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PubMed2005

Antisecretory activity of plants used to treat gastrointestinal disorders in Mexico.

Aqueous and methanolic extracts from 26 medicinal plants used in Mexico to treat gastrointestinal disorders were screened to evaluate their antisecretory activity on cholera toxin-induced intestinal secretion in rat jejunal loops model. Extracts were tested at a dose of 300 mg/kg. From 56 samples tested, both extracts from Chiranthodendron pentadactylon, Hippocratea excelsa and Ocimum basilicum were the most potent with inhibition values ranging from 68.0 to 87.6%. On the other hand, the methanolic extract of Geranium mexicanum (aerial parts) and the aqueous extract of Bocconia frutescens showed the highest activity with inhibition values of 93.4 and 86.0%, respectively. The results obtained in this study give some scientific support to the use of the Mexican medicinal plants employed for the treatment of gastrointestinal disorders such as diarrhea.

Animals↗
PubMed1999

Somatic nerve stimulation and cholera-induced net fluid secretion in the small intestine of the rat: evidence for an opioid effect.

The effects of somatic nerve stimulation on cholera toxin induced secretion was investigated in vivo in anaesthetised rats. Small intestinal secretion was induced with cholera toxin and measured by a gravimetric technique. Afferent stimulation (pulse frequency within train; 100 Hz; train duration: 50 ms; train frequency: 3 Hz) of the sciatic nerve over 30 min significantly reduced the net fluid secretion both during (P < 0.05) and after cessation of the stimulation (P < 0.01). The greatest effect was obtained immediately after the termination of the nerve stimulation when the secretion was reversed to net fluid absorption. The opioid receptor antagonist naloxone (10 mg kg(-1) i.v.) administrated during the stimulation, significantly inhibited the antisecretory effect seen after the stimulation, thus no significant difference was seen between the control period and the periods after cessation of the stimulation. The opioid receptor antagonist naloxone methiodide (10 mg kg(-1) i.v.), which does not cross the blood-brain barrier, partly inhibited the antisecretory effects but not with the same magnitude as naloxone, thus the net fluid secretion was still significantly inhibited after the stimulation (P < 0.05). We conclude that afferent stimulation of the sciatic nerve strongly inhibits the cholera toxin induced secretion in the small intestine. This inhibition involves primarily a central opioid mechanism and to a lesser extent peripheral opioid mechanism.

Acupuncture Therapy↗
PubMed2001

Effects of YM905, a novel muscarinic M3-receptor antagonist, on experimental models of bowel dysfunction in vivo.

We investigated the effects of YM905 [(+)-(1S,3'R)-quinuclidin-3'-yl 1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate monosuccinate], a new orally active muscarinic M3-receptor antagonist, on bowel dysfunction in vivo using experimental models that reproduce the symptoms present in irritable bowel syndrome (IBS). YM905 potently inhibited restraint stress-induced fecal pellet output in fed rats (ED50: 4.0 mg/kg) and diarrhea in fasted rats (ED50: 1.7 mg/kg), with similar potencies to the inhibition of bethanechol-, neostigmine- and nicotine-induced fecal pellet output in rats (ED50: 3.3, 7.9 and 4.5 mg/kg, respectively). YM905 also inhibited 5-hydroxytryptamine (5-HT)-, prostaglandin E2- and castor oil-induced secretory diarrhea in mice (ED50: 5.5, 14 and 6.3 mg/kg, respectively), but showed no significant effect on cholera toxin-induced intestinal secretion in mice. In addition, YM905 (3, 10 mg/kg) reversed morphine-decreased postprandial defecation in ferrets, a model of spastic constipation, whereas remosetron, a 5-HT3-receptor antagonist, was not effective. The mode of YM905 action was similar to that of darifenacin, a selective M3-receptor antagonist, with equivalent potencies. By contrast, propantheline, an antimuscarinic drug that has been used for IBS, was much less potent. These results show that YM905 ameliorates a wide spectrum of bowel dysfunctions through the blockade of M3 receptors, suggesting its therapeutic potential for treating IBS.

