weeks. In patients who developed radiation pneumonitis, t1/2 values decreased and reached the nadir at the time of manifest pneumonitis, indicating increased pulmonary epithelial permeability. Increased pulmonary epithelial permeability was observed not only in the pneumonic regions but also in the contralateral normal lung regions. Steroid therapy reversed these changes. Increased pulmonary epithelial permeability was observed in 2 out of 5 patients who did not develop radiation pneumonitis. In summary, pulmonary epithelial permeability changes occur not only in regions of radiation pneumonitis but also in non-irradiated lung regions following radiation therapy. We consider that the judicious use of this method enables detection of changes in pulmonary epithelial permeability prior to the development of clinical manifestations of radiation pneumonitis.

Aerosols↗

PubMed2006

[Calciumdependent mechanisms in vasopressin regulation of osmotic water permeability in the mouse kidney collecting duct cells].

In the study, the role of PKC and Ca++ in vasopressin regulation of the plasma membrane water permeability was studied in the cells of the mouse kidney collecting duct. Coefficient of osmotic water permeability of total cell surface (Pf) was calculated from the initial rate of cell swelling following the osmotic shock caused by changing the medium osmolarity from isotonic to hypotonic (300 mOsm to 200 mOsm). Desmopressin (dDAVP 1 nM) increased the Pf in hydrated mice from 168.4 +/- 11.8 microm/s up to 231.3 +/- 14.7 microm/s. The Ca++ chelator BAPTA prevented the desmopressin-induced increase in water permeability. Inhibition of PKC (Ro-31-8220 0.1 microM) also abolished the desmopressin-stimulated increase of plasma membrane water permeability, whereas inhibitor of PKC alone did not suppress the stimulation of the water permeability by db-cAMP. The PKC activity and calciumdependent second messengers seem to be important for regulation of water permeability by vasopressin.

Animals↗

PubMed2006

Comparative permeability of fresh and frozen/thawed porcine buccal mucosa towards various chemical markers.

Sometimes it is not feasible or convenient to use tissue samples immediately and they are then stored at -85 degrees C after being snap-frozen in liquid N2. Previous studies have shown that, although snap-freezing in liquid N2 does not alter the permeability properties of human buccal and vaginal mucosae towards various markers significantly, some tissue damage does occur. Slight increases in the permeability properties of the frozen/thawed human buccal mucosa towards markers were found, although these were not statistically significant. The damage does, however, not seem to affect the lipid permeability barrier to a meaningful extent. Because porcine buccal mucosa is a popular choice as a substitute for human buccal mucosa in many permeability studies, it was decided to evaluate the effect that snap-freezing, storage and thawing would have on the permeability of this mucosa when compared to human mucosae. Fresh and frozen/thawed buccal mucosa specimens were collected from freshly slaughtered pigs and permeability experiments at 20 degrees C and 1.5 ml/h, over a 24 hour time period, performed using a flow-through diffusion apparatus. The permeants tested were water, arecoline, vasopressin and 17beta-estradiol. Statistically significant differences were obtained between the flux values at steady state for water, arecoline and vasopressin through fresh and frozen/thawed porcine buccal mucosa. The estimated mean steady state flux values for 17beta-estradiol showed no statistically significant differences between the fresh appear to indicate that the lipid barrier of porcine buccal mucosa is not as resistant to snap-freezing, storage and thawing procedures as that of human mucosal tissue.

Animals↗

PubMed1990

Alteration of epithelial paracellular permeability during corneal epithelial wound healing.

We studied the paracellular permeability to mannitol of corneas with epithelium of corneal, limbal, or conjunctival origin. Corneas with epithelial defects reepithelialized by corneal or limbal epithelium were nonvascularized; the corneal permeability was initially increased and returned to normal 3 days later. When epithelial defects extended beyond the limbus, they were healed by conjunctival epithelium. If corneas remained avascular or minimally vascularized, the conjunctiva-derived epithelium underwent a transdifferentiation process into a cornealike morphology in which the corneal permeability was initially increased upon complete reepithelialization, and gradually decreased to a level similar to that of normal cornea, 4 weeks after healing. However, when corneas became vascularized, the conjunctiva-derived epithelium retained its original phenotype, and corneal permeability remained increased throughout the 8-month period of study. The deranged barrier functions noted in the above vascularized cornea were demonstrated further by horseradish peroxidase tracer, which was found in the intercellular spaces of conjunctiva-derived epithelium of vascularized corneas but not in the avascular corneas with epithelia of corneal or limbal origin, or transdifferentiated conjunctival epithelium. To study further the effect of subsequent ocular surface trauma, conjunctival biopsy was performed on transdifferentiated avascular corneas 3 months after initial wounding. The biopsy resulted in extensive vascularization in three of eight previously nonvascularized corneas. Two weeks later, the corneal permeability was increased to a level similar to that of conjunctiva. These results indicate that corneal epithelial paracellular permeability correlates well with the status of the epithelial phenotype.

