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BICARBONATE MAY BE SECRETED INTO THE INTESTINAL LUMEN IN CHOLERA BECAUSE: HCO(3) (-) ions are transported, or because OH(-) ions accumulate and react with dissolved CO(2) to form HCO(3) (-). If HCO(3) (-) ions are transported into the lumen from the interstitial fluid, lumenal P(CO2) should increase (HCO(3) (-) right harpoon over left harpoon OH(-) + CO(2)); if OH(-) accumulates, P(CO2) should diminish. Net movement of H(2)O, and HCO(3) (-), and changes in pH and P(CO2) in lumenal fluid were studied in adjacent segments of rabbit ileum in vivo, one of which was exposed to choleragen. 4 h after exposure, segments were drained and infused with gassed Krebs-Henseleit solution whose P(CO2) exceeded arterial P(CO2). After 45 min, fluid was collected anaerobically from control and cholera segments. Among 13 cholera segments, lumenal P(CO2) diminished by a mean of 8.4 torr and was less than femoral arterial blood in six instances. In the paired control segments, mean P(CO2) increased by 4.4 torr, and was always greater than arterial P(CO2). Dilution could not account for the low P(CO2) in cholera segments because in hypertonic solutions that caused water to move into the lumen, the P(CO2) did not differ from control values obtained with isotonic solutions. The results suggest that OH(-) accumulation (by addition of OH(-) or removal of H(+)) causes HCO(3) (-) secretion in cholera. This does not result from secretion of some other base (e.g., HPO(4) (-)), because HCO(3) (-) accounts for most of the base in the lumenal fluid. The P(CO2) changes suggest that OH(-) reacts with CO(2) at the cell-lumen interface, but reaction at the cell-interstitial fluid interface cannot be excluded.

Human pancreatic lipase in duodenal secretions was studied under conditions of maximal activation by porcine colipase and maximal inhibition by sodium taurodeoxycholate. In almost all samples, total lipase activity in 4 mM sodium taurodeoxycholate was activated by the addition of porcine colipase. Activation was linear until saturation by cofactor was reached, and maximum activity was greater than that obtained in the absence of bile salts. At pH 8.0 in 4 mM sodium taurodeoxycholate, lipase activity was due to pancreatic lipase in samples from normal and steatorrheic individuals and was proportional to the concentration of endogenous colipase in samples that could be activated by exogenous colipase. In these samples, therefore, colipase activity could be conveniently assayed as the lipase activity at pH 0.8 in 4 mM sodium taurodeoxycholate. Colipase to total pancreatic lipase ratios varied widely from individual to individual and on average were significantly lower in steatorrheic patients. In individual samples, colipase secretion was stimulated by pancreozymin and secretin roughly in parallel with total pancreatic lipase, but some variation in the ratio of the two was often seen in successive collection periods. Because pancreatic lipase is usually unsaturated with respect to cofactor, lipolytic activity in duodenal secretions may be finely controlled by modulation of colipase secretion.

The inhibitory effect of salicylates on intestinal secretion in 1- to 5-day-old calves given Escherichia coli heat-stable enterotoxin (ST)-induced intestinal fluid response was investigated. Purified ST was diluted in isotonic saline solution to obtain 1:10, 1:25, 1:50, 1:75, and 1:100 dilutions. Each dilution (1 ml) was inoculated into ligated loops in the distal part of the jejunum of each calf. Acetylsalicylic acid (aspirin) given orally (100 mg/kg) at 4 hours before ST was inoculated did not substantially alter the intestinal fluid response to ST. Sodium salicylate (IV) infusion, begun simultaneously when, or at 1 hour after, ST was inoculated, significantly (P less than 0.05) decreased fluid accumulation in those loops inoculated with ST dilutions of 1:25 or greater. The sodium and potassium concentrations of the accumulated fluid did not differ significantly between or within treatment groups. These results indicate that sodium salicylate infusion may be beneficial in treating enterotoxic colibacillosis in calves. Aspirin given orally at the dose used in the present study, would not have any beneficial effect.

Neurotensin (NT) is released from N cells in the small intestinal epithelium. Among other effects NT is known to elicit fluid secretion in the small intestine. This study was carried out in order to elucidate the mechanism by which NT elicits this secretion. Neurotensin infusions at two rates (4.5 and 45 pmol min-1 kg-1 body wt) to isolated segments of cat ileum in vivo, caused a steady rate of net fluid secretion and a release of vasoactive intestinal polypeptide into the mesenteric vein. The secretion was totally inhibited by tetrodotoxin. Hexamethonium, a nicotinic receptor antagonist, inhibited the secretion elicited by the lower but not by the higher dose of NT. Met-enkephalin also inhibited the induced secretion while pyrilamine, a histamine-I receptor antagonist had no effect. No significant change in enteric blood flow was caused by the NT infusion. These results indicate that NT elicits a nervous reflex in the enteric nervous system which, accordingly, turns the transport of the enterocytes into net fluid secretion.

Jejunal fluid secretion induced by perfusion with oleic acid can be reduced by the addition of cholesterol. The present study was performed to test the specificity of this effect by comparing the effects of cholesterol with that of a plant sterol, beta-sitosterol during perfusion of the jejunum in healthy volunteers. In addition, we compared the solubilities of cholesterol and beta-sitosterol in micellar solutions and their jejunal absorption rates. One millimolar beta-sitosterol was as effective as 1 mM cholesterol in reducing jejunal fluid secretion induced by 6 mM oleate (n = 7). In mixed micellar solutions consisting of 10 mM taurocholate and 6 mM oleate, solubility of beta-sitosterol is about one third of cholesterol solubility. When cholesterol was gradually replaced by beta-sitosterol in the incubation mixture, beta-sitosterol reduced cholesterol solubility to a greater extent than would be expected from an equimolar replacement of cholesterol by beta-sitosterol. Absorption of beta-sitosterol was limited by its solubility in mixed micellar solutions and both sterols were absorbed at equal rates as long as their solubility limits were not exceeded (n = 5).

Intravenous injection of caseine hydrolysate, hydrolysin or amino-peptide to dogs was not attended by any substantial changes in the activity of retinylpalmitate- and retinyl-acetate-hydrolase in the intestinal juice, as compared to the juice secreted on an empty stomach. The mutual relation of these enzymes activity in the intestinal juice and jejunal wall was dissimilar, which testifies to their different localization in the intestinal tissues.

Chronic experiments on dogs with gastric and duodenal fistulas were made to study the effect of pentagastrin (6 micrograms/kg, s. c.) on the motor and secretory components of periodical activity of the gastroduodenal organs. Gastric secretion was collected from the open fistulas. To detect the role of the nervous mechanisms, subject to comparison were similar parameters of the periodic activity in 5 dogs with intact stomach innervation and in 6 dogs with preliminary circular gastrotomy in the upper third of the fundal part. Gastrotomy did not impair the periodical rhythm but led to the prolongation of the activity periods, decreased the contraction amplitude and shortened the periods of rest. The quantity of the periodical duodenal secretion was also diminished. In dogs with intact stomach innervation, pentagastrin inhibited the periodic contractions, stimulated the duodenum motility and caused an intensive special period of duodenal secretion. In disturbed innervation, these effects were less pronounced or completely disappeared. It is concluded that central parasympathetic innervation plays an important role in he mechanism of the pentagastrin effect on the periodic activity of the gastroduodenal organs.

The effect of VIP and somatostatin on secretion of epidermal growth factor and bicarbonate from Brunner's glands was investigated in the rat. Vasoactive intestinal polypeptide infused in doses of 10 and 100 ng/kg/h significantly increased epidermal growth factor and bicarbonate output, but the concentrations did not change. Somatostatin infused at doses of 1, 10, 100 and 1000 ng/kg/h against a background of VIP 100 ng/kg/h inhibited in dose-dependent fashion the stimulated epidermal growth factor and bicarbonate outputs from rat Brunner's gland pouches. Also basal secretion was inhibited by somatostatin. Infusion of antisomatostatin serum stimulated Brunner's gland secretion. By immunohistochemical studies of rat duodena, it was found that epidermal growth factor, is almost exclusively present in the secretory cells of Brunner's glands. It is concluded that VIP stimulates secretion of epidermal growth factor and bicarbonate from Brunner's glands, an effect which is inhibited by somatostatin. A possible role for somatostatin in the control of Brunner's gland secretion is suggested.

In previous reports we have suggested that nervous reflexes are involved in the pathophysiology of cholera secretion and that these nervous reflexes involve a cholinergic synapse and a neuron with vasoactive intestinal polypeptide (VIP) as neurotransmitter. These proposals were further analyzed in this study. Tetrodotoxin (TTX) and lidocaine applied on the serosal surface inhibited cholera secretion in segments of rat small intestine. Fluid absorption in control rats was not significantly changed. Hexamethonium given i.v. decreased cholera secretion in the cat. No additional inhibition of cholera secretion was observed after giving TTX close i.a. Furthermore, the intestinal secretion evoked by VIP was not influenced by hexamethonium given i.v. or TTX given close i.a. The present observations support the hypothesis of a role for nervous reflexes in cholera secretion. The results suggest that at least a major part of the proposed nervous reflex(es) in cholera have a cholinergic synapse. Furthermore, the VIP-ergic neuron is situated "distal" to the cholinergic neuron in the reflex(es) closer to the effector cells.

The possible role of local motility in the pathogenesis of duodenal ulcers was investigated in rats using cysteamine. Duodenal motor activity was measured as intraluminal pressure recordings by means of a balloon positioned in the proximal duodenum. Subcutaneous administration of cysteamine (100 mg/kg) produced two linear bandlike lesions in the proximal duodenum within 6 hr. This dose of cysteamine significantly increased gastric acid secretion in acute fistula rats, and decreased duodenal HCO3- secretion caused by acid. During this period, this agent inhibited gastric motility but did produce markedly enhanced contractions in the duodenum. The changes in duodenal motility appeared within 5-10 min and were dose-dependent for cysteamine (10-100 mg/kg). Pretreatment with subcutaneously administered atropine (10 mg/kg), 16,16-dmPGE2 (30 micrograms/kg) or dopamine (10 or 30 mg/kg) significantly reduced the development of duodenal lesions caused by cysteamine, the inhibition being 86.8%, 49.7%, 54.5% or 67.8%, respectively. In the presence of cysteamine, dopamine had minimal effect on both acid and HCO3- secretion, while atropine or 16,16-dmPGE2 markedly inhibited acid secretion or increased HCO3- secretion, respectively. The enhanced duodenal motility induced by cysteamine was blocked partially by atropine and only slightly by 16,16-dmPGE2. Dopamine showed a dose-dependent inhibition on the duodenal hypermotility following cysteamine, and at 30 mg/kg almost completely abolished the development of contractions. These results suggest that abnormal hypermotility in the duodenum may be partly involved in the pathogenesis of cysteamine-induced duodenal ulcers.

We studied the influence of morphine on intestinal secretion induced by three different secretogogues in an attempt to elucidate the mechanism for its antisecretory activity. In rabbit ileal mucosa in vitro morphine (10(-4) M) did not influence the electrical response to the subsequent administration of prostaglandin E2 or of acetylcholine but did inhibit the net secretion of chloride provoked by both agents and prevented the reduction of sodium adsorption induced by the prostaglandin. Morphine reduced the peak electrical response to cholera toxin and reduced toxin-induced net chloride secretion. The modes of action of morphine appeared to be by both enhancing adsorption, as it does in control, nonsecreting mucosa, and by inhibiting secretogogue activity.

1 Anesthetized rats (225 to 300 g) were used to study the inhibitory effect of morphine on fluid secreted by the small intestine. 2 Small intestinal fluid secretion was stimulated by infusion of prostaglandin E1 (PGE1) into the aortic arch, the jejunum being more sensitive than the ileum. Infusion of PGE1 2 microgram/min caused maximal net fluid secretion in the jejunum but inhibited net fluid absorption in the ileum. 3 Morphine caused a dose-related inhibition of maximal PGE1-stimulated fluid secretion in the jejunum. At the higher doses of morphine used (5 to 20 mg/kg) the fluid transporting function of the jejunum was restored almost to normal net absorption. 4 The inhibitory effect of morphine on PGE1-stimulated fluid secretion was antagonized by naloxone. Naloxone caused a parallel shift to the right of the dose-response curve for morphine. 5 Two other narcotic analgesics were assayed relative to morphine and their descending order of potency was oxymorphone greater than morphine greater than pethidine. 6 It is suggested that the antisecretory effect of morphine in the small intestine may contribute to its efficacy as an anti-diarrhoeal drug. Further studies on the rat jejunum may show it to be a useful model for predicting narcotic drug activity and as such, may give some insight into the mechanisms of action of these drugs.

The effects of net volume secretion on blood flow, oxygen extraction, and oxygen extraction, and oxygen uptake were analyzed in autoperfused segments of cat ileum. Intestinal secretion was induced by local intraarterial infusion of glucagon, histamine, theophylline, prostaglandin E1, or vasoactive intestinal peptide, and, by intraluminal placement of cholera toxin or ricinoleic acid. Net volume secretion rates were determined using a volume recovery method. Intestinal oxygen uptake was increased by all secretagogues. The increases oxygen uptake by the screening intestine resulted from an increased blood flow or oxygen extraction or both. Significant positive correlations between intestinal oxygen uptake and secretion rate were acquired only during cholera toxin, theophylline, and prostaglandin E1, secretion. The results indicate that the metabolic work incurred in the small bowel during secretory states greatly exceeds that reported for the absorptive state.

Small bowel cutaneous fistula appearing after laparotomy was treated with the tetradecapeptide somatostatin in six patients to reduce the volume and enzyme content of the intestinal secretion. Continuous intravenous infusion of somatostatin diminished output from the fistula in all cases. Spontaneous fistula closure occurred after 11 to 33 days of treatment in four patients. There were no complications such as sepsis, peritonitis, or wound or skin problems from the contact with intestinal secretion. The hospital stay ranged from 19 to 50 days and bowel function was restored to normal. These preliminary results indicated that somatostatin can promote healing of small bowel fistula by inhibiting intestinal secretions.

Methylxanthines produce intracellular accumulation of cyclic 3'5'-AMP (cAMP) by inhibition of phosphodiesterase and mucosal cAMP accumulation. Cyclic AMP is thought to mediate small intestinal secretion caused by some enterotoxins, hormones, and methylxanthines. These studies were designed to evaluate the effect of caffeine on small intestinal net fluid movement and transit times. The administration of caffeine in amounts ordinarily contained in many beverages and medications (75 to 300 mg) resulted in striking net secretion in the jejunum which lasted at least 15 minutes. This occurred in six of seven studies. Baseline net absorption of 0.5 ml per cm per hr was reversed to net secretion of 6.0 +/- 2.2 ml per cm per hr after oral caffeine ingestion (P less than 0.01). Net secretion also occurred in the ileum in seven of eight studies, but the onset of secretion appeared 35 min later than in the jejunum. These patterns of secretion correlated best with the passage of the intestinal bolus of caffeine rather than plasma caffeine levels. In contrast to other net secretory conditions, which increase the speed of transit, small intestinal transit times, as determined by dye dilution methods, were unchanged by caffeine. It is possible that methylxanthine-induced small intestinal secretion may play a role in the symptoms experienced by some patients with functional diarrhea.

The net rates of glucose and water absorption from, and secretion of water into, the lumen of the rat small intestine were compared using alpha-chloralose, halothane, pentobarbitone, and urethane as anesthetics. Water and glucose transport were determined by recirculation of perfusion fluid through the lumen of the jejunum. Net fluid secretion was stimulated by intraarterial (i.a.) infusion of prostaglandin E1 (PGE1) and vasoactive intestinal peptide (VIP). The results show that the anesthetics used exert only minimal influence on the physiological rates of glucose and water absorption and there is no correlation between the small differences in glucose and water absorption among the anesthetics. However, when the fluid secretory mechanism of the mucosa is stimulated with either PGE1 or VIP, pentobarbitone allows the greatest rates of secretion, but halothane prevents secretion. It is suggested that of the anesthetics used, pentobarbitone is the most appropriate for intestinal secretion experiments.

Clostridium perfringens enterotoxin, when inoculated into the ligated intestinal loop of mice, caused marked distension due to fluid accumulation. The increase in weight of the intestinal loop was proportional to the log dose of enterotoxin within a range from 1 to 16 micrograms. The fluid accumulation was arrested by washing the loop with saline or by injection of the specific anti-enterotoxin serum into the loop 5 or even 30 min after inoculation of the enterotoxin. A significant increase in weight of the loop was found as early as 10 min after inoculation of the toxin. These results may suggest that entergotoxin is neither bound firmly to the mucosal membrane nor permeates into the cells of the intestinal wall. The mouse intestinal loop test is economical, simple to perform, and applicable for quantitative determination of the enteropathogenic activity of C. perfringens enterotoxin.

Approximately 45-cm length of jejunoileum of 7-week-old chickens was found to be responsive and suitable for testing the enterotoxin of Clostridium perfringens by the ligated intestinal loop technique. Injections of 20 to 30 mug of enterotoxin per loop caused positive response of fluid accumulation. Chickens were found to be more convenient and economical for this purpose than other laboratory and domestic animals.

The effects of omeprazole, a benzimidazole derivative, have been determined on the secretory responses to modified sham feeding and pentagastrin, and upon serum gastrin and pancreatic polypeptide concentrations in duodenal ulcer patients. Intragastric administration of omeprazole in doses of 2 and 6 mumol/kg produced, respectively, about 50% and 90% reduction in acid outputs in responses to modified sham feeding and pentagastrin without affecting serum gastrin and pancreatic polypeptide response to modified sham feeding.

The effects of porcine vasoactive intestinal peptide (VIP) and bovine pancreatic polypeptide (PP) on jejunal, ileal, and colonic fluid transport were studied in the rabbit. VIP produced secretion in the small intestine (jejunum greater than ileum) but did not affect absorption in the colon. PP had no secretory effects in jejunum, ileum, or colon. The small intestinal secretion induced by VIP was not associated with raised cAMP concentrations in the mucosa; this suggests that the secretory effects of VIP in vivo are mediated by a mechanism other than stimulation of adenylate cyclase.

In this study a perfusion technique has been used to investigate jejunal secretion in response to the dibasic amino acid L-arginine. L-arginine at 5, 15, and 40 mmol/l in isotonic saline solutions induced net intestinal secretion of water and Na+. The structurally similar dibasic amino acid L-lysine caused net absorption at 5 and 15 mmol/l, and only modest net secretion of water and Na+ at 40 mmol/l, although absorption rates of the two amino acids were similar. D-arginine (15 mmol/l) was without effect on net water and Na+ absorption. L-arginine 15 mmol/l inhibited glucose-stimulated water and Na+ absorption when perfused in the same intestinal segment, but was without effect when perfused in separate jejunal or ileal segments. Parenteral chlorpromazine inhibited L-arginine induced jejunal water and Na+ secretion. Jejunal secretion induced by L-arginine thus appears not to be due to passive osmotic water flow, nor to release of circulating secretagogues. Stimulation of a mucosal secretory process is most likely to be the mechanism.

The use of nicotinic acid for preventing intestinal secretion caused by cholera toxin and by the heat-stable enterotoxin of Escherichia coli has been investigated in the weanling pig. Secretory effects were measured in ligated jejunal loops of halothane-anesthetized pigs by dilution of a nonabsorbable marker added to the loop fluid. Different routes of administration and different initial pH values for nicotinate solutions were studied to determine optimal conditions for secretory inhibition. The neutral sodium salt of nicotinic acid had no significant antisecretory activity under any conditions used in these trials. Inhibition of secretion was most effective with partly neutralized nicotinic acid at pH 4.5 added directly to loops containing enterotoxin. Net fluid secretion induced by cholera toxin or heat-stable enterotoxin of E. coli was prevented by this treatment. Reversal of secretion was not accompanied by any measurable changes in cyclic nucleotide concentration in intestinal mucosa. Nicotinic acid antagonism of a secretory step common to cholera toxin and heat-stable enterotoxin of E. coli but subsequent to cyclic nucleotide involvement is indicated by these data.

The possible role of vasoactive intestinal peptide as an inhibitor of stimulated gastric secretion was investigated. Awake dogs with Heidenhain pouches were stimulated with pentagastrin alone and in combination with intraduodenal instillation of various potential inhibitors of gastrointestinal secretion including isotonic phenylalanine, 3 percent hypertonic saline solution and 0.16 normal hydrochloric acid. Plasma vasoactive intestinal peptide is significantly increased by pentagastrin, and this release is enhanced by intraduodenal hydrochloric acid. Simultaneously, there is significant inhibition of pentagastrin-stimulated Heidenhain pouch secretion. These findings provide evidence for a possible physiologic role of vasoactive intestinal peptide as an inhibitor of gastric secretion, at least in dogs.

Cholera toxin produces intestinal secretion and elevation of intestinal cyclic AMP. Nicotinic acid has been shown to prevent these responses. The effect of nicotinic acid on cholera toxin-induced secretion could be caused by decreased plasma-to-lumen flux, increased lumen-to-plasma flux, or a combination of both. The purpose of this study was to define the effects of nicotinic acid on net fluid movement and unidirectional sodium fluxes in rabbit jejunal loops exposed to cholera toxin. In the untreated animals receiving no nicotinic acid, the cholera toxin-exposed loops secreted 0.91 ml/cm/4h above the control loops receiving no cholera toxin (p < 0.01). On the other hand, pretreatment with 100 mg/kg nicotinic acid caused a striking decrease in secretion in the cholera toxin loop, so that the cholera toxin loop was not significantly different from the control loop. Unidirectional sodium fