Search

Aim: d-myo-inositol-1,2,6-trisphosphate (alpha-trinositol, PP56), is a synthetic isomer of the intracellular second messenger, d-myo-inositol-1,4,5-trisphospahate. The pharmacological actions of alpha-trinositol include potent anti-inflammatory properties and inhibition of the secretion induced by cholera toxin and obstructive ileus. In the present study, we investigated whether alpha-trinositol was able to influence the secretion induced by heat-stable ST-toxin from Escherichia coli in the rat jejunum., Methods: A midline abdominal incision was performed in anaesthetized male Sprague-Dawley rats and a 6-7 cm long jejunal segment was isolated with intact vascular supply and placed in a chamber suspended from a force displacement transducer connected to a Grass(R) polygraph. Intestinal net fluid transport was continuously monitored gravimetrically. Crystalline ST-toxin (120 mouse units) was introduced into the intestinal lumen and left there for the rest of the experiment. When a stable secretion was observed, alpha-trinositol (60 mg kg-1 h-1) or saline were infused during 2 h, followed by a 2-h control period., Results: alpha-Trinositol induced a significant (P < 0.001) inhibition of ST-toxin secretion within 30 min, lasting until 2 h after infusion had stopped. The agent also moderately increased (P < 0.05) net fluid absorption in normal jejunum. Mean arterial pressure (P < 0.001) and heart rate (P < 0.001) were reduced by alpha-trinositol., Conclusion: The inhibition by alpha-trinositol of ST-toxin induced intestinal secretion is primarily secondary to inhibition of secretory mechanisms and only to lesser extent due to increased absorption. The detailed mechanisms of action have not been clarified but may involve suppression of inflammation possibly by means of cellular signal transduction.

1. The main aim of the present study was to establish the functional in vivo effects of tachykinins on net fluid transport by the jejunum and ileum of anaesthetized rats. Tachykinins were administered by retrograde infusion in saline into the left common carotid artery. The possible involvement of 5-hydroxytryptamine (5-HT) in tachykinin-induced intestinal secretion was also investigated. 2. Some tachykinins were potent at reversing net absorption to secretion, particularly in the jejunum, where the rank order of potency was neurokinin (NK) A > substance P (SP) > NKB. The potency of the NK1 receptor-selective agonist [Sar9,Met(O2)11]-SP was the same as SP. Neurokinin A reduced net fluid absorption from the lumen of the jejunum at an intra-arterial infusion rate of 0.64 microg/kg per min. Infusions of NKA at 1.6 and 4 microg/kg per min induced net secretion into the lumen of the jejunum. These two higher infusion rates also affected fluid transport by the ileum, although not to the same extent as seen in the jejunum. The relative potency of SP was not affected by captopril (10 mg/kg, i.v.). 3. The secretory response of the jejunum to infusion of 4 microg/kg per min SP was blocked in animals administered the NK1 receptor antagonist SR 140 333 (1 mg/kg, i.v.). In addition, SR 140 333 blocked the secretory response to 4 microg/kg per min NKA. However, NKA still induced secretion in animals that had received the NK2 receptor antagonist SR 48 968 (0.3 mg/kg, i.v.). 4. A role for an endogenous tachykinin in the intestinal secretory action of 5-HT was not clearly established using the present model. Although SR 140 333 increased the absorption rate from the jejunum in animals infused intra-arterially with 5-HT, 5-HT itself did not cause a significant reduction in absorption. There were no significant differences in the absorption rates from the ileum between the control group and groups infused with 5-HT with and without SR 140 333. 5. The present study provides functional evidence for the existence of NK1 receptors in the rat small intestine, particularly in the proximal region, where their activation influences fluid transport. It is suggested that the presently used rat model is suitable for screening tachykinin antagonists for potential antidiarrhoeal activity.

There has been a search for more than 20 years for agents that will directly inhibit intestinal secretory mechanisms and thereby reduce stool volume in patients with high volume watery diarrhoea. Recent work has highlighted the importance of neurohumoral mechanisms in the pathogenesis of diarrhoea, notably the role of 5-hydroxytryptamine, substance P, vasoactive intestinal polypeptide and neural reflexes within the enteric nervous system. Cholera toxin and Escherichia coli enterotoxins are known to invoke these mechanisms in some diarrhoeal states. This new dimension of intestinal pathophysiology has suggested possible novel targets for anti-secretory therapy including, 5-hydroxytryptamine receptor antagonists, substance P antagonists, vasoactive intestinal polypeptide antagonists and the possibility for potentiating the pro-absorptive effects of endogenous enkephalins by use of enkephalinase inhibitors. There now seems to be a real possibility that anti-secretory therapy will become more widely available in the future.

Specific effects of the cytotoxic secondary lipid oxidation product, 4-hydroxynonenal (10(-8)-10(-4) M), on intact sheets of rat jejunum were measured as changes in short circuit current (delta(I)sc) following cumulative addition to either the mucosal or serosal side, using the analogous aldehyde, nonenal, as reference. 4-Hydroxynonenal stimulated I(sc) from the serosal side (maximal delta(I)sc = 27.2 +/- 3.5 microA/cm2, mean +/- SEM, N = 32) while nonenal stimulated I(sc) primarily from the mucosal side (maximal delta(I)sc = 16.2 +/- 3.4 microA/cm2, N = 20). Inhibition by 100 microM bumetanide (4-hydroxynonenal: 88.9 +/- 3.0%, N = 6, p < 0.05, nonenal: 69.3 +/- 2.9%, N = 6, P < 0.05) indicated chloride secretion. Nonenal-induced delta(I)sc was inhibited (72.5 +/- 1.2%, N = 8, P < 0.05) by a combination of nordihydroguaiaretic acid (100 microM) and piroxicam (10 microM), while 4-hydroxynonenal-induced delta(I)sc, was abolished by piroxicam (N = 8, P < 0.001) and inhibited by 1 microM tetrodotoxin (69.8 +/- 9.7%, N = 6, P < 0.001). These data indicate that 4-hydroxynonenal stimulates chloride secretion mediated by prostaglandins and the enteric nervous system. The site of action (serosal) being opposite to the reference aldehyde.

We have investigated the effect piperine on castor oil-stimulated fluid accumulation in the mouse small intestine. Piperine (2.5-20 mg/kg, i.p.) dose-dependently reduced castor oil-induced intestinal fluid accumulation. The inhibitory effect of piperine (10 mg/kg i.p.) was strongly attenuated in capsaicin (75 mg/kg in total, s.c.)-treated mice but it was not modified by the vanilloid receptor antagonist capsazepine (30 mg/kg i.p.). Pretreatment of mice with hexamethonium (1 mg/kg i.p.), naloxone (2 mg/kg i.p.), yohimbine (1 mg/kg i.p.) or the cannabinoid CB(1) receptor antagonist SR141716A (0.3 mg/kg i.p.) did not modify the inhibitory effect of piperine (10 mg/kg i.p.). These results suggest that piperine reduces castor oil-induced fluid secretion with a mechanism involving capsaicin-sensitive neurons, but not capsazepine-sensitive vanilloid receptors.

