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At least 271 records · Page 15Linked to original sources
PubMed2001

Pretreatment with potent P-glycoprotein ligands may increase intestinal secretion in rats.

The expression of P-glycoprotein is induced in cell cultures upon exposure to various inducers. Therefore, the aim of the present study was to evaluate the in-vivo relevance of this observation, i.e. the influence of chronic pretreatments with selected drugs -- all of which are ligands to P-glycoprotein (P-gp) as demonstrated in radioligand binding studies and all of which have some or a considerable effect on P-gp expression in Caco-2 cells -- on the effective intestinal permeabilities of the model compound talinolol in rats employing in-situ single-pass intestinal perfusion of three different gut segments. Talinolol was selected, because it shows high selectivity for one of the exsorptive transporters (P-gp) and its intestinal permeability is very sensitive to changes in exsorption when the perfusate concentration is low. Prior to the induction study the perfusion model was optimized regarding the type and concentration of a competitive inhibitor which may be used to block the exsorption-related permeability reduction (through intestinal exsorption) during an ongoing perfusion and would permit an intra-individual comparison of the effective permeability without and with blockade of exsorption. While repetitive verapamil and talinolol dosing had no statistically significant exsorption-inducing effect, vinblastine and rifampicin pretreatments resulted in decreased intestinal talinolol permeabilities in the three tested gut segments, duodenum, jejunum, and colon [e.g., S-talinolol in jejunum: control, 2.50 x 10(-4) cm/s; vinblastine induction, 1.48 x 10(-4) cm/s (P<0.05); rifampicin induction, 1.51 x 10(-4) cm/s (P<0.05)]. Addition of an efficient secretion inhibitor (vinblastine) to the perfusate permitted the determination of the impact of inhibitable secretory processes on the total effective permeabilities and an estimation of passive permeability in the respective individual. The inhibitable permeability fractions were higher for vinblastine than for any other pretreatment and the difference from control pretreatment was statistically significant for all intestinal segments (duodenum, 61.8%; jejunum, 63.1%; colon, 43,7%; S-talinolol). Statistically significant differences were also detected for rifampicin in the perfused duodenum and jejunum (33.1 and 27.5% increase in inhibitable fraction, respectively, for S-talinolol). These differences are explained by a significant induction of outside-directed transport in the intestinal enterocytes by vinblastine and rifampicin.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

Involvement of multidrug resistance-associated protein 2 in intestinal secretion of grepafloxacin in rats.

We investigated the contribution of multidrug resistance-associated protein 2 (MRP2) to the secretory transport of grepafloxacin and compared its functional role with that of P-glycoprotein (P-gp) by using Sprague-Dawley rats (SDRs) and Eisai hyperbilirubinemic rats (EHBRs), in which MRP2 is hereditarily defective. In intestinal tissue from SDRs mounted in Ussing chambers, the level of transport in the direction from the serosal layer to the mucosal layer was twofold greater than that in the direction from the mucosal layer to the serosal layer. This secretory transport of grepafloxacin was diminished by both probenecid, an MRP2 inhibitor, and cyclosporine, a P-gp inhibitor. In intestinal tissue from EHBRs, the secretory transport of grepafloxacin was lower than that in intestinal tissue from SDRs and was inhibited by cyclosporine but not by probenecid. The absorption of grepafloxacin from intestinal loops in SDRs was in the order of duodenum > jejunum > ileum and was increased by cyclosporine but not by probenecid. The absorption in EHBRs was not higher than that in SDRs. The intestinal secretory clearance in SDRs after intravenous administration of grepafloxacin was shown to be greater for the ileum than for the duodenum, which is in good agreement with the previously reported regional expression profile of MRP2 mRNA. The intestinal secretory clearance was lower in EHBRs than in SDRs. Accordingly, in addition to P-gp, MRP2 might play a role in the secretory transport of grepafloxacin. The function of MRP2 in facilitating grepafloxacin transport in the secretory direction is more pronounced both in vitro and in vivo, while the restriction of entry from the lumen into the cell by MRP2 seems to be negligible, compared with that by P-gp, in the case of grepafloxacin.

Animals↗
PubMed1992

Intestinal secretion after jejunal bypass in the ground squirrel.

The preceding paper [H. V. Carey, Am. J. Physiol. 263 (Regulatory Integrative Comp. Physiol. 32): R1202-R1208, 1992] demonstrated that a 3-day fast or the extended fast of hibernation enhanced the chloride secretory responses to a variety of agonists in the ground squirrel jejunum. Here we examined the effect of jejunal bypass on intestinal secretory capacity in squirrels that either remained active and continued to feed (ACT), or were induced to hibernate (HIB). Mucosal wet weights were reduced in jejunal segments that had little or no exposure to the luminal stream (all segments from HIB and bypassed segments from ACT) compared with segments in contact with luminal contents (sham and in continuity segments of ACT). Tissue conductances were greater in those segments not exposed to luminal contents. Short-circuit current (Isc) responses to electrical stimulation of submucosal neurons, or to serosal carbachol, were greater in segments not exposed to luminal contents when responses were normalized to serosal surface area. Normalization of secretory responses to crypt area produced a similar pattern. Isc responses to mucosal alanine, which reflect electrogenic Na+ absorption, were greatest in segments with little or no exposure to luminal contents. Tissue wet weights, conductances and secretory responses of bypassed segments of HIB and ACT squirrels were always similar. These results suggest that luminal contents directly influence jejunal secretory capacity.

Alanine↗
PubMed1991

New model for analysis of mucosal immunity: intestinal secretion of specific monoclonal immunoglobulin A from hybridoma tumors protects against Vibrio cholerae infection.

Secretory immunoglobulin A (sIgA) plays a role in defense against Vibrio cholerae and other microorganisms that infect mucosal surfaces, but it is not established whether sIgA alone can prevent disease. We report here a strategy for identifying the antigen specificities of monoclonal sIgA antibodies that are capable of providing such protection. IgA hybridomas were generated from Peyer's patch lymphocytes after oral immunization with V. cholerae Ogawa 395. A clone was selected that produced dimeric monoclonal IgA antibodies directed against an Ogawa-specific lipopolysaccharide carbohydrate antigen exposed on the bacterial surface. Hybridoma cells were used to produce subcutaneous "backpack" tumors in syngeneic mice, resulting in secretion of monoclonal sIgA onto mucosal surfaces. Neonatal mice bearing anti-lipopolysaccharide hybridoma backpack tumors were specifically protected against oral challenge with 100 50% lethal doses of virulent Ogawa 395 organisms. Thus, the IgA hybridoma backpack tumor method identifies protective epitopes in the mucosal system and demonstrates that a single monoclonal sIgA can be sufficient to protect against intestinal disease.

Animals↗
PubMed1997

Platelet-activating factor contributes to immune cell and oxidant-mediated intestinal secretion.

The sensitivity of the Ussing-chambered rat colon to stimulation of Cl- secretion (as measured by the change in short-circuit current) by exogenous platelet-activating factor (PAF) was increased significantly by washing the colon in vitro with Ringer's solution containing fatty acid-free albumin. When the wash solution was extracted with chloroform/methanol and the lipid extract was added back to Ussing-chambered colons, inhibition of PAF-stimulated short-circuit current was observed, whereas short-circuit current responses to bradykinin or vasoactive intestinal peptide were not affected. Hypoxia appears to be an important trigger for the down-regulation of the PAF response. These data suggest that hypoxia releases PAF or an endogenous lipid PAF inhibitor that desensitizes PAF receptors on colonic epithelial or mucosal cells. The short-circuit current response of rabbit colon to the chemotactic peptide formyl-methionyl-leucyl-phenylalanine was not inhibited by any PAF antagonist devoid of cyclooxygenase inhibitory activity but was strongly inhibited by indomethacin. In contrast, anti-IgE- or H2O2-stimulated short-circuit current in rat colon was inhibited by specific PAF antagonists, and this inhibition was additive with indomethacin. Both anti-IgE and H2O2 significantly increased PAF production by rat colon. These data suggest that PAF plays an important role in oxidant (H2O2)- and anti-IgE-mediated colonic Cl- secretion but not in Cl- secretion mediated by formyl-methionyl-leucyl-phenylalanine-stimulated phagocytes.

Animals↗
PubMed1981

Loperamide reduces the intestinal secretion but not the mucosal cAMP accumulation induced by choleratoxin.

The effect of loperamide on net fluid transport and epithelial cAMP accumulation was tested in choleratoxin-exposed ligated colon loops of the rat in vivo. Purified choleratoxin (50 micrograms/ml saline, for 5 h) induced net secretion and doubled cAMP levels in comparison with saline-treated controls. Loperamide (4 mg/kg intragastrically) reduced this secretion by 75%, without diminishing cAMP accumulation; it had no effect on basal fluid transport or cAMP. The data suggest that the opiate analogue interferes with the secretory process at a point beyond the cAMP increase caused by activation of adenylate cyclase.

Animals↗
PubMed1999

The sodium concentration of enteral diets does not influence absorption of nutrients but induces intestinal secretion of water in miniature pigs.

Contradictory opinions exist as to whether the sodium concentration of enteral diets influences absorption of macronutrients and transepithelial movement of sodium and water. Therefore, we investigated the effects of various sodium concentrations of enteral diets on absorption of macronutrients and on net fluxes of sodium and water. In unanesthetized miniature pigs, a 150-cm jejunal segment was perfused with an oligopeptide (Peptisorb), an oligomeric and a polymeric diet. The polymeric diet was supplemented with pancreatic enzymes. The sodium concentrations varied between 30 and 150 mmol/L. The energy density was 3.4 MJ/L. The sodium concentration of the diets did not influence absorption of macronutrients and of total energy. However, increasing sodium concentrations of the diets were associated with increasing osmolality of the solutions, resulting in a linear increase in net secretion of water and flow rate of chyme. With all diets and sodium concentrations net secretion of sodium occurred. The sodium secretion was independent of the initial sodium concentration of the diets. It was linearly correlated with net flux of water and was largest in miniature pigs infused with the oligomeric diet. The sodium concentration of the jejunal effluent did not correspond to the initial sodium concentration of the diets. The present results indicate that enteral feeding of diets with high energy density inevitably increases net secretion of water and sodium as sodium concentration increases. Therefore, the sodium concentration of diets should be as low as possible to meet only the minimal daily requirement of sodium. Low sodium concentrations of diets have no negative effects on absorption of macronutrients.

Animals↗
PubMed2001

delta-opioid receptors inhibit neurogenic intestinal secretion evoked by mast cell degranulation and type I hypersensitivity.

Histamine and the mast cell degranulator, compound 48/80 produced elevations in short-circuit current, an electrical measure of active anion secretion, across porcine ileal mucosa sheets mounted in Ussing chambers. Luminally-applied beta-lactoglobulin produced similar effects in mucosal sheets from cow's milk-sensitized pigs. Their secretory effects were attenuated by blockers of H(1)-histamine receptors, neuronal conduction or epithelial Na(+)/K(+)/Cl(-) cotransport. The delta-opioid agonist [D-Pen(2), D-Pen(5)]enkephalin suppressed mucosal responses to these substances in a naltrindole-reversible manner. Furthermore, submucosal mast cells and delta-opioid receptor-immunoreactive nerve fibers were observed in close juxtaposition. Intestinal neural pathways linking immediate hypersensitivity to secretory host defense appear to express inhibitory delta-opioid receptors.

Animals↗
PubMed1999

In vitro analysis of the role of DCC in mucus-secreting intestinal differentiation.

The deleted in colorectal cancer (DCC) gene was initially described as a colon cancer-associated tumor suppressor gene and subsequently proposed to be involved in goblet cell differentiation, but its precise role in normal intestine physiology and in cancer remains to be established. We have analyzed DCC mRNA expression in a panel of human colorectal cancer cell lines with a variety of differentiation phenotypes by reverse transcription-polymerase chain reaction (RT-PCR) and have shown that (1) most cell lines showed lower levels of DCC mRNA than normal colonic tissue; (2) only 1 cell line lacked detectable levels of DCC mRNA expression; (3) a discrepancy was found between the detectability of RT-PCR products corresponding to the extracellular and intracellular domains of DCC; and (4) there was no association between the presence of DCC transcripts and the differentiation phenotype. Specifically, DCC was not exclusively associated with the mucus-secreting phenotype, as determined by Alcian blue staining and Northern blotting with mucin gene probes. This was further supported by immunohistochemical results on DCC product and mucins in normal colon: DCC was detected in both goblet and absorptive cells. The introduction of full-length DCC cDNA in undifferentiated HT-29 cells did not have any effect on their differentiation phenotype, as shown by morphological studies and analysis of markers for this process in colon, such as mucins, dipeptidylpeptidase IV, villin and sucrase-isomaltase. There were no effects on cell proliferation in vitro. Our results indicate that DCC is not selectively involved in the mucosecretory differentiation pathway and that it is neither sufficient nor essential for normal intestinal differentiation.

Cell Adhesion Molecules↗
PubMed1994

NG-nitro-L-arginine methyl ester modulates intestinal secretion and motility produced by carbachol.

The effects of the nitric oxide (NO) synthesis inhibitor, NG-nitro-L-arginine methyl ester, on carbachol-induced diarrhoea, fluid accumulation and motility changes were studied. Pretreatment of mice with NG-nitro-L-arginine methyl ester (1-25 mg/kg i.p.) and NG-nitro-L-arginine (2.5-50 mg/kg i.p.) but not NG-nitro-D-arginine methyl ester (25 mg/kg i.p.) prevented in a dose-related manner the carbachol (0.5 mg/kg i.p.)-induced diarrhoea in mice. L-Arginine (150-1500 mg/kg i.p.) administered to mice pretreated with NG-nitro-L-arginine methyl ester counteracted the antidiarrhoeal activity of NG-nitro-L-arginine methyl ester in a dose-related manner. Pretreatment of rats with NG-nitro-L-arginine methyl ester (2.5-25 mg/kg i.p.) decreased the intestinal fluid accumulation induced by carbachol in rats. NG-Nitro-D-arginine methyl ester was without effect. Intraperitoneal pretreatment of rats with NG-nitro-L-arginine methyl ester (2.5-25 mg/kg) reduced the increase in small intestinal transit induced by carbachol. NG-nitro-L-arginine methyl ester had no effect. These results provide evidence that nitric oxide may play a role in diarrhoea, intraluminal fluid accumulation and motility changes induced by carbachol.

Amino Acid Oxidoreductases↗
PubMed1982

Effect of berberine on intestinal secretion mediated by Escherichia coli heat-stable enterotoxin in jejunum of pigs.

Intraluminal perfusion with Escherichia coli heat-stable enterotoxin (ST) reversed water and electrolyte movements from net absorption to net secretion in porcine jejunal segments. Addition of berberine hydrochloride (3.2 X 10(-5) M) to the perfusate reduced the jejunal secretory response of water, sodium, potassium, and chloride to ST and enhanced water and electrolyte absorption in control segments. At lower concentrations (1.1 X 10(-5) M), berberine reduced the secretory response in ST-exposed segments, but only the decrease of sodium flux was significant. In the presence of berberine, the mucosal enzyme activities of adenosine triphosphatase and disaccharidases were not significantly different between control and ST-exposed segments. Doses of 1, 2, 3, 4, 5, and 10 mg of berberine were injected into ligated loops of proximal part of the jejunum with 1 ml of ST filtrate. At doses of 2 or more mg/loop, berberine was effective in reducing water and electrolyte secretions induced by ST; the effect was dose-dependent. These findings indicate that berberine may be an effective antidiarrheal agent in E coli heat-stable enterotoxin mediated secretory diarrhea and provide a basis for the frequent empirical use of berberine alkaloid and berberine-containing plants in gastroenteritis and infectious diarrhea in Asian and other countries.

Animals↗
PubMed1983

Entamoeba histolytica causes intestinal secretion: role of serotonin.

Lysates of the protozoan parasite Entamoeba histolytica altered active electrolyte transport when present on the serosal surface of rabbit ileum and rat colon. The lysate-induced effects on electrolyte transport were similar to those caused by serotonin, and were blocked by bufotenine, an analog known to inhibit the action of serotonin. The transport effects were partially inhibited by antibody to serotonin. The amebic lysates were shown to contain serotonin by radioimmunoassay, high-performance liquid chromatography, and thin-layer chromatography. These results suggest that the serotonin present in Entamoeba histolytica may be important in the diarrhea seen in amebiasis.

Amebiasis↗