Animals↗

PubMed1990

Permeability alteration of the sarcolemmal membrane, particularly at the site of macrophage contact, in experimental chronic Trypanosoma cruzi myocarditis in mice.

Sarcolemmal membrane permeability characteristics have been investigated, particularly at the site of macrophage contact, in experimental chronic Trypanosoma cruzi myocarditis in BALB/c mice, employing ruthenium red (RR) as an electron tracer. The ultrastructural features of the myocardium from infected animals were similar to those previously described. Briefly, focal myocarditis was detected, with areas of myocytolytic necrosis, atrophic myofibres, an inflammatory response composed of mononuclear cells, predominantly macrophages and a few lymphocytes, and interstitial fibrosis. This study provided the following new information: (I) the cytoplasmic components of mononuclear cells have a very high affinity for RR. It is conceivable that mononuclear cell activation parallels a physiological change in plasma membrane permeability; (2) RR diffusely strains the sarcoplasm of cardiocytes with anomalous contraction bands, indicating leaky sarcolemmal membranes; (3) most non-degenerating cardiocytes from experimental animals appear darker with RR staining than controls. They also frequently show rows of RR-stained sub-plasmalemmal tiny vesicles. Both changes probably reflect increased membrane permeability; (4) RR intensely labels the cytoplasmic components of cardiocytes at the site of macrophage contact or close apposition, indicating areas of altered membrane with remarkably increased permeability. This observation provides insight into a role for the macrophages in myocardial cell damage in experimental chronic Trypanosoma cruzi myocarditis. An obvious consequence of increased membrane permeability is that it may cause impairment of the transmembrane ion gradients and cause loss of intracellular elements, thus contributing to cardiocyte death. Furthermore, the findings in the present study imply that one of the consequences of macrophage-mediated cytotoxicity may be alteration in the permeability of the plasma membranes of nearby target cells, possibly due to a change in the structural integrity of the membrane resulting from peroxidation of cell membrane lipids.

Animals↗

PubMed1991

Intestinal mucosal permeability in inflammatory rheumatic diseases. II. Role of disease.

Gut permeability as measured by the 51Cr-EDTA resorption test was determined in 56 patients with rheumatoid arthritis (RA), 73 patients with spondyloarthropathies (SpA), 18 patients with inflammatory bowel disease (IBD) and 97 controls (42 patients with no inflammatory rheumatic diseases and 55 healthy controls). Gut permeability was found to be increased in the 3 patient groups, partially due to the intake of antiinflammatory drugs. When only patients not taking these drugs were considered, an increased gut permeability was found in patients with SpA and IBD. In patients with RA gut permeability could not be evaluated as they were all taking antiinflammatory medication. Ileocolonoscopy with biopsies of the gut was performed in 62 of the 73 patients with SpA and disclosed subclinical gut inflammation in 21. No difference in gut permeability was found between patients with or without gut inflammation. However, when the type of gut inflammation was considered, a significant increase of gut permeability was found in patients with chronic gut inflammation compared with patients presenting acute lesions. Our findings again suggest that the chronic gut inflammation seen in SpA is fundamentally different from acute gut inflammation and possibly related to the gut inflammation of IBD.

Adult↗

PubMed1990

Cholestasis, altered junctional permeability, and inverse changes in sinusoidal and biliary glutathione release by vasopressin and epinephrine.