The antisecretory factor is a protein inhibiting enterotoxin-induced intestinal inflammation and hypersecretion. We studied the signaling pathway of three antisecretory factor-derived peptides (A1, A3 and A4) in the proximal and distal porcine small intestine. In vivo (ligated loops), only A3 significantly reduced the cholera toxin-induced fluid accumulation and only in proximal loops. A3 and A4 reduced Escherichia coli heat-labile enterotoxin-induced fluid accumulation in the proximal segment, whereas A1 and A3 reduced the Escherichia coli heat-labile enterotoxin-induced fluid accumulation in the distal segment. The secretory response to intraluminally added 5-hydroxytryptamine was not significantly inhibited by the peptides. The amount of intraluminal 5-hydroxytryptamine accumulated in cholera toxin-stimulated loops from the proximal segment was significantly reduced by A3. In vitro,the effect of A3 on secretagogue-induced increases in short-circuit current was recorded from proximal small intestine by the Ussing chamber technique. A3 decreased the tetrodotoxin sensitive effect of substance P. The in vivo results suggest that the antisecretory effect may involve inhibition of the local release of 5-hydroxytryptamine induced by cholera toxin, but not inhibition of secretory reflexes induced by 5-hydroxytryptamine. The in vitro results suggest that the effect of A3 lies beyond the surface epithelium, and involves mucosal neuronal structures.

Background: Heightened visceroperception and a decreased duodenal motor response to intraduodenal acid infusion have been reported in functional dyspepsia., Aim: To investigate the effect of treatment with a proton pump inhibitor on sensorimotor impairment in 19 patients with functional dyspepsia., Methods: Patients were assigned double-blind to pantoprazole (n=10) or placebo (n=9) treatment for 2 weeks. Antropyloroduodenal manometry was performed before and after treatment, using a 21-channel catheter, and the responses to intraduodenal infusion of 5 mL of saline and acid were assessed. Nausea, fullness and epigastric pain were scored before and after each infusion., Results: Acid induced a modest duodenal motor response and suppression of antral pressure waves, not altered by either treatment. However, acid evoked isolated pyloric pressure waves after pantoprazole treatment (P < 0.02), and not after placebo. Saline induced no motor response. Acid (not saline) induced nausea, both before and after treatment in both groups (all P < 0.05). Subgroup analysis of the seven acid-hypersensitive patients (37%) showed a tendency towards a decrease in nausea in all four pantoprazole-treated patients (P=0.07), in contrast to the three placebo-treated patients (P=1.0)., Conclusions: In functional dyspepsia, pantoprazole influenced the acid-induced duodenogastric feedback mechanism, but not the impaired duodenal motor response. Duodenal acid hypersensitivity was decreased to some extent.

A 4-week feeding trial on 22 grey partridges Perdix perdix was conducted in this study. Seven birds were fed commercial poultry food, seven natural food and eight commercial poultry food containing 6% of quebracho-tannin. Our results suggest that 6% dietary tannin, when added to a commercial food with high protein content, effects the grey partridge only slightly. No difference was seen in food consumption and body mass remained stable. However, birds fed tannin had longer small intestines, which most probably indicate gastrointestinal detoxication. They also excreted a high amount of tannin in their faeces. In addition, no between-group variation was seen in cytochrome P450 enzymes. Birds fed natural food had high concentration of nitrogen in intestinal excreta and high plasma alanine concentrations. They also suffered a rapid decrease in body mass after the change in diet and their body mass remained low. This may indicate increased protein excretion and/or catabolism of endogenous nutrient reserves. Potential short-term effects of the change in diet were seen in plasma. These findings coincide with the high mortality period of birds released into the wild.

The mechanism by which Clostridium difficile toxin A causes substance P (SP) release and subsequent inflammation in the rat ileum is unknown. Pretreatment with the vanilloid receptor subtype 1 (VR1) antagonist, capsazepine, before toxin A administration significantly inhibited toxin A-induced SP release and intestinal inflammation. Intraluminal administration of the VR1 agonist capsaicin caused intestinal inflammation similar to the effects of toxin A. Pretreatment with capsazepine before capsaicin administration also significantly inhibited capsaicin-induced intestinal inflammation. These results suggest that intraluminal toxin A causes SP release from primary sensory neurons via stimulation of VR1 receptors resulting in intestinal inflammation.

Aim: The protective effect of L-carnitine on stress-induced gastric mucosal injury was investigated in rats exposed to cold-restraint stress (CRS)., Methods: The animals were divided into four groups. Groups 1 and 3 received saline by intragastric gavage for 10 days. Groups 2 and 4 received L-carnitine (50 mg/Kg/day) in the same manner. Groups 3 and 4 were exposed to CRS in the form of immobilization at 4 degrees C for 4 h on day 10. Ulcer index, gastric acid secretion and hemoglobin leakage, and gastric mucosal mucin and PGE2 content were measured., Results: In rats exposed to CRS, as compared to control rats (group 1), ulcer index was higher, gastric acid production was lower, hemoglobin leakage into the gastric lumen was increased, and gastric mucosal mucin and PGE content were reduced. L-carnitine treatment prior to CRS led to attenuation of changes in ulcer index, gastric acid secretion, amount of hemoglobin leakage into the gastric lumen and gastric PGE2 content. In rats receiving L-carnitine but not exposed to CRS, gastric acid secretion, mucin and PGE2 content of gastric mucosa were similar to those in control rats., Conclusion: L-carnitine decreases CRS-induced gastric mucosal injury.

In vitro somatostatin is a potent inhibitor of intestinal ion secretion in animal models and cultured human cell lines, providing a rationale for its use in secretory diarrheas. However, the effects of somatostatin on ion transport in native human colonic epithelium have not been reported. In this study the effects of somatostatin and octreotide on the basal short-circuit current and the cAMP- and Ca2+-stimulated short-circuit current were studied in isolated human colonic mucosa mounted in Ussing chambers. Under basal conditions somatostatin and octreotide (1 micromol/liter) stimulated a small, bumetanide-sensitive increase in short-circuit current. Following stimulation of secretion with prostaglandin E2, somatostatin and octreotide further increased the short-circuit current in a dose dependent fashion (ED50 approximately 10 nmol/liter for both). This stimulation of short-circuit current was not affected by pretreatment of the tissue with basolateral tetrodotoxin (1 micromol/liter) or mucosal amiloride (10 micromol/liter). In contrast, somatostatin and octreotide had no effect when secretion was stimulated with 8-bromo-cAMP, and pretreatment of the tissue with somatostatin and octreotide (0.1 micromol/liter) did not alter the secretory response to carbachol. The absence of any inhibitory effect of somatostatin and octreotide on electrogenic secretion in the human colon may explain the variable results obtained when somatostatin or octreotide are used for the treatment of secretory diarrheas.

