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PubMed1991

Localization of sodium absorption and chloride secretion in an intestinal epithelium.

Hen coprodeum absorbs sodium electrogenically and, when stimulated by theophylline, secretes chloride. In this study the vibrating microprobe technique was used to localize the transport of these ions to intestinal villi/folds and crypts. With the isolated, stretched epithelium, controlled by light microscopy and scanning electron microscopy, in open circuit, currents were inward, 40 +/- 7 microA/cm2, 50 microns vertically above villi, and outward, 36 +/- 7 microA/cm2 above crypts. The currents decayed exponentially to near zero at 300 microns with the same length constant. A physical model simulating the observed loci of current sources and sinks predicts potential profiles consistent with our data. Extrapolation of the currents gives a surface potential of 45 microV, negative on villi and positive above crypts. Short circuiting increased villus current to 86 +/- 27 microA/cm2 at 50 microns, and amiloride treatment reduced it to -8 microA/cm2; in both cases crypt currents were abolished. The inward currents are compatible with sodium absorption. Induction of chloride secretion after amiloride treatment, resulted in current circuits similar to those induced by sodium absorption, with villus currents of 23 +/- 7 microA/cm2. This is in accord with chloride secretion at the villi. Quantitative estimates of crypt number (860/cm2) and opening diameter (15 microns), in conjunction with isotopic measurements of active and electrical potential-driven ion fluxes demonstrate, however, that only 4% of the potential-driven co-ion transport occurs through the crypts. This indicates that nearly all chloride secretion comes from the sodium-absorbing villar area. Were the chloride secretion to occur solely from the crypts, the current should have been in the opposite direction and 10,000-fold larger.

Amiloride↗
PubMed2000

Properties and actions of heat-stable enterotoxin of Escherichia coli.

The heat-stable enterotoxins (STs) produced by enterotoxigenic Escherichia coli are classified into two groups, methanol-soluble (STI) and methanol-insoluble (STII) enterotoxins. These are distinct toxins with unique properties. Their features in common include heat-stability, low molecular weight, secretion from the bacteria, and ability to induce fluid secretion from the intestine. STI is an 18- or 19-amino acid extracellular peptide with three intramolecular disulfide bonds, which is produced by proteolytic cleavage of 72 amino acid precursor. The STI in the lumen of the intestine binds to specific protein receptors (guanylate cyclase C) located in the brush border membrane and leads to elevation of intracellular cyclic GMP level. Several factors involved in the activation of guanylate cyclase by STI have been identified. Elevation of cyclic GMP level induces intestinal fluid secretion by stimulation of chloride secretion. Cystic fibrosis transmembrane conductance regulator, which is a chloride channel, might be involved in chloride secretion. In contrast, STII is a 48-amino acid peptide with two intramolecular disulfide bonds, which results from 71 amino acid precursor. Compared with STI, the steps that lead to intestinal fluid secretion by STII are not well established. It has been proposed that sulfatide in the brush border is a receptor for STII and that the STII bound to the receptor opens GTP-binding regulatory protein-linked calcium channels. These actions of STII induce not only stimulation of the production of secretagogues such as prostaglandin E2 and serotonin, but also activation of the calcium-calmodulin-dependent protein kinase II in the cells.

Animals↗
PubMed2004

Bacteroides fragilis enterotoxin induces intestinal epithelial cell secretion of interleukin-8 through mitogen-activated protein kinases and a tyrosine kinase-regulated nuclear factor-kappaB pathway.

Enterotoxigenic Bacteroides fragilis (ETBF) secretes a 20-kDa metalloprotease toxin termed B. fragilis toxin (BFT). ETBF disease in animals is associated with an acute inflammatory response in the intestinal mucosa, and lethal hemorrhagic colitis may occur in rabbits. In this study, we confirmed recent reports (J. M. Kim, Y. K. Oh, Y. J. Kim, H. B. Oh, and Y. J. Cho, Clin. Exp. Immunol. 123:421-427, 2001; L. Sanfilippo, C. K. Li, R. Seth, T. J. Balwin, M. J. Menozzi, and Y. R. Mahida, Clin. Exp. Immunol. 119:456-463, 2000) that purified BFT stimulates interleukin-8 (IL-8) secretion by human intestinal epithelial cells (HT29/C1 cells) and demonstrate that stimulation of IL-8 production is dependent on biologically active BFT and independent of serum. Induction of IL-8 mRNA expression occurs rapidly and ceases by 6 h after BFT treatment, whereas IL-8 secretion continues to increase for at least 18 h. Our data suggest that BFT-stimulated IL-8 secretion involves tyrosine kinase-dependent activation of nuclear factor-kappaB (NF-kappaB) as well as activation of the mitogen-activated protein kinases (MAPKs), p38 and extracellular signal-related kinase. Simultaneous activation of NF-kappaB and MAPKs appears necessary for secretion of IL-8 by HT29/C1 cells treated with BFT.

Bacteroides fragilis↗
PubMed2006

Inhibition of intestinal motility and secretion by extracts of Epilobium spp. in mice.

Ethanol extracts of the fresh aerial parts of various Epilobium species were tested to elucidate the mechanism of their gastrointestinal activity in animals. The methods of charcoal meal, castor oil-induced diarrhoea, and enteropooling assay were used to evaluate their effect on mouse gut at various dose levels. The extracts were found to have a significant activity in all models. Moreover, the extracts resulted to possess very little toxicity. Thus, it can be concluded that Epilobium possesses anti-diarrhoeal, anti-motility, and anti-secretory activities and can prove beneficial in the treatment of gastrointestinal disorders.

Animals↗
PubMed1989

Pituitary vasoactive intestinal peptide regulates prolactin secretion in the hypothyroid rat.

In this study, we demonstrated that the cell content and basal secretion of vasoactive intestinal peptide (VIP) in primary rat pituitary cell cultures were increased in hypothyroidism. VIP release from hypothyroid pituitary cells in vitro was stimulated by thyrotropin releasing hormone (TRH 10(-8) to 10(-6) M) and growth hormone (GH)-releasing hormone (GHRH 10(-9) to 10(-8) M) but not by corticotropin-releasing hormone or luteinizing hormone-releasing hormone in concentrations up to 10(-6) M. In the presence of anti-VIP antisera, there was a significant decrease in basal prolactin secretion from cultured hypothyroid pituitary cells (p less than 0.005) indicating that VIP exerts a tonic stimulatory effect on prolactin (PRL) secretion. The increment in PRL secretion following TRH was not affected by exposure to anti-VIP indicating that PRL release after TRH is not mediated by VIP at the pituitary level. In contrast to changes in PRL, exposure to anti-VIP had no effect on basal GH secretion, indicating that the PRL changes are hormone specific. Similarly, GHRH-induced GH release was unaffected by VIP immunoneutralization.

Animals↗
PubMed1993

Insulin-like growth factor binding protein profile secreted by human intestinal epithelial cells varies with polarity.

The actions of insulin-like growth factors (IGFs) are modulated by interaction with a family of secreted binding proteins (IGFBPs). We have now demonstrated in intestinal epithelial cells (Caco-2) that the secretion of different members of this family depends on the cell surface secreting them. Polarized monolayers of cells secreted IGFBP-3 mainly into the medium adjacent to the apical surface, while IGFBP-2 was secreted predominantly through the basolateral surface. The secretion of IGFBP-1 and -4 was equivalent from both surfaces. However, administration of epidermal growth factor (EGF) induced polarized secretion of IGFBP-4 by increasing secretion from the apical surface more than from the basolateral aspect. It did not affect the polarity of the other IGFBPs. We believe that this is the first evidence that epithelial cells can interact with extrinsic agents in a polarized fashion at sites other than the membrane surface.

Adenocarcinoma↗
PubMed1998

P-glycoprotein transporters and the gastrointestinal tract: evaluation of the potential in vivo relevance of in vitro data employing talinolol as model compound.

Among the different application routes peroral administration remains the one most widely used. Hence, mechanisms affecting p.o. bioavailability are of particular interest, also in drug development. In recent years, intestinal drug secretion mediated by the multi-drug resistance gene product P-glycoprotein (Pgp) has been discovered as a possible mechanism of low and erratic bioavailability. Due to the saturability of this process, a dose-dependent apparent oral clearance may be observed which decreases upon increasing dose. However, in vivo intestinal secretion might be revealed only in the lower or subtherapeutic dose range. In permeability studies with Caco-2 cell monolayers, the MDR-reversing agent verapamil inhibits secretion of P-glycoprotein substrates and, hence, increases apical-to-basolateral permeability. The aim of the rat studies with talinolol presented here was to test the relevance of the intestinal secretion process as well as the extent of inhibition by verapamil in ex vivo, in situ, and in vivo talinolol/verapamil drug-drug interaction studies. Intestinal secretion of talinolol was detected indirectly in ex vivo studies via transport inhibition with verapamil and directly in in situ intestinal perfusions in rats following a talinolol i.v. bolus. Both i.v. and p.o. verapamil appear to affect the concentration-time profiles of talinolol. Relevant observations with respect to drug absorption are the decreased apparent oral clearance upon verapamil coadministration as well as the decreased tmax and mean absorption times at high verapamil doses. Talinolol may be regarded as a potential model compound for mechanistic studies on Pgp interactions, including permeability as well as binding studies and the involvement of transporters other than Pgp.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

Mucus secretion from single submucosal glands of pig. Stimulation by carbachol and vasoactive intestinal peptide.

Secretion rates of >700 individual glands in isolated tracheal mucosa from 56 adult pigs were monitored optically. "Basal" secretion of 0.7 +/- 0.1 nl x min(-1) gland(-1) was observed 1-9 h post-harvest but was near zero on day 2. Secretion to carbachol (10 microm) peaked at 2-3 min and then declined to a sustained phase. Peak secretion was 12.4 +/- 1.1 nl x min(-1) gland(-1); sustained secretion was approximately one-third of peak secretion. Thapsigargin (1 microm) increased secretion from 0.1 +/- 0.05 to 0.7 +/- 0.2 nl x min(-1) gland(-1); thapsigargin did not cause contraction of the trachealis muscles. Isoproterenol and phenylephrine (10 microm each) were ineffective, but vasoactive intestinal peptide (1 microm) and forskolin (10 microm) each produced sustained secretion of 1.0 +/- 0.5 and 1.7 +/- 0.2 nl x min(-1) gland(-1), respectively. The density of actively secreting glands was 1.3/mm(2). Secretion to either carbachol or forskolin was inhibited (approximately 50%) by either bumetanide or HCO(3)(-) removal and inhibited approximately 90% by the combined treatments. Mucus secreted in response to carbachol or forskolin was acidic by approximately 0.2 pH units relative to the bath and remained acidic by approximately 0.1 pH units after bumetanide. The strong secretory response to vasoactive intestinal peptide, the acidity of [cAMP](i)-stimulated mucus, and its inhibition by bumetanide were unexpected.

Animals↗
PubMed2002

Insulin-like growth factor-binding protein-5 (IGFBP-5) stimulates growth and IGF-I secretion in human intestinal smooth muscle by Ras-dependent activation of p38 MAP kinase and Erk1/2 pathways.

Insulin-like growth factor-binding protein-5 (IGFBP-5) and insulin-like growth factor-I (IGF-I) are produced by human intestinal smooth muscle cells. Endogenous IGF-I stimulates growth and increases IGFBP-5 secretion. IGFBP-5 augments the effects of IGF-I by facilitating interaction of IGF-I with the IGF-I receptor tyrosine kinase. Andress (Andress, D. L. (1998) Am. J. Physiol. 274, E744-E750) and Berfield et al. (Berfield, A. K., Andress, D. L., and Abrass, C. K. (2000) Kidney Int. 57, 1991-2003) have shown that in osteoblasts and kidney mesangial cells, IGFBP-5 stimulates proliferation and filopodia formation independently of IGF-I, presumably by activating a distinct IGFBP-5 receptor serine kinase. The present study determined whether IGFBP-5 exerts direct effects on growth in human intestinal smooth muscle cells and identified the intracellular signaling pathways involved. IGFBP-5 caused a concentration-dependent increase in [(3)H]thymidine incorporation and an increase in IGF-I secretion that occurred independently of IGF-I and the IGF-I receptor tyrosine kinase. IGFBP-5-induced phosphorylation of p38 MAP kinase, which was abolished by SB203580, or expression of a dominant negative Ras mutant, Ras(S17N), and phosphorylation of Erk1/2, which was abolished by a Raf1 kinase inhibitor, U1026, or expression of Ras(S17N). IGFBP-5-stimulated [(3)H]thymidine incorporation and IGF-I secretion were partly inhibited by SB203580 or U1026 and abolished by the combination of the two inhibitors or by expression of Ras(S17N). These data show that IGFBP-5 stimulates growth and IGF-I secretion in human intestinal smooth muscle cells by activation of p38 MAP kinase-dependent and Erk1/2-dependent pathways that are independent of IGF-I. A positive feedback mechanism therefore links IGFBP-5 and IGF-I secretion that reinforces their individual effects on growth.

Cell Division↗
PubMed2005

Intestinal assembly and secretion of highly dense/lipid-poor apolipoprotein B48-containing lipoprotein particles in the fasting state: evidence for induction by insulin resistance and exogenous fatty acids.

Emerging evidence suggests that overproduction of intestinally derived apolipoprotein (apo) B48-containing lipoprotein particles may be an important contributor to both fasting and postprandial dyslipidemia in insulin-resistant states. Mechanisms regulating the assembly and secretion of apoB48-containing lipoproteins are not fully understood particularly in the diabetic/insulin-resistant intestine. In the present study, we have investigated the density profile of apoB48 lipoproteins assembled in primary hamster enterocytes. Both intracellular and secreted apoB48 particles were examined in intestinal enterocytes isolated from normal or insulin-resistant fructose-fed hamsters, as well as in enterocytes treated with exogenous oleic acid. Microsomal luminal contents and culture media were analyzed by discontinuous and sequential ultracentrifugation on sucrose and KBr gradients, respectively. ApoB48 was mostly secreted on VLDL-, LDL-, and denser HDL-sized particles in the fasting state. In pulse-chase labeling experiments, nascent apoB48-containing particles initially accumulated in the microsomal lumen as HDL-sized particles, with subsequent formation of apoB48-VLDL particles, with only a minute amount of chylomicrons observed. Treatment with 720 mu mol/L of oleic acid, increased microsomal apoB48 HDL synthesis, and induced a marked shift toward lighter more buoyant particles. A marked enhancement in assembly of apoB48-containing lipoproteins was also observed in the microsomal lumen of fructose-fed hamster enterocytes, suggesting facilitated assembly and secretion of dense intestinal lipoprotein particles in insulin-resistant states. Overall, these observations suggest that a major proportion of apoB48-containing lipoprotein particles is assembled and secreted as highly dense, HDL-sized particles. The production of these small, dense, and potentially atherogenic apoB48 particles can be stimulated by increased free fatty acid flux as well as in insulin-resistant diabetes.

Animals↗
PubMed1997

Fluoroquinolone (ciprofloxacin) secretion by human intestinal epithelial (Caco-2) cells.

1. Human intestinal epithelial Caco-2 cells were used to investigate the mechanistic basis of transepithelial secretion of the fluoroquinolone antibiotic ciprofloxacin. 2. Net secretion and cellular uptake of ciprofloxacin (at 0.1 mM) were not subject to competitive inhibition by sulphate, thiosulphate, oxalate, succinate and para-amino hippurate, probenecid (10 mM), taurocholate (100 microM) or bromosulphophthalein (100 microM). Similarly tetraethylammonium and N-'methylnicotinamide (10 mM) were without effect. 3. Net secretion of ciprofloxacin was inhibited by the organic exchange inhibitor 4,4'-diisothiocyanostilbene-2-2'-disulphonic acid (DIDS, 400 microM). 4. Net secretion of ciprofloxacin was partially inhibited by 100 microM verapamil, whilst net secretion of the P-glycoprotein substrate vinblastine was totally abolished under these conditions. Ciprofloxacin secretion was unaltered after preincubation of cells with two anti-P-glycoprotein antibodies (UIC2 and MRK16), which both significantly reduced secretory vinblastine flux (measured in the same cell batch). Ciprofloxacin (3 mM) failed to inhibit vinblastine net secretin in Caco-2 epithelia, and was not itself secreted by the P-glycoprotein expressing and vinblastine secreting dog kidney cell line, MDCK. 5. Net secretion and cellular uptake of ciprofloxacin (at 0.1 mM) were not subject to alterations of either cytosolic or medium pH, or dependent on the presence of medium Na+, Cl- or K+ in the bathing media. 6. The substrate specificity of the ciprofloxacin secretory transport in Caco-2 epithelia is distinct from both the renal organic anion and cation transport. A role for P-glycoprotein in ciprofloxacin secretion may also be excluded. A novel transport mechanism, sensitive to both DIDS and verapamil mediates secretion of ciprofloxacin by human intestinal Caco-2 epithelia.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed2002

Contribution of the ADP-ribosylating and receptor-binding properties of cholera-like enterotoxins in modulating cytokine secretion by human intestinal epithelial cells.

When epithelial cells first encounter cholera toxin (Ctx) produced by Vibrio cholerae they secrete not only chloride ions responsible for causing diarrhoea, but also a number of cytokines that may contribute to the toxin's potent immunomodulatory properties. Much less is known about the ability of the heat-labile enterotoxin of Escherichia coli (Etx), a close homologue of Ctx, to elicit cytokine secretion by epithelial cells. This study shows that treatment of human intestinal epithelial T84 cells with Etx induces expression of IL-6, IL-10, IL-1R antagonist, as well as IL-1alpha and IL-1beta and low levels of IL-8. Such induction was totally dependent on the intrinsic ADP-ribosylating activity of the toxin A-subunit, and could be mimicked by cAMP-elevating agents, such as forskolin and dibutyryl cAMP. By comparison, neither an enzymically inactive mutant of Etx nor EtxB was able to induce cytokine secretion. The behaviour of Ctx and CtxB was very similar to that of Etx and EtxB, respectively. The spectrum of cytokines released by Etx and Ctx indicates that the toxins may create a local microenvironment that strongly biases the immune response towards an anti-inflammatory and a polarized Th2 response.

Bacterial Toxins↗
PubMed1994

Nitric oxide and the interrelation between intestinal motility and pancreatic secretion in fasted and fed dogs.

Intestinal motility and pancreatic secretion show synchronous cyclic changes (MMC) that are interrupted by feeding. The aim of this study was to determine the possible implication of nitric oxide (NO) (that was proposed as nonadrenergic noncholinergic neurotransmitter) in the motor and secretory components of MMC in 5 conscious dogs equipped with monopolar electrodes implanted along the small bowel and pancreatic fistulas. In fasted dogs with typical MMCs, L-NNA (an inhibitor of NO synthase) (5 mg/kg-h i.v.) decreased the MMC interval from control value of 80 +/- 7 to 60 +/- 4 min while increasing significantly the slow waves with spikes and suppressing the phase III-related increase in pancreatic secretion. Infusion of L-arginine (L-Arg) (a substrate of NO synthase) (10 mg/kg-h i.v.) increased the MMC interval from control 79 +/- 7 to 96 +/- 8 min and reduced the slow waves spikes by about 25%. Pancreatic secretion showed significant increase to about 20%. CCK maximum. Similar but transient effects were observed when glyceryl trinitrate (GTN) (a donor of NO) (1 mg/kg-h) was administered. After ingestion of meal, the MMC cycles were replaced by irregular spike activity with an average of about 35% slow waves with spikes and pancreatic secretion rose to about 70% of CCK maximum. Infusion of L-Arg (10 mg/kg-h) reduced by about 90% the postprandial spike activity but failed to affect significantly the pancreatic secretion. Also, injection of GTN (1 mg/kg-h) reduced the spike activity but did not influence pancreatic secretion. L-NNA in fed dogs caused an initial increase in spike activity followed by phase III and about 60% inhibition of pancreatic secretion. L-NNA added to L-Arg infusion reversed in part both intestinal motility and pancreatic secretory effects of L-Arg infusion. We conclude that NO system exerts a tonic inhibitory influence on intestinal myoelectric activity by reducing the frequency of MMC pacesetter and by suppressing the postprandial activity but stimulates pancreatic secretion.

Animals↗
PubMedDate not supplied

Use of pilocarpine-induced alimentary secretions to measure intestinal shedding of Salmonella enteritidis in chickens.

A technique has been developed that uses the parasympathomimetic drug pilocarpine to induce alimentary secretions in chickens for measuring local immune responses to Salmonella enteritidis strain SE6. A study was conducted to determine if these secretions could also be used to detect intestinal SE6 shedding. White leghorn chickens infected with 1 x 10(9) SE6 were samples weekly using cloacal swabs, and the isolation rates from these samples were compared with alimentary secretions induced by oral administration of phosphate-buffered saline followed 45 minutes later with an intraperitoneal injection of 5% pilocarpine. At 9 days postinfection, isolation rates from the alimentary secretions were significantly higher than isolation rates from the swabs, and by day 16 they were double those from the swabs. In separate small experiments, alimentary secretions induced by pilocarpine alone also had significantly more SE6 isolations than did cloacal swabs on two of three sampling times examined. Direct culture of feces resulted in numerically but not significantly greater SE6 isolations than did cloacal swabs on two of three sampling times. These results indicate that induced intestinal material is a better sample source than cloacal swabs for detecting S. enteritidis intestinal infections in chickens and could have many applications in intestinal pathogenesis research.

Animals↗
PubMed1994

5-HT receptor subtypes involved in luminal serotonin-induced secretion in rat intestine in vivo.

The purpose of this study was to compare the 5-hydroxytryptamine (5-HT) receptor subtypes involved in secretion of water and electrolytes (sodium, potassium, and chloride) induced by luminally administered serotonin in rat jejunum and ileum in vivo. Ketanserin partially inhibited and ICS 205-930 totally inhibited serotonin-evoked secretion. Ketanserin induced mild basal secretion while ICS 205-930 alone reduced basal absorption. There were no differences in the effects of ketanserin or ICS 205-930 on serotonin-induced secretion by rat jejunum versus ileum. Neither N-acetyl-5-hydroxytryptophyl-5-hydroxytryptophanamide nor methysergide altered the secretory effect of serotonin in rat ileum. The substituted benzamides, cisapride, and BRL 24924, and the 5-HT4 agonist, 5-methoxytryptamide, induced water and electrolyte secretion. While BRL 24924 did not alter the subsequent serotonin-induced secretory fluxes, cisapride slightly inhibited the induced secretion. These results suggest that (1) in both segments of the intestine, 5-HT2, 5-HT3, and/or 5-HT4 receptor subtypes are involved in the regulation of intestinal transport of water and electrolytes under basal conditions; (2) serotonin-induced water and electrolyte secretion is mediated by pathways involving 5-HT2, 5-HT3, and 5-HT4 receptor subtypes in both rat jejunum and ileum; (3) 5-HT1 receptors do not seem to be involved in the mediation of intestinal water and electrolyte transport; (4) these effects are similar to those described for systemically administered 5-HT.

5-Methoxytryptamine↗
PubMedDate not supplied

Secretory actions of vasoactive intestinal polypeptide, peptide histidine isoleucine and helodermin in rat small intestine: the effects of putative VIP antagonists upon VIP-induced ion secretion.

Vasoactive intestinal polypeptide (VIP), peptide histidine isoleucine (PHI), and helodermin stimulate electrogenic anion secretion in preparations of rat jejunum stripped of muscularis propria. Concentration-response curves to exogenously applied peptides yielded EC50 values of 12 nM, 12 nM and 100 nM for VIP, PHI and helodermin respectively. These secretory responses were most probably mediated via the same receptor population given that cross-desensitisation was observed between all 3 analogues. Four putative VIP antagonists, namely, two growth hormone releasing factors (GRF); [AcTyr1, D-Phe2]GRF-(1-29)-NH2 and [AcTyr1]hGRF-(1-40)-OH as well as [4Cl-D-Phe6,Leu17]VIP and VIP-(10-28) were tested for their ability to inhibit VIP induced electrogenic ion secretion. None of the above exhibited any intrinsic agonist activity nor were they competitive antagonists, although some inhibition was observed with [AcTyr1]hGRF-(1-40)-OH and VIP-(10-28). Their use as selective VIP antagonists is therefore limited in rat jejunal mucosa.

Animals↗
PubMed1982

Intestinal filtration-secretion due to increased intraluminal pressure in rabbits.

The mechanism of changes in small intestinal transport due to acutely increased intraluminal hydrostatic pressure (IHP) was investigated in detail using perfused in vivo rabbit intestinal segments. IHP affected passive transport in vivo by increasing effective mucosal surface area in the small intestine (indicated by 3HOH transport and tissue architectural changes) and increasing small intestinal permeability (indicated by a proportionately greater increase in mannitol than erythritol secretory clearance). IHP did not alter ileal blood flow rate measured by radioactive microspheres, despite grossly evident venous dilatation, or active intestinal transport in the ileum as measured by a) in vitro ion transport in the absence of elevated hydrostatic pressure, b) mucosal adenylate cyclase or Na-K-ATPase activities, and c) glucose-stimulated water and electrolyte absorption. Acutely increased IHP appears to influence the hydrodynamics of the mucosal microcirculation in the rabbit ileum to produce a driving force for passive filtration-secretion, which is associated with and possibly augmented by increased tissue permeability and effective surface area.

Animals↗
PubMed2003

Guanylin and its lysine-containing analogue in the isolated perfused rat kidney: interaction with chymotrypsin inhibitor.

Guanylin and uroguanylin are two novel peptides that activate membrane-bound guanylate cyclases found in the kidney and intestine, influencing fluid and electrolyte homeostasis by cyclic GMP. Their natriuretic and kaliuretic activities are well documented. Since guanylin is inactivated by chymotrypsin in vitro, experiments were designed to evaluate the role of chymotrypsin-like proteases in renal metabolism of guanylin. Using the isolated perfused rat kidney, guanylin and a recombinant derivative containing a lysine residue in the N-terminus of the native peptide was tested. There were three experimental groups. In the first group, lys-guanylin (0.1-2.5 microg/ml) was placed into perfusate reservoir. In the second group, chymostatin (6 microg/ml), a chymotrypsin inhibitor, was placed into solution. In the third group, after 30 min. of perfusion with chymostatin (6 microg/ml), guanylin (0.3 microg/ml) was placed into solution. A maximal decrease in fractional Na+ reabsorption (%TNa+) was achieved at 1.0 microg/ml of lys-guanylin (from 73.25+/-2.29 to 54.97+/-0.10, P<0.05). Lys-guanylin (1.0 microg/ml) also decreased fractional K+ reabsorption (%TK+) from 59.26+/-3.93 to 30.75+/-0.78 (P<0.05). Chymostatin had no detectable effects in electrolyte reabsorption in this assay. When introduced after chymostatin, guanylin lowered %TNa+ (from 81.2+/-1.86 to 72.6+/-2.45, P<0.05) and %TK+ (from 69.4+/-4.12 to 65.8+/-2.81, P<0.05). At this subthreshold concentration, guanylin alone lacks effects in %TNa+ or %TK+. Furthermore, the ability of both peptides to promote increases in intestinal fluid secretion was evaluated in the in vivo suckling mouse model. When administered per os, guanylin failed to stimulate intestinal secretion. When chymostatin was present in the test solution, guanylin induced intestinal secretion in this assay. In marked contrast, lys-guanylin alone induced diarrhoea in the suckling mouse. The present paper concludes that guanylin undergoes metabolism in target tissues such as the intestine and kidney and its lysine-containing analogue retains full biological activity.

Amino Acid Sequence↗