Animals↗
PubMed1980

Glucose-stimulated fluid absorption in the pig small intestine during the early stage of swine dysentery.

Kinetics of glucose-stimulated water absorption and small bowel absorptive function in normal pigs and pigs affected with swine dysentery were examined with a steady-state perfusion technique. Glucose-dependent stimulation of solute and water absorption was shown in normal pigs with a transport constant of 46.9 mM and a maximum change in volume transport capacity of 78.3 ml/h/50 cm of jejunum. The entire small intestine of normal pigs absorbed 10 mg/min of an isotonic fluid when the luminal glucose concentration was 80 mM, whereas the intestine secreted 3 ml/min when glucose was replaced by mannitol. These absorptive and secretory rates in infected pigs were identical to those in control pigs. Electrolyte and acid-base values in arterial blood were unchanged after the rapid administration of 500 ml of a glucose-electrolyte solution into the proximal portion of the small bowel, and the plasma glucose response in control and infected pigs was identical. Seemingly, small bowel absorptive function is normal in pigs with swine dysentery and provides a rational approach to oral, glucose-electrolyte therapy for restoring the extracellular fluid losses that occur with this disease.

Animals↗
PubMed2001

Effect of an enteric-release formulation of naloxone on intestinal transit in volunteers taking codeine.

INTRODUCTION: Constipation is a common side-effect of opioid therapy; in addition to their analgesic effect, opioids reduce intestinal secretion and motility with an increase in whole-gut transit time. Naloxone, a specific opioid antagonist, reverses these effects but may also cause symptoms of opioid withdrawal in patients on long-term therapy. AIM: To use an enteric-release formulation, designed to produce a topical effect in the gut, with minimum systemic effects. METHODS: Naloxone 10 mg b.d. and codeine 30 mg b.d. were used with identical placebo capsules in four sets of studies; 12 male volunteers were given the drugs alone and in combination, with a control study involving double placebo, during each of four study periods. Whole-gut transit time was calculated and compared for each treatment period. RESULTS: Naloxone, both alone and with codeine, significantly shortened the mean whole-gut transit time compared with the control period, respectively, from 53.1 to 42.1 h (P=0.005) and to 40.7 h (P=0.024). Urgency to defecate was reported by two volunteers on naloxone alone and by three on combination therapy. CONCLUSIONS: The results show that the naloxone formulation counteracts the effect of codeine on intestinal transit, suggesting that it may have useful clinical applications.

Administration, Oral↗
PubMed2006

Effect of a selective chloride channel activator, lubiprostone, on gastrointestinal transit, gastric sensory, and motor functions in healthy volunteers.

Chloride channels modulate gastrointestinal neuromuscular functions in vitro. Lubiprostone, a selective type 2 chloride channel (ClC-2) activator, induces intestinal secretion and has been shown to relieve constipation in clinical trials; however, the effects of lubiprostone on gastric function and whole gut transit in humans are unclear. Our aim was to compare the effects of the selective ClC-2 activator lubiprostone on maximum tolerated volume (MTV) of a meal, postprandial symptoms, gastric volumes, and gastrointestinal and colonic transit in humans. We performed a randomized, parallel-group, double-blind, placebo-controlled study evaluating the effects of lubiprostone (24 microg bid) in 30 healthy volunteers. Validated methods were used: scintigraphic gastrointestinal and colonic transit, SPECT to measure gastric volumes, and the nutrient drink ("satiation") test to measure MTV and postprandial symptoms. Lubiprostone accelerated small bowel and colonic transit, increased fasting gastric volume, and retarded gastric emptying. MTV values were reduced compared with placebo; however, the MTV was within the normal range for healthy adults in 13 of 14 participants, and there was no significant change compared with baseline measurements. Lubiprostone had no significant effect on postprandial gastric volume or aggregate symptoms but did decrease fullness 30 min after the fully satiating meal. Thus the ClC-2 activator lubiprostone accelerates small intestinal and colonic transit, which confers potential in the treatment of constipation.

Adolescent↗
PubMed1993

A 5-HT2 receptor mediates serotonin-induced electrolyte transport in rat left colon.

Serotonin (5-hydroxytryptamine, 5-HT) is a potent mediator of diarrhea in the carcinoid syndrome. However, the mechanisms of serotonin-induced intestinal secretion remain unclear. The purpose of this study was to determine whether 5-HT stimulates electrolyte transport by a direct action at a mucosal receptor. Serotonin-stimulated electrolyte transport was studied in flat sheet preparations of rat left colon using flux chambers. 5-HT stimulated a concentration-dependent rise in short-circuit current in sheets stripped of muscularis propria. The half-maximal concentration required to produce this effect was 50 microM. The preferential 5-HT2 antagonist ketanserin produced a rightward shift of the serotonin concentration-response curve with a pA2 value of 7.7. Serotonin stimulated electrolyte transport by inhibiting mucosa to serosa movement of both sodium and chloride. The 5-HT1 antagonist N-acetyl-5-hydroxytryptophyl 5-hydroxytryptophan amide and the 5-HT3 antagonist 3-tropanyl-indole-3-carboxylate methiodide had no effect on these actions of serotonin on electrolyte transport. In contrast, ketanserin inhibited the actions of serotonin on both sodium and chloride movement and inhibited the rise in short-circuit current induced by 100 microM 5-HT. This study demonstrates that a 5-HT2 receptor located in the vicinity of the mucosa is involved in the regulation of serotonin-stimulated intestinal electrolyte transport.

Animals↗
PubMed2005

Induction of local protective immunity to Eimeria acervulina by a Lactobacillus-based probiotic.

Previously we have shown that resistance to Eimeria acervulina (EA) infection in broiler chickens was enhanced by a probiotic treatment. In the present studies, we examined cytokine and oocyst production under similar conditions using a commercial Lactobacillus-based probiotic. Day-old male broiler chicks were fed control or probiotic diets and were orally challenged with either 2x10(4) (Experiment 1) or 1x10(4) (Experiment 2) oocysts of EA at 3 weeks of age. For the first experiment, fecal oocyst shedding and IFN-gamma levels in the culture supernatants of ConA-stimulated spleen lymphocytes were evaluated. Humoral and local cell-mediated immunity in the second experiment were assessed by evaluating antibody and cytokine (IFN-gamma and IL-2) levels in sera and intestinal secretions on a 3-day interval post inoculation. Results showed small but significant (P<0.05) differences in cytokine levels and oocyst production but not antibody levels between the probiotic-treated and control groups. Collectively, these data suggest a positive impact of the probiotic on cellular immune responses of infected broilers as compared to control chickens resulting in enhanced resistance to EA as shown in reduced fecal oocyst shedding. The results showed an immunoregulatory effect of probiotic diets on the local cell-mediated immunity in poultry and provide a rationale for further study to investigate the beneficial effects of Lactobacillus-based probiotics in food animals.

Animals↗
PubMed1999

The regulation of mineral absorption in the gastrointestinal tract.

The absorption of metal ions in the mammalian single-stomached gut is fortunately highly selective, and both luminal and tissue regulation occur. Initially, assimilation of metal ions in an available form is facilitated by the intestinal secretions, chiefly soluble mucus (mucin) that retards hydrolysis of ions such as Cu, Fe and Zn. Metal ions then bind and traverse the mucosally-adherent mucus layer with an efficiency M+ > M2+ > M3+. At the mucosa Fe3+ is probably uniquely reduced to Fe2+, and all divalent cations (including Fe2+) are transported by a membrane protein (such as divalent cation transporter 1) into the cell. This minimizes absorption of toxic trivalent metals (e.g. Al3+). Intracellular metal-binding molecules (such as mobilferrin) may be present at the intracellular side of the apical membrane, anchored to a transmembrane protein such as an integrin complex. This mobilferrin would receive the metal ion from divalent cation transporter 1 and, with part of the integrin molecule, transport the metal to the cytosol for safe sequestration in a larger complex such as ferritin or 'paraferritin'. beta 2-Microglobulin and HFE (previously termed human leucocyte antigen H) may be involved in stabilizing metal mobilferrin-integrin to form this latter complex. Finally, a systemic metal-binding protein such as transferrin may enter the antiluminal (basolateral) side of the cell for binding of the sequestered metal ion and delivery to the circulation. Regulatory proteins, such as HFE, may determine the degree of ion transport from intestinal cells to the circulation. Gradients in pH and perhaps pCa or even pNa could allow the switching of ions between the different transporters throughout this mechanism.

Aluminum↗
PubMed1997

Evidence for a nonneural electrogenic effect of cholera toxin on human isolated ileal mucosa.

Cholera toxin-induced intestinal secretion in intact rats requires a functioning myenteric plexus. The aim of this investigation was to determine whether neural elements were essential for cholera toxin to produce a secretory effect in human isolated ileum. Mucosal preparations were mounted in Ussing chambers. Cholera toxin was applied apically and short-circuit current monitored for 3 hr, at which point forskolin was given. Cholera toxin (10 microg/ml) induced a tetrodotoxin-insensitive increase in short-circuit current in muscle-stripped preparations of human ileum. The increase was not additive with the action of forskolin (25 microM). Cholera toxin exerts a marked nonneural secretory effect in human ileal mucosa in vitro, probably by the same mechanism as forskolin, namely elevation of cyclic AMP.

Biological Transport, Active↗
PubMed1995

Rotavirus diarrhea is caused by nonreplicating viral particles.

Rotaviruses infect the villous epithelium of the small intestine and cause severe diarrhea in young children. The mechanism by which rotavirus causes diarrhea has not been elucidated. It has been hypothesized that rotavirus replication in the intestinal epithelium causes a loss of viable absorptive cells, leading to an imbalance of intestinal secretion and absorption. Cell destruction has generally been thought to result from rotavirus transcription and replication. However, the widely used heterologous murine model of rotavirus infection demonstrates minimal viral replication and histological changes limited to epithelial vacuolation on the distal villus despite the simultaneous occurrence of voluminous liquid diarrhea. We have genetically inactivated rotaviruses to test the importance of viral replication in the pathogenesis of rotavirus-induced diarrhea. We present direct evidence that transcription- and replication-defective rotaviruses cause diarrhea in an animal model. These findings suggest that rotavirus attachment or entry into cells is sufficient for the induction of diarrhea. The mechanism of rotavirus-induced diarrhea is therefore consistent with a viral toxin-like effect exerted during virus-cell contact.

Animals↗
PubMed1996

Oral immunization with a model protein entrapped in microspheres prepared from derivatized alpha-amino acids.

A model antigen, ovalbumin (OVA), was encapsulated in microspheres prepared from derivatized alpha-amino acids and administered orally to mice. These microspheres are quickly and easily prepared, without the use of organic solvents, high temperatures, or complex purification techniques. Immunological responses included induction of OVA-specific antibodies in both sera (IgG) and in intestinal secretions (sIgA), as well as antigen-dependent proliferation of splenic CD4+ T cells following, in some cases, as little as a single oral priming dose containing 0.1 mg OVA. Oral administration of microspheres was also found to be effective as a secondary immunization following a subcutaneous prime with soluble antigen. In addition, the protective effect of co-encapsulation of cholera toxin, a mucosal adjuvant, was demonstrated in a whole virus model (infectious bursal disease in chickens). These results indicate that oral administration of antigen-loaded derivatized alpha-amino acid microspheres can induce local and systemic antibody production and/or stimulation of effector cells.

Administration, Oral↗
PubMed1984

Plasma lipid transport.

The main plasma lipid transport forms are free fatty acid, triglyceride and cholesteryl ester. Free fatty acid, derived primarily from adipocyte triglycerides, is transported as a physical complex with plasma albumin. Triglycerides and cholesteryl esters are transported in the core of plasma lipoproteins. The intestine secretes dietary fat in chylomicrons, lipoproteins that transport triglyceride to tissues for storage. Dietary cholesterol is transported to the liver by chylomicron remnants which are formed from chylomicrons. Triglyceride is released from the liver in very low density lipoproteins for utilization and storage in extrahepatic tissues. Very low density lipoproteins are converted to low density lipoproteins in the plasma; in the process, they become enriched in cholesteryl esters. High density lipoproteins take up cholesterol from tissues and other plasma lipoproteins. After the cholesterol is esterified, it is transferred ultimately to low density lipoproteins for uptake by the tissues. Phospholipids are structural components of lipoproteins and provide fatty acid for cholesteryl ester formation in the plasma, but they are not a primary transport form of lipid. Six enzymes, together with apolipoprotein cofactors and lipid transfer proteins, facilitate the plasma lipid transport process.

Albumins↗
PubMed1976

The problem of bacterial diarrhoea.

The reported incidence of "pathogenic" bacteria, as judged by serotype, in the stools of children with acute diarrhoea has varied from 4 to 33% over the last twenty years. Techniques such as tissue culture provide a means for detecting enterotoxin-producing strains of bacteria, strains which often do not possess "pathogenic" serotypes. "Pathogenicity" requires redefinition, and the aetiological importance of bacteria in diarrhoea is probably considerably greater than previous reports have indicated. Colonization of the bowel by a pathogen will result in structural and/or mucosal abnormalities, and will depend on a series of complex interactions between the external environment, the pathogen, and the host and its resident bacterial flora. Enteropathogenic bacteria may be broadly classified as (i) invasive (e.g. Shigella, Salmonella and some Escherichia coli) which predominantly affect the distal bowel, or (ii) non-invasive (e.g. Vibrio cholerae and E. coli) which affect the proximal bowel. V. cholerae and E. coli elaborate heat-labile enterotoxins which activate adenylate cyclase and induce small intestinal secretion; the secretory effects of heat-stable E. coli and heat-labile Shigella dysenteriae enterotoxins are not accompanied by cyclase activation. The two major complications of acute diarrhoea are (i) hypernatraemic dehydration with its attendant neurological, renal and vascular lesions, and (ii) protracted diarrhoea which may lead to severe malnutrition. Deconjugation of bile salts and colonization of the small bowel with toxigenic strains of E. coli may be important in the pathophysiology of the protracted diarrhoea syndrome. The control of bacterial diarrhoea requires a corrdinated political, educational, social, public health and scientific attack. Bacterial diarrhoea is a major health problem throughout the world, and carries an appreciable morbidity and mortality. This is particularly the case during infancy, and in those developing parts of the world where malnutrition is common. This paper is concerned mainly with acute bacterial diarrhoea, and reviews the problem as a whole.

Child↗
PubMed1998

Enterotoxic effect of the vacuolating toxin produced by Helicobacter pylori in Caco-2 cells.

Preliminary clinical evidence suggests that Helicobacter pylori may be associated with diarrhea through its vacuolating toxin (VacA). To establish whether VacA induces intestinal secretion, epithelial damage, or both, purified pH-activated VacA was added to Caco-2 cell monolayers mounted in Ussing chambers, and electrical parameters were monitored. Mucosal addition of VacA induced an increase in short circuit current, consistent with enterotoxic effect. The effect was time- and dose-dependent and saturable. It was not found if the toxin was not pH-activated, added to the serosal side, or preheated. In cells preloaded with the Ca2+ buffering compound BAPTA/AM or with the Cl- channel inhibitor 5-nitro-2-3-(3-phenylpropylamino)benzoic acid, short circuit current did not change, indicating that VacA induces activation of Ca2+-dependent Cl- channels. VacA did not show cytopathic effects, as judged by tissue resistance. These results support the hypothesis that H. pylori may be associated with diarrhea through production of VacA.