Gum arabic (GA), a soluble fiber with emulsifying properties, enhances intestinal water and electrolyte absorption in normal and secreting rats. Our aim was to assess the effect of GA, 2.5 and 5.0 g/liter, on cholera toxin-induced water and electrolyte secretion in rat jejunum in vivo. After a 2-hr exposure to cholera toxin, jejunal segments of adult rats were perfused in vivo with at plasma electrolyte solution containing GA, 0, 2.5 or 5.0 g/liter. 24Na was used as a marker of sodium influx. Cholera toxin-induced secretion was reduced by GA, 2.5 and 5.0 g/liter. 24Na secretion into the lumen was reduced by GA. GA caused a morphological expansion of intercellular spaces in the villi but not crypts. In conclusion, GA promotes lumen to blood intestinal transport of water and sodium despite cholera toxin activation. These observations support a potential role for GA in enhancing the efficacy of ORS.

Using 3H-Tyr-D-Ala-Gly-Phe-D-Leu-OH (3H-DADLE) as a radioligand, delta-opioid binding sites on the IRD 98 rat epithelial cell line were identified. These sites were found to be reversible, saturable, specific and displayed high affinity for DADLE. Scatchard analysis revealed a dissociation constant (Kd) of 4.9+/-0.5 nmol/l, a maximum binding capacity (Bmax) of 1.7 pmol/mg protein, and 5x10(5) binding sites per cell. The presence of opioid receptors suggests the possibility that enkephalins directly control ion transport in enterocytes. In order to verify this hypothesis, investigations were designed to determine whether these receptors are functional and whether enkephalins can inhibit the stimulation of adenosine 3',5' cyclic monophosphate (cAMP) synthesis induced by cholera toxin. The increase in cAMP synthesis induced by cholera toxin was inhibited in a dose-dependent manner by H-Tyr-D-Ser-Gly-Phe-Leu-Thr-OH (DSLET), a delta-agonist. The enkephalinase inhibitor thiorphan potentiated this effect on IRD 98 cells, which contain enkephalinase. The action of DSLET was increased by 40% in the presence of this inhibitor. This effect was reversed by naltrindole, a potent delta-antagonist. Enkephalins can regulate intestinal secretion by acting directly on enterocytes: they thus have an antidiarrheal role, especially in the presence of an enkephalinase inhibitor.

Troglitazone is a new, orally effective antidiabetic agent that decreases plasma glucose in obese patients with non-insulin-dependent diabetes mellitus. Unfortunately, troglitazone also has a propensity to cause edema. This study was designed to determine how troglitazone affects intestinal ion transport and water absorption. Short circuit current (I(sc)) was measured in rat and human duodenal mucosa in Ussing chambers. Five minutes later, the serosal addition of troglitazone caused I(sc) to decrease gradually, and after 50 min, I(sc) reached the peak of decrease. EC(50) values and maximum response to I(sc) in rat and human mucosa were 8.4 and 8.7 microM and 8.56 +/- 1.0 and 8.00 +/- 2.0 microA/cm(2), respectively. In an HCO(3)(-)/CO(2)-free system, the decrease in I(sc) caused by troglitazone was 1.31 +/- 0.83 microA/cm(2). When 10 mM acetazolamide was preadministered, the small decrease in I(sc) evoked by troglitazone (20 microM) was 4.56 +/- 0.22 microA/cm(2), whereas the preadministration of 100 microM amiloride and 100 nM tetrodotoxin did not influence the decrease in I(sc) evoked by troglitazone. The serosal preadministration of 100 nM vasoactive intestinal peptide potently enhanced the decrease in I(sc) evoked by 20 microM troglitazone (21.1 +/- 1.63 microA/cm(2)). The cyclic AMP contents of rat duodenal mucosa incubated with and without troglitazone (20 microM) for 50 min were 3.2 +/- 0.25 and 5. 8 +/- 0.46 pmol/mg protein, respectively (P <.01). These results indicate that the ionic basis for the decrease in I(sc) that is induced by troglitazone may be inhibition of electrogenic bicarbonate secretion. The alteration of intestinal ion transport by troglitazone could cause edema.

Aim: The possible induction of functional or morphologic changes in the exocrine pancreas of the rat by oral calcium overload was studied to determine the possible relationship to predisposition of acute pancreatitis over the acinar theory., Materials and Methods: Oral chloride calcium (0.45 and 0.25 g/kg body weight/day) plus cholelecalciferol (300,000 UI/kg i.m.) were administered to male Wistar rats over 1 to 3 months. Half of each group, including a control were submitted to cholinergic stimulation with carbamylcholin. After anesthesia, blood and pancreatic tissue and duodenal fluid were extracted for enzymatic and ultrastructural studies., Results: In the rats treated with high doses of calcium for 1 month greater tissue concentrations of amylase, lipase and trypsin were observed. Moreover, there was a greater trend to the presence of dilated ergastoplasm. In the rats treated with high doses over 3 months a lower enzyme concentration was observed in the animals not stimulated that in the control group. On stimulation with carbamylcholin, higher concentrations of enzymes were observed in tissue than in those not stimulated. This was accompanied by a lower number of exocytosis in this experimental group that in the control., Conclusions: A possible increase in the calcium concentration in the acinar cell may lead to dysfunction in the secretory mechanisms favoring the intracellular accumulation of digestive enzymes, predisposing intracellular activation, in the context of the acinar or lysosomal hypothesis of acute pancreatitis.

Background: Escherichia coli heat stable enterotoxin (STa) is a major cause of secretory diarrhoea in humans., Aims: To assess the effects of instilling STa into the ileum on remote fluid secretion in the jejunum and colon in rats in vivo by a gravimetric technique., Methods and Results: Ileal STa (55 ng/ml) stimulated fluid secretion in both ileal and jejunal loops but not in the colon. The fluid secretion induced by ileal STa was inhibited by L-NAME (Nomega-nitro-L-arginine methyl ester, 40 mg/kg intraperitoneally) but not by D-NAME (Nomega-nitro-D-arginine methyl ester). Ileal carbachol (183 mg/ml) instilled into the lumen stimulated ileal secretion but not jejunal secretion, and was unaffected by L-NAME. Capsaicin (10 microM), instilled luminally with STa in the ileum, blocked both the ileal and jejunal fluid secretion. Acute bilateral vagotomy prevented luminal ileal STa from inducing jejunal fluid secretion but not from activating ileal fluid secretion., Conclusion: Ileal E coli STa stimulates remote secretion in the rat jejunum but not in the colon, probably by a nitrinergic, vagal reflex mediated by C fibres. This neural pathway will amplify the action of the toxin in its generation of secretory diarrhoea.

The neuropeptide neurotensin mediates several intestinal functions, including chloride secretion, motility, and cellular growth. However, whether this peptide participates in intestinal inflammation is not known. Toxin A, an enterotoxin from Clostridium difficile, mediates pseudomembranous colitis in humans. In animal models, toxin A causes an acute inflammatory response characterized by activation of sensory neurons and intestinal nerves and immune cells of the lamina propria. Here we show that neurotensin and its receptor are elevated in the rat colonic mucosa following toxin A administration. Pretreatment of rats with the neurotensin receptor antagonist SR-48, 692 inhibits toxin A-induced changes in colonic secretion, mucosal permeability, and histologic damage. Exposure of colonic explants to toxin A or neurotensin causes mast cell degranulation, which is inhibited by SR-48,692. Because substance P was previously shown to mediate mast cell activation, we examined whether substance P is involved in neurotensin-induced mast cell degranulation. Our results show that neurotensin-induced mast cell degranulation in colonic explants is inhibited by the substance P (neurokinin-1) receptor antagonist CP-96,345, indicating that colonic mast activation in response to neurotensin involves release of substance P. We conclude that neurotensin plays a key role in the pathogenesis of C. difficile-induced colonic inflammation and mast cell activation.

Diquat, a nonselective desiccant herbicide, induces a significant secretion of fluid into the lumen of the gastrointestinal tract of rats at sublethal doses (from 0.5 to 50 mg/kg). This study investigated the effect of an acute low-level exposure to diquat (0. 1, 0.5, and 1 mg/kg) on intestinal net water flux and the mechanisms involved. In anesthetized rats, an intestinal loop (7 cm) was infused with Ringer's buffer containing [14C]-polyethylene glycol 4000. After equilibration, diquat (0.1, 0.5, and 1 mg/kg) was added to Ringer's buffer during 60 min. Net water flux was calculated according to [14C] activity determined in the effluent collected at 15-min intervals. Infused in the intestinal loop for 60 min at doses of 0.5 and 1 mg/kg but not at 0.1 mg/kg, diquat induced an intestinal net water secretion during 180 min with a maximal effect at the highest dose used and during the first hour following the end of diquat infusion. Diquat-induced (1 mg/kg) intestinal net water secretion was blocked by a neurotoxin, tetrodotoxin (5 micrograms/kg iv), doxantrazole (5 mg/kg ip), a mast cell stabilizer, and two inhibitors of NO synthases: l-NAME (25 mg/kg ip) and aminoguanidine (2 mg/kg ip). It is concluded that a single low-level (0.5 and 1 mg/kg) intrajejunal administration of diquat induces a net water intestinal secretion and that this secretory effect is nerve-mediated, implying mast cell degranulation and NO release., (Copyright 1998 Academic Press.)

Tolcapone (T) is a novel catechol-O-methyltransferase (COMT) inhibitor recently introduced for the treatment of Parkinson's disease. In clinical efficacy studies, T has been associated with a low incidence of diarrhea. The objectives of the study were to examine whether T and its adjunctive drug Sinemet (S) could influence intestinal fluid and electrolyte transport as a possible cause for the diarrhea. The studies were conducted in conscious dogs surgically prepared with Thiry-Vella loops constructed from a 40-cm jejunal segment. A physiologically buffered test solution was perfused into the orad stoma and collected from the caudad stoma. Secretions were collected at 15-min intervals and analyzed for volume, electrolytes, lipid phosphorus, and protein. The acute oral administration of T (10 and 30 mg/kg doses) was well tolerated. Concurrent acute administration of S (25 mg/kg) with T (30 mg/kg) was also well tolerated. The acute oral administration of T induced a dose-dependent efflux of intestinal fluid and electrolytes (sodium, potassium, chloride, and bicarbonate) secretion (P < 0.05). The oral coadministration of S (25 mg/kg) with T (30 mg/kg) accelerated the onset of the stimulation of intestinal secretion. Despite the significant stimulation of intestinal secretion, none of the dogs developed diarrhea, indicating the importance of intestinal compensatory mechanisms. Neither T nor T&S affected calcium, lipid, or protein efflux rates, suggesting that the stimulated secretion was not a consequence of intestinal mucosal injury. The chronic (seven-day) administration of T and T&S was associated with reduced intestinal secretory responses when compared with the acute administration of the same drugs; S enhanced the T-induced tolerance development. The basis for such tolerance is unknown. In conclusion, the stimulatory systemic actions of tolcapone on intestinal secretion may, under certain conditions, contribute to the induction of diarrhea in susceptible patients.

Glicentin (GLIC) and oxyntomodulin (OXM) are released from the ileum and colon during digestion. Both hormones reduce fluid and proton secretion in the stomach. The luminal concentration of sodium and chloride underlying the nutrient absorption, the effect of OXM on electrolyte transport through the small intestine, was assessed in vivo using ligated loops and in vitro using Ussing chambers. In vivo, a zero transport state, estimated by the net water, chloride, and sodium fluxes, was observed when an 80 mM NaCl normoosmolar solution (274 mosm) was administered intraluminally. Active secretion was observed with hyperosmotic challenge (474 mosm). The amplitude of this active secretion increased 2.5- to 3-fold when an electrogenic challenge (NaCl 40 mM) was substituted to the hyperosmotic one. OXM (800 fmol/ml plasma) did not modify the basal transport in the duodenum or in the jejunum (t = 45 min). When active secretion was induced by the hyperosmotic challenge, OXM (200 fmol/ml plasma) had no effect on duodenal or jejunal transport (t = 50 min). When active secretion was induced by an electrogenic challenge, OXM (300 fmol/ml plasma) preferentially reduced the hydromineral transport in jejunum. In vitro, OXM also induced a reduction in the ion transport towards the jejunal lumen (EC50 = 20 pM), the amplitude of which depended upon the integrity of the tetrodotoxin-sensitive neurons. In conclusion, OXM was able to reduce the large secretion induced in rat jejunum in vivo by an electrogenic gradient. In vitro, the antisecretory effect of OXM was partly mediated by the neurons present in the intrajejunal wall.

Investigations of intestinal secretion are often performed under anaesthesia. This study evaluates the influence of anaesthetic agents on the intestinal secretion induced by cholera toxin (CT) in the pig. CT was instilled for 4 h in ligated jejunal loops under anaesthesia with halothane, saffan, alpha-chloralose, or propofol. Cardiovascular parameters, blood gas data, plasma cortisol levels, net fluid accumulation, intraluminal mediators (serotonin (5-HT), prostaglandin E2 (PGE2)) and electrolyte concentrations in the accumulated fluid were determined. The systolic blood pressure and heart rate was highest for saffan-anaesthetized pigs (blood pressure: saffan > alpha-chloralose > propofol = halothane; heart rate: saffan > alpha-chloralose = propofol = halothane), while blood gases and cortisol levels were within the same range. CT induced a dose-dependent fluid accumulation under all four anaesthetics. The fluid accumulation was significantly higher in pigs treated with saffan, alpha-chloralose and propofol than in halothane-treated pigs (saffan = alpha-chloralose > propofol > halothane). There was no significant difference in electrolyte concentrations in the accumulated fluid or in the luminal content of 5-HT and PGE2 between anaesthetics. The results demonstrate that anaesthetic agents profoundly influence the secretory response in the small intestine and indicate the importance of the choice of anaesthetic in this type of experiment.

Extract of Nelumbo nucifera rhizome (RNN) was used as anti-diarrheal agent to combat the diarrhea in experimental rats. The RNN extract in graded doses (100, 200, 400 and 600 mg/kg body wt.) reduced not only the frequency of defecation, wetness of fecal dropping and PGE2 induced enteropooling but also the propulsive movements of charcoal meal significantly.

Antisecretory effect of intravenous quamatel (Q) and gastrocepin (G) was studied in 59 patients with duodenal ulcer. Mean maximal pH and delta-pH in antral portion of the stomach and its body were similar for Q and G, but pH responded to Q administration faster. The antisecretory effect of Q was more pronounced in males and young patients and was inversely proportional to initial acidity.

The interaction of PYY and VIP was studied in stripped and intact rat jejunum preparations mounted in Ussing chambers. PYY decreased basal Isc in intact as well as in stripped jejunum. Stripping was necessary to evidence a stimulation of basal Isc by VIP. When PYY and VIP were administered at the same time in the serosal bath, their effects seemed additive; VIP stimulation took over when VIP was present in ten times larger amounts than PYY, while PYY inhibition predominated at isomolar concentrations (10(-7) M) of both peptides. However, when PYY was administered three to six minutes before isomolar amounts of VIP, the VIP stimulation developed without being notably hampered. At this time, however, the amount of radioimmunoassayable PYY in the serosal compartment represented still 60% of the added amount. In conclusion, the experimental conditions can significantly change the results: stripping the longitudinal muscle/myenteric plexus impairs the effect of PYY and VIP in a different fashion, while the timing and order of administration of the peptides may change the apparent interaction between VIP stimulation and PYY inhibition.

Background: Antisecretory factor (AF) is a recently identified regulatory protein which inhibits the intestinal fluid secretion induced by cholera toxin., Aims: To test the effect of AF on: (a) inflammation and hypersecretion induced by toxin A from Clostridium difficile; and (b) morphological changes and hypersecretion induced by okadaic acid (the blue mussel toxin) in rat intestinal mucosa., Methods: Morphological changes and fluid accumulation were observed in intestinal loops challenged with 1 microgram of toxin A or 3 micrograms of okadaic acid administered before or after injection of 0.1 microgram of recombinant AF (rAF)., Results: The cytotoxic and inflammatory reaction caused by toxin A was abolished after treatment with rAF given either intraveneously or intraluminally prior to the toxin or one hour after the toxin. The intestinal fluid response induced by toxin A and okadaic acid was reduced 55-80% by rAF. However, the characteristic increase in goblet cells at the tips of villi in the okadaic acid treated mucosa was not inhibited by rAF., Conclusion: Results suggest that AF might be involved in protection against inflammation and in counteracting dehydration caused by enterotoxins. Both effects are probably mediated via the enteric nervous system.

Opioids have long been known to inhibit intestinal fluid and electrolyte secretion. They act locally on central and peripheral opiate receptors where they are rapidly degraded by neuropeptidases, the major one being enkephalinase (EC 3.4.24.11). A number of studies have shown that, when the problem of degradation can be overcome, enkephalins have potent antisecretory properties. In 1980, an enkephalinase inhibitor was described which increased the functional availability of enkephalins. More recently an orally active enkephalinase inhibitor, acetorphan, has been shown to inhibit infectious and chemically induced diarrhoea. Acetorphan does not appear to affect gastrointestinal motility and, although it also inhibits the breakdown of a range of other neuropeptides, such as substance P and neuropeptide Y, it is a promising agent with therapeutic potential.

Background & Aims: Diarrhea is a major cause of illness and death in children and young animals. The aim of this study was to investigate the possible therapeutic effect of bromelain, a proteolytic extract obtained from pineapple stems on bacterial toxin and second-messenger agonist-induced intestinal secretion., Methods: The effect of bromelain pretreatment on short-circuit responses to Escherichia coli heat-labile enterotoxin, heat-stable enterotoxin, and Vibrio cholerae cholera toxin was evaluated in rabbit ileum mounted in Ussing chambers., Results: Bromelain was 62% effective in preventing heat-labile enterotoxin-induced secretion, 51% effective against cholera toxin, and 35% effective against heat-stable enterotoxin [corrected]. Bromelain also prevented secretory changes caused by prostaglandin E2, theophylline, calcium-ionophore A23187, 8-bromoadenosine 3':5'-cyclic monophosphate, and 8-bromoguanosine 3':5'-cyclic monophosphate, well-known intracellular mediators of ion secretion. The efficacy of bromelain was not caused by reduced tissue viability resulting from its proteolytic effects on enterocytes, indicated by experiments measuring uptakes of nutrients into intestinal cells and experiments measuring short-circuit responses to glucose., Conclusions: Bromelain prevents intestinal fluid secretion mediated by secretagogues that act via adenosine 3':5'-cyclic monophosphate, guanosine 3':5'-cyclic monophosphate, and calcium-dependent signaling cascades. It may be clinically useful as an antidiarrheal drug.

The heat-stable enterotoxin of Escherichia coli binds to an intestinal receptor, guanylyl cyclase-C, and produces cGMP to induce diarrhea. Guanylin is an endogenous ligand of this receptor. In the present in vivo study, the intestinal water and ion secretion induced by mucosal application of 2 nmol/ml guanylin or 5 or 10 units/ml heat-stable enterotoxin into closed loops was compared in the rat. The characteristics of secretion induced by cAMP following intravenous perfusion of 1.2 nmol/100 g per h vasoactive intestinal peptide were compared to those induced by cGMP. Unidirectional Na+ and Cl- fluxes were estimated by addition of 22Na into the loop and i.v. injection of 36Cl. Guanylin induced less water and ion secretion than that produced by heat-stable enterotoxin in the colon, confirming the results of in vitro studies, and also in duodenum and ileum. The cAMP- or cGMP-mediated response had a similar pattern, i.e., an inhibition of Na+ absorption and an increase in anion secretion.

Background: Uroguanylin and guanylin are intestinal peptides that activate a receptor-guanylate cyclase, which is also a receptor for Escherichia coli heat-stable enterotoxin (STa). These peptides may have a role in the body's regulation of fluid and electrolytes., Methods: STa, bioactive guanylin, and bioactive uroguanylin were evaluated for effects in: 1) the suckling mouse intestinal fluid secretion assay; 2) an in vitro suckling mouse intestinal loop assay; 3) an intestinal receptor autoradiography assay; 4) a control or agonist-stimulated assay for cGMP response in T84 cells; and 5) an in vivo renal function assay in mice., Results: In vivo, orally administered uroguanylin and STa but not guanylin, stimulated intestinal fluid secretion. All three peptides activated intestinal guanylate cyclase and had common intestinal receptors. In vitro, after pretreatment with chymotrypsin, only uroguanylin and STa retained agoinst activity. Chymostatin preserved guanylin activity. STa and uroguanylin induced diuresis, natriuresis, and kaliuresis. Guanylin was less potent than uroguanylin and STa., Conclusions: The results suggest that the endogenous intestinal peptides, uroguanylin and guanylin, regulate water and electrolyte homeostasis both through local effects on intestinal epithelia and endocrine effects on the kidney.