The mechanism for the vasopressin- and epinephrine-induced decrease in bile formation and increase in sinusoidal efflux of glutathione was investigated in rat livers perfused with recirculating fluorocarbon emulsion. Vasopressin and epinephrine transiently decreased bile flow and excretion of endogenous bile acids and glutathione and increased the bile/perfusate ratio of [14C]sucrose, suggesting an increase in junctional permeability, but had no effect on the bile/perfusate ratio of [3H]polyethylene glycol-900. The decreased biliary glutathione was balanced by an increase in sinusoidal efflux, such that total hepatic release remained unchanged. The adrenergic antagonist dihydroergotamine blocked the effects of epinephrine. To examine whether an increase in junctional permeability per se could account for the changes in glutathione efflux, biliary permeability was increased by either bile duct ligation, lowering of perfusate Ca2+ concentration with ethylene glycol bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA), or addition of taurolithocholate, a cholestatic bile acid. All three maneuvers produced a decrease in biliary glutathione excretion and a concomitant increase in sinusoidal glutathione efflux, whereas total glutathione release was largely unaffected. The effects of EGTA were partially reversed if CaCl2 was reintroduced into the perfusate. Because the GSH/GSSG ratio in perfusate could not be measured in this experimental system due to the spontaneous oxidation of GSH to GSSG, additional experiments in the nonrecirculating mode examined the effects of vasopressin and bile duct ligation on sinusoidal release of GSH and GSSG. In control livers there was no detectable GSSG in perfusate (less than 0.5 nmol.min-1.g-1). After vasopressin administration, the additional sinusoidal glutathione was mainly as GSH, although there was also a significant amount of GSSG (1-2 nmol.min-1.g-1). The additional glutathione released into perfusate after bile duct ligation was 47% as GSSG. When vasopressin was administered to livers whose bile duct had been ligated, its ability to enhance sinusoidal glutathione release was diminished, suggesting that the effects of vasopressin and bile duct ligation are not additive. These observations support previous findings that vasopressin and epinephrine can modulate hepatocyte tight junctional permeability and demonstrate that these hormones produce cholestasis and inverse changes in sinusoidal and biliary glutathione efflux. Other maneuvers that increased biliary permeability to [14C]sucrose also produced cholestasis and a redistribution of glutathione efflux from bile to perfusate, suggesting that an increase in junctional permeability may allow biliary glutathione to reflux from bile to plasma.

Animals↗

PubMed1990

Resistance of essential fatty acid-deficient rats to endotoxin-induced increases in vascular permeability.

Resistance to endotoxin in essential fatty acid-deficient (EFAD) rats is associated with reduced synthesis of certain arachidonic acid metabolites. It was hypothesized that EFAD rats would manifest decreased vascular permeability changes during endotoxemia as a consequence of reduced arachidonic acid metabolism. To test this hypothesis, changes in hematocrit (HCT) and mesenteric localization rate of technetium-labeled human serum albumin (99mTc-HSA) and red blood cells (99mTc-RBC) were assessed in EFAD and normal rats using gamma-camera imaging. Thirty minutes after Salmonella enteritidis endotoxin, EFAD rats exhibited less hemoconcentration as determined by % HCT than normal rats (47 +/- 2% vs. 54 +/- 1% respectively, P less than 0.01). Endotoxin caused a less severe change in permeability index in the splanchnic region in EFAD rats than in normal rats (1.2 +/- 0.6 x 10(-3)min-1 vs. 4.9 +/- 1.7 x 10(-3)min-1 respectively, P less than 0.05). In contrast to 99mTc-HSA, mesenteric localization of 99mTc-RBC was not changed by endotoxin in control or EFAD rats. Supplementation with ethyl-arachidonic acid did not enhance susceptibility of EFAD rats to endotoxin-induced splanchnic permeability to 99mTc-HSA. Leukotrienes have been implicated as mediators of increased vascular permeability in endotoxin shock. Since LTC3 formation has been reported to be increased in EFA deficiency, we hypothesized that LTC3 may be less potent than LTC4. Thus the effect of LTC3 on mean arterial pressure and permeability was compared to LTC4 in normal rats. LTC3-induced increases in peak mean arterial pressure were less than LTC4 at 10 micrograms/kg (39 +/- 5 mm Hg vs. 58 +/- 4 mm Hg respectively, P less than 0.05) and at 20 micrograms/kg (56 +/- 4 mm Hg vs. 75 +/- 2 mm Hg respectively, P less than 0.05). LY171883 (30 mg/kg), an LTD4/E4 receptor antagonist, attenuated the pressor effect of LTC4, LTD4, and LTC3. Infusion of LTC4 (4 micrograms/kg/min) in normal rats induced a rise in HCT from 44 +/- 1% to 51 +/- 1% (P less than 0.01), which was greater (P less than 0.05) than the rise induced by LTC3 (47 +/- 1% to 49 +/- 1%). The results showing that EFAD rats are resistant to endotoxin-induced increases in HCT and vascular permeability raise the possibility that this may, in part, be a result of preferential LTC3 production that is less potent than LTC4.

Animals↗

PubMed1989

[Capillary permeability factor produced by C 6 glioma cells: role in peritumoral brain edema and possible mechanism of glucocorticoid action].

We studied whether C6 glioma cells produce a diffusible factor that increases capillary permeability of rat brains. Culture supernatant after 4 hours' incubation of C6 glioma cells in serum-free medium was obtained (SUP-N). SUP-N was concentrated 80-fold by dialysis-concentration (MW cut off was 10 kd) (SUP-C). These two supernatant fractions were tested for capillary permeability activity by their infusion into normal rat brains (right caudate-putamen). Control materials (MEM or concentrated MEM) were also infused into the left caudate-putamen as well as supernatants. Capillary permeability was measured by a quantitative autoradiographic method with 14C-aminoisobutyric acid (AIB) and expressed as an unidirectional blood-to-brain transfer constant (K). Effects of infusates were quantitatively estimated by two parameters, i.e., the highest K value (Kmax) (microliter/g/min) and the spatial extent (D1/2) (mm). The protein concentration of SUP-N and SUP-C was 15 and 950 micrograms/ml, respectively. SUP-N showed a slight increase of capillary permeability, particularly, around the needle track (infusion site) in the brain, but it was not significantly different from the control on the value of Kmax. On the other hand, SUP-C markedly increased capillary permeability (Kmax; SUP-C: 10.83 +/- 0.99, control: 2.53 +/- 0.22, p less than .001) and the effect was much more extensive than that of SUP-N (D1/2; SUP-C: 2.23 +/- 0.26, SUP-N: 0.83 +/- 0.07). A factor in SUP-C increased capillary permeability after a lag phase of 1.5 hours reaching the maximum after 6 hours of infusion, and 24 hours later the effect declined to 30% of Kmax at 6 hours.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1988

IL-1 and IFN-gamma increase vascular permeability.

We examined the effect of cytokines on vascular permeability in vivo. Wistar rats received intradermal injections of various cytokine preparations and the permeability index (delta PI) was calculated from the difference between the absorption values of cytokine- and vehicle-treated skin sections after the extraction of accumulated Evans blue vital dye. Injections of a mixture of recombinant interleukin-1 alpha and beta (Il-1 alpha, IL-1 beta) and interferon-gamma (IFN-gamma) caused a maximal increase of permeability after 30 min (delta PI = 2). The administration of single recombinant cytokines revealed that the increase of permeability is mainly due to the action of IL-1 beta (delta PI = 1.4) and IFN-gamma (delta PI = 2.9) (P less than 0.001) at doses of 1-20 microU per injection site. IL-1 alpha slightly increased vascular permeability, whereas recombinant IL-2 and recombinant tumour necrosis factor alpha had no significant effects. Histological observations revealed significantly increased numbers of degranulated mast cells in skin sections pretreated with IL-1 beta (P less than 0.005) or IFN-gamma (P less than 0.001). The cytokine-mediated rise of vascular permeability could be suppressed by pretreatment of the animals with the vasoactive amine antagonizing drugs methysergide, pizotifen and cyproheptadine. Our experiments indicate an important role of IL-1 beta and IFN-gamma as vasoactive substances besides their function as hormone-like messengers between leucocytes.

Animals↗

PubMed1988

Effect of parathyroid and antidiuretic hormone on water and calcium permeability in the rat collecting duct.

Because the rat papilla has parathyroid hormone (PTH)-sensitive adenylate cyclase and because of indirect evidence that PTH may alter collecting duct water and also calcium transport, the effects of PTH on rat papillary collecting duct water and calcium transport have been studied. PTH in concentrations of 50 and 500 ng/ml significantly increased diffusional water permeability by 20 and 38%, respectively, while 5,000 ng/ml had no additional effect. This permeability response was small when compared to a 78% increase in water permeability with a maximal (0.5 ng/ml) concentration of antidiuretic hormone (ADH). The normal increase in water permeability with ADH was depressed in the presence of PTH (500 ng/ml) but was overcome when the ADH concentration was increased from 0.5 to 5 ng/ml. Neither PTH nor ADH altered the permeability of the collecting duct to calcium which was low (0.19 +/- 0.03 micron/s). Increasing either the bath or perfusate calcium concentration from 1 to 5 mM did not alter calcium permeability. These studies suggest that PTH acts as a partial agonist to ADH within the papillary collecting duct and that PTH is unlikely to have a major role in collecting duct calcium transport.

Animals↗