Bacterial Proteins↗
PubMed2004

Multidrug resistance P-glycoprotein: crucial significance in drug disposition and interaction.

This article reviews recent advances in our understanding of the structure, drug interaction mechanism, and substrate molecular requirements of P-glycoprotein (P-gp) and its emerging crucial role in drug disposition and the modulation of drug interaction. In view of its wide localization in normal tissues, the broad variety of structurally and functionally unrelated substrates of P-gp, and its ATP-dependent outward-oriented transport, P-gp actively participates in intestinal secretion, blood-tissue barriers, and biliary and renal excretions for many exogenous substrates, and also performs a protective role to prevent entry of xenobiotics. Moreover, the importance of P-gp-mediated drug interactions in clinical practice can hardly be underestimated, since it may result in severe side effects, such as digitalis drug interaction. Polymorphism or single nucleotide polymorphism (SNP) associated with P-gp may exert a significant effect on the pharmacokinetic behavior of its substrates, a fact which has major clinical implications and suggests careful dose adjustment for individual treatment. Moreover, dietary components and pharmaceutical excipients may modulate P-gp activity, and as a result affect in vivo drug disposition and therapeutic efficacy; examples include grapefruit juice, Pluronic P85, PEG 300, etc. In summary, it should be emphasized that P-gp is an integral component in the process of drug discovery, development strategy,

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Inhibition of potassium (KATP) channels reduces the short-circuit current response of rat colonic mucosa to acetylcholine.

Intestinal secretion depends upon electrogenic chloride transport into the gut lumen, which requires maintenance of an electrically negative cell-membrane voltage. We have investigated whether secretory responses of rat colonic mucosa to acetylcholine were sensitive to inhibition of potassium channels and whether selective inhibition could indicate the nature of the channel involved. Rat colonic mucosa was set up in Ussing chambers, short-circuit current responses obtained to acetylcholine, and the sensitivity of such responses to inhibition of potassium channels was investigated. Non-selective potassium-channel blockade by barium induced concentration-dependent inhibition of responses to acetylcholine. Similar inhibitory effects were obtained using 4-aminopyridine and glibenclamide. 5-Hydroxydecanoate and phentolamine also inhibited the increase in short-circuit current. However, a combination of charybdotoxin plus apamin was without effect. We conclude that a basolateral outward movement of potassium ions is required for the secretory action of acetylcholine on rat colonic mucosa. The potassium channel involved seems to be ATP-dependent and calcium-insensitive.

Acetylcholine↗
PubMed1976

Activation of intestinal mucosal adenylate cyclase by Shigella dysenteriae I enterotoxin.

Because the mechanism whereby Shigella dysenteriae I enterotoxin induces intestinal secretion is unclear, the effect of this toxin on adenylate cyclase activity in rabbit ileal mucosa was studied under various in vitro and in vivo conditions. Activation of adenylate cyclase by Shigella enterotoxin was observed only when substrate (ATP) concentrations above the Km of adenylate cyclase were employed. These concentrations of ATP are greater than those required to demonstrate activation of adenylate cyclase by cholera toxin. Under optimal assay conditions, doses of Shigella toxin between 5.4 and 900 mug of toxin protein and in vivo incubation times between 6 and 18 hr all increased adenylate cyclase activity by about 100%. Shigella toxin produced significant but highly variable increases in mucosal cyclic AMP concentrations, which were less that the rises seen with a comparable dose of cholera toxin. This variability in cyclic AMP response to Shigella toxin and the disparity between Shigella and cholera toxins' effects on mucosal cyclic AMP are probably the result of the different kinetics of adenylate cyclase activated by these enterotoxins. Mucosal Na-K-ATPase activity was unaffected by Shigella toxin. These observations suggest that alterations in fluid and electrolyte transport induced by Shigella enterotoxin may, in part, be mediated by the adenylate cyclase-cyclic AMP system.

Adenosine Triphosphatases↗