We assessed the clinical usefulness of the intraductal secretin test in order to ascertain whether it can substitute for the conventional duodenal secretin test. Duodenal juice was obtained with a triple-lumen tube and pure pancreatic juice was obtained by retrograde cannulation of the main pancreatic duct using a duodenofiberscope. Pancreatic secretion was stimulated by a bolus intravenous injection of secretin (100 units). The two tests showed comparable interindividual coefficients of variation, significantly good correlations, and comparable diagnostic efficiencies. The intraductal secretin test showed no less reproducibility than that of the duodenal secretin test as reported in the literature. In the intraductal secretin test, secretory volume, peak flow rate, bicarbonate output, and lipase output yielded the best diagnostic efficiency, followed by amylase output and maximal bicarbonate concentration. In the intraductal secretin test, a 10-min collection provided as much information as a 20-min collection. We conclude, therefore, that the 10-min intraductal secretin test is as useful as the conventional duodenal secretin test in assessing exocrine pancreatic function and that the most discriminatory parameters are secretory volume, bicarbonate output, and amylase (or lipase) output.

The enterotoxin E. coli STa induced fluid secretion in the rat jejunum, ileum and proximal colon in vivo that was greatly inhibited by the co-presence of luminal capsaicin, which is a specific neural toxin of afferent C fibres. The same dose of capsaicin had no effect on the fluid secretion activated by carbachol in the jejunum, ileum and proximal colon. Afferent C fibres appear to be involved in the activation by STa of fluid secretion in the rat intestine in vivo.

Background: The profuse fluid losses and morbidity of patients suffering from obstructive ileus are closely related to inflammatory changes in the obstructed bowel wall. Previous experimental studies have shown that use of steroids and NSAIDs can reduce fluid losses in obstructive ileus. In the present study, we investigated the effects of lidocaine on fluid losses since local anesthetics have been shown to possess wide and potent anti-inflammatory properties. Hexamethonium and atropine were used to study the importance of the autonomic nervous system in bowel obstruction., Method: Experiments were performed in rats in vivo. After 18 h of total obstruction of the jejunum by thread ligation, a segment of the obstructed jejunum was placed in a chamber with intact nervous and vascular supply and net fluid transport was continuously registered by a gravimetric technique. Extravasation of Evans blue albumin as marker of inflammation was quantified by spectrophotometry., Results: Hexamethonium (10 mg.kg-1 i.v.) significantly inhibited net fluid secretion (P < .05), while atropine (0.25 mg.kg-1 i.v.) had no significant effect. Net fluid secretion was reversed into absorption following an intravenous bolus dose of lidocaine (2 mg.kg-1) (P < 0.01) and topical administration of lidocaine (20 mg) on the serosa of the obstructed gut (P < 0.01). Single topical administration of lidocaine (20 mg) immediately before ligation significantly reduced net fluid secretion (P < 0.05) and inflammation (P < 0.05) in the obstructed bowel 20 h post-ligation compared to obstructed controls., Conclusion: Lidocaine significantly inhibited or prevented fluid losses when administered intravenously or topically to the obstructed gut. Mechanisms of action could be inhibition of nerve reflexes involved in fluid secretion and by inhibition of inflammation in the bowel wall. The inhibition of fluid losses by hexamethonium further supports the importance of the autonomic nervous system in the pathophysiology of bowel obstruction.

Guanylin is an endogenous peptide synthesized by several mammalian species that mimics the effects of a thermostable enterotoxin of Escherichia coli (STa: NTFYCCELCCNPACAGCY) in the gut. We have cloned a lysine-1 derivative of rat guanylin (Lys-1-NTCEICAYAACTGC) and tested its effects on ileal tissue membranes in Ussing chambers and in the isolated perfused rat kidney. Rabbit ileal mucosa membranes were mounted into a Ussing chamber and the effects of Lys-1 guanylin (Lys-1 G) and STa enterotoxin peptide on chloride secretion were determined by changes in short-circuit current (Isc). Lys-1 G (10 to 100 nM) showed a dose-dependent effect on chloride secretion with a maximal response estimated to be 52 microA/cm2. Lys-1 G mimics the effect of STa peptide, but the enterotoxin elicited a greater maximal effect of 120 microA/cm2 (P < 0.01). Lys-1 G (2.5 micrograms/ml) promoted an increase in both urine flow (from 0.13 +/- 0.07 to 0.40 +/- 0.01 ml g-1 min-1, N = 4; P < 0.05) and glomerular filtration rate (from 0.68 +/- 0.02 to 0.85 +/- 0.00 ml g-1 min-1, N = 4; P < 0.01) in the isolated perfused kidney and a reduction of the fractional reabsorption of sodium (from 76.0 +/- 0.03 to 59.5 +/- 0.85%, N = 4; P < 0.01). These maximal effects were accompanied by intense natriuretic effect observed 30 and 60 min after drug administration. The Lys-1 G analog similar to STa enterotoxin elicited intestinal chloride secretion and a natriuretic effect. These data demonstrate that the cloned peptide analog retains the biological activity of the native hormone and presents activity similar to STa. The properties of Lys-1 G resemble those of a factor formed during perfusion of the hypoxic rabbit kidney and named by us factor natriureticus similis (FNS).

The proton pump inhibitor, omeprazole, surprisingly resulted in higher rates of proximal duodenal mucosal bicarbonate secretion than previously reported using an H2 receptor antagonist for gastric acid inhibition. Gastroduodenal perfusions were performed in healthy volunteers to evaluate whether this incidental finding is explained by more potent gastric acid inhibition by omeprazole or might be caused by the different mode of drug action. Basal and stimulated gastric and duodenal bicarbonate secretion rates were measured in the same subjects in control experiments (n = 17) and after pretreatment with high dose omeprazole (n = 17) and ranitidine (n = 9), respectively, by use of a technique permitting simultaneous measurements. Concentrations of bicarbonate were measured in the respective effluents by the method of back titration. Both omeprazole and ranitidine completely inhibited gastric acid secretion (pH 6.9 v 6.8; p > 0.05). Omeprazole caused higher rates of basal (mean (SEM)) (597 (48) v 351 (39) mumol/h; p < 0.02) and vagally stimulated (834 (72) v 474 (66) mumol/h; p < 0.02), but not acid stimulated (3351 (678) v 2550 (456) mumol/h; p > 0.05) duodenal bicarbonate secretion compared with control experiments. Also the combination of omeprazole and ranitidine increased (p = 0.05) duodenal bicarbonate secretion, while ranitidine alone caused no change in either basal or stimulated secretion. In the stomach basal as well as vagally stimulated bicarbonate secretion was independent of the means of acid inhibition. These results show that the proton pump inhibitor, omeprazole, promotes proximal duodenal mucosal bicarbonate secretion apparently independent of its gastric acid inhibitory effect. The mechanism of action remains speculative.

A Chinese hamster ovary (CHO) cell-elongating toxin produced by Aeromonas hydrophila was purified from cell-free supernatant fluids by ammonium sulfate precipitation and fast protein liquid chromatography. The purified toxin had an isolelectric point (pl) of 3.7 and a molecular weight of 70,000 in a single band on isoelectric focusing (IEF) gels and SDS-PAGE gels, respectively. The N-terminal sequence, amino acids 1-20, and the amino acid content were determined from Western blots of the 70 kDa band. No homology with any known microbial toxin was found. CHO cell activity was not neutralized by antiserum to cholera toxin (anti-CT), and the toxin did not react with anti-CT on Western blots. The toxin did not increase cyclic AMP, cyclic GMP, or prostaglandin E2 levels in CHO cells. No cytotoxic activity was observed. Intragastric administration of purified toxin (5 x 10(4) and 5 x 10(8) CHO cell units) induced intestinal fluid accumulation in infant mice. These results suggest that this toxin may be a novel cytotonic toxin distinct from previously described toxins produced by A. hydrophila or A. sobria.

The role of somatostatin-14 in duodenal mucosal HCO3- secretion was investigated in anesthetized, indomethacin-treated guinea pigs. Net HCO3- output from the isolated, perfused (24 mM NaHCO3 + 130 mM NaCl) proximal duodenum was measured during intravenous infusion (alone or in combination) of somatostatin-14, carbachol, vasoactive intestinal peptide (VIP), and prostaglandin E2 (PGE2). In homogenates of duodenal enterocytes, the effect of these agents on adenylate cyclase activity was studied. Basal duodenal HCO3- secretion (3.5 +/- 0.2 mumol/cm/10 min) was reduced dose dependently by somatostatin-14 (10(-11) mol/kg, 10(-9) mol/kg, and 10(-7) mol/kg). Carbachol, VIP, and PGE2 (all 10(-8) mol/kg) increased basal duodenal HCO3- secretion two- to threefold. Somatostatin-14 (10(-7) mol/kg) abolished the stimulatory effect of carbachol and VIP, but not that of PGE2. Basal adenylate cyclase activity in isolated duodenal enterocytes (9.4 +/- 1.0 pmol cAMP/mg protein/min) was unaltered by somatostatin (10(-6) mol/liter) or carbachol (10(-3) mol/liter). VIP (10(-8) mol/liter) and PGE2 (10(-7) mol/liter) increased adenylate cyclase activity two- to threefold, and these effects were unchanged by somatostatin-14 (10(-6) mol/liter). In conclusion, somatostatin-14 inhibits basal and carbachol- and VIP-stimulated duodenal HCO3- secretion, and its mechanism of action is not via inhibition of adenylate cyclase activity in duodenal enterocytes.

The inhibition of nitric oxide (NO) production by NO synthase inhibitors stimulates HCO3- secretion in the rat duodenal mucosa. Therefore, we examined the effects of NG-nitro-L-arginine methyl ester (L-NAME, the NO synthase inhibitor) and nitroprusside (the exogenous NO donor) on the duodenal HCO3- and ulcerogenic responses in anesthetized rats. Animals were administered mepirizole (200 mg/kg, subcutaneously) for induction of duodenal ulcers, and gastric acid and duodenal HCO3- secretions were measured with or without pretreatment with L-NAME (5 mg/kg, intravenously) or nitroprusside (4 mg/kg, intravenously). Mepirizole increased acid secretion, decreased the acid-induced duodenal HCO3- secretion, and induced hemorrhagic lesions in the proximal duodenum. The inhibition of NO production by L-NAME potentiated the acid secretory response, increased the duodenal HCO3- secretion, and prevented the duodenal lesions, and these changes were all antagonized by simultaneous administration of L-arginine (200 mg/kg, intravenously) but not D-arginine. On the other hand, nitroprusside slightly reduced the acid response but further decreased the HCO3- output, resulting in aggravation of duodenal lesions induced by mepirizole. These data suggest that the inhibition of endogenous NO production by the NO synthase inhibitor L-NAME increases duodenal HCO3- secretion and protects the duodenal mucosa against acid injury.

Pyloric exclusion is advocated in the treatment of duodenal injury. The beneficial effect is thought to be due to diversion of gastric secretions and resultant reduction of biliary and pancreatic secretions. The long-acting somatostatin analog, Octreotide, makes the inhibitory actions of somatostatin on gastric, biliary, and pancreatic secretions a potential alternative to pyloric exclusion. We compared the effect of pyloric exclusion to the effect of Octreotide on the volume of gastrointestinal secretions entering the duodenum by creating a duodenal fistula using a canine model. Five animals had modified Thomas cannulas placed in the duodenum. Two animals had staple closure of the pylorus with a gastrojejunostomy in addition to the cannula. Gastrointestinal secretions were measured in 2- or 3-hour collection periods performed every third or fourth day. Animals were administered saline or Octreotide (100 micrograms/hour) intravenously during each collection. Up to 9 hours of collections under both saline and Octreotide (18 hours total) were done on each dog. Octreotide alone reduces gastrointestinal secretions entering the duodenum more than pyloric exclusion alone. Pyloric exclusion and Octreotide together offered no additional reduction in gastrointestinal secretions entering the duodenum over Octreotide alone.

In vitro data suggest that the serotonin receptor subtype 4 (5-HT4) mediate part of the serotonin (5-HT)-induced intestinal secretion. This study elucidates the involvement of the intestinal 5-HT4 receptor subtype and the anti-diarrhoeal therapeutic potentials of tropisetron and octreotide in 5-HT-induced intestinal hypersecretion in vivo. The effects of intraluminal 5-HT, 5-methoxytryptamine, and tropisetron (ICS 205-930), and subcutaneous octreotide (SMS 201-995) on fluid hypersecretion (accumulation) was studied in tied-off loops in pig jejunum. 5-HT, 5-methoxytryptamine (5-HT4 agonist), and tropisetron (5-HT3/5-HT4 antagonist) all induced a dose-dependent hypersecretion. Low doses of tropisetron reduced, while high doses of tropisetron enhanced the 5-HT and 5-methoxytryptamine responses. Taking into account the hypersecretory effect by itself, tropisetron seemed to completely block the hypersecretory effects of 5-HT and 5-methoxytryptamine. Finally, octreotide reduced the hypersecretory effect of 5-HT, maximally by 30%. These results suggest the involvement of the intestinal 5-HT4 receptor subtype in 5-HT-induced hypersecretion in pig jejunum in vivo. Furthermore, this study demonstrates a potential therapeutic value for octreotide in 5-HT-related diarrhoeagenic disorders in the pig.

1. Previous studies have shown that the mixed A1/A2 adenosine agonist 5'-N-ethylcarboxamido-adenosine (NECA) inhibits intestinal fluid secretion which is thought to contribute to its antidiarrhoeal effect in the rat. The aim of this study was to characterize the adenosine receptor mediating this antisecretory effect via functional studies using a range of selective agonists and antagonists and by applying the pharmacological criteria of relative agonist and antagonist potencies. 2. Adenosine agonists and antagonists were administered i.v. to anaesthetized rats. Intestinal secretion was then stimulated by i.a. infusion of vasoactive intestinal peptide (VIP, 0.8 microgram min-1) and the net fluid transport across the wall of the jejunum was measured by a recirculation technique. 3. The rank order of agonist potency to reduce the response to VIP was: NECA > N6-cyclopentyladenosine (CPA) > R-N6-(2-phenylisopropyladenosine) (R-PIA) > S-PIA > chloroadenosine (2-CADO) > 2-phenylaminoadenosine (CV-1808). This order best complies with the rank order of agonist potency that represents activation of the recently described A2B receptor: NECA > 2-CADO > R-PIA = CHA > S-PIA > = CV-1808 > = CGS-21680. The most potent agonists (NECA, CPA and RPIA) had ED50 values in the low microgram range. 4. The anitsecretory action of NECA (submaximal dose of 40 micrograms kg-1) was antagonized equally (approximately 50%) by the selective adenosine antagonists 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 0.1 mg kg-1) and 8-phenyltheophylline (8-PT, 0.1 mg kg-1). This equipotent activity indicates the presence of an A2 and not an A1 receptor. 5. It is suggested that adenosine A2B receptor agonists could be evaluated for potential use as antidiarrhoeal drugs.

Some complex mechanisms of intestinal absorption are commented in relation to their link with interactions among nutrients, or to the alimentary system itself. The nutrient bioavailability is also considered in relation to the individual nutritional status in order to emphasize the need of depth knowledge in physiology for the best understanding of nutrition and reciprocally.

Bile salt-induced diarrhoea, net water and electrolyte secretion, gastrointestinal transit and nitric oxide (NO) synthase activity were studied in rats. NG-Nitro-L-arginine methyl ester (2.5-25 mg/kg i.p.), an inhibitor of NO synthase, and dexamethasone (0.03-0.3 mg/kg i.p.), an inhibitor of the inducible isoform of NO synthase, antagonized the diarrhoeal response. The NO precursor, L-arginine and isosorbide-5-mononitrate (an NO donor), reversed the inhibitory effect of NG-nitro-L-arginine methyl ester. The bile salt-stimulated fluid secretion, transit through the gut and NO synthase all were inhibited by NG-nitro-L-arginine methyl ester (but not NG-nitro-D-arginine methyl ester). NO synthase activity also was inhibited by dexamethasone. The results are consistent with bile salt induction of epithelial cell injury and concomitant synthesis of NO, mainly through activation of the inducible form of the enzyme. We believe that in this study NO is a mediator of intestinal secretion and motility changes that enhance transit of luminal contents through the gut, resulting in diarrhoea.

Background: Serotonin antagonists have been proven antisecretory in cholera toxin (CT)-induced hypersecretion in the small intestine of rodents. The pig small intestine is a good model for the human small intestine with regard to physiologic and pharmacologic processes., Methods: The antisecretory effect of intraluminally administered methysergide, renzapride, ketanserin, granisetron, and tropisetron on CT-induced hypersecretion was tested in isolated pig jejunal loops in vivo., Results: Methysergide, ketanserin, and granisetron reduced the hypersecretory effect of CT maximally by 25%, 80%, and 50%, respectively. Tropisetron enhanced whereas renzapride did not alter the CT response. Combination of ketanserin and granisetron gave a maximal inhibitory effect of about 85%. Surprisingly, renzapride, granisetron, and tropisetron each induced hypersecretion. Taking into account the hypersecretory effect of the antagonists, they all reduced this CT-elicited hypersecretion., Conclusions: Results suggest involvement of the 5-hydroxytryptamine-2 and 5-hydroxytryptamine-3 receptor subtypes as mediators in CT-induced hypersecretion in pig jejunum, and antidiarrheal therapeutic potentials of ketanserin and granisetron.

This study aimed to determine whether the antidiarrhoeal effect of the mixed A1/A2 adenosine agonist NECA (5'-N-ethylcarboxamido adenosine) is due to inhibition of intestinal fluid transport or to contractility. Intestinal secretion was stimulated in anaesthetized rats by intra-arterial infusions of PGE2 (4 micrograms min-1) or vasoactive intestinal peptide (0.8 micrograms min-1). NECA reversed PGE2-induced secretion in the jejunum (ED50 16 micrograms kg-1) and ileum (ED50 21 micrograms kg-1, i.v.) and inhibited VIP-induced secretion in the jejunum (ED50 21.5 micrograms kg-1). NECA inhibited twitch responses (0.1 Hz, 1 ms, IC50 11.2 nM) but not tetanic contractions at 10 Hz of the transmurally stimulated guinea-pig ileum. Likewise, NECA (10 microM) did not inhibit frequency-related contractions over the range of 2.5 to 40 Hz of rat jejunum or ileum. However, NECA was shown to be a potent inhibitor (30 nM) of the peristaltic reflex in the rat ileum. The results indicate that adenosine receptors are involved in modulating peristalsis as well as the secretory activity of the mucosa in the rat small intestine.

Background: The purpose of the study was to examine the effect of stimulation and inhibition of duodenal mucosal bicarbonate secretion on pancreatic and hepatic bicarbonate secretion in response to acid., Methods: The effect of inhibition (indomethacin) or stimulation (misoprostol) of duodenal mucosal bicarbonate secretion on pancreatic and biliary bicarbonate secretion in response to intraduodenal infusion of HCl or intravenous infusion of secretin was studied in anaesthetized pigs., Results: The hepatic and pancreatic response to exogenous secretin was not significantly altered by stimulation/inhibition of duodenal bicarbonate secretion. However, pancreatic and biliary bicarbonate secretion in response to duodenal acidification was significantly augmented by inhibition of duodenal mucosal bicarbonate secretion; conversely, it was reduced by stimulation of duodenal bicarbonate secretion. The increase in plasma secretin levels in response to duodenal acidification was reduced by stimulation and augmented by inhibition of duodenal mucosal bicarbonate secretion., Conclusions: Duodenal mucosal bicarbonate secretion can serve as a modulator of both pancreatic and biliary bicarbonate secretion in response to luminal acidification, possibly through regulation of the release of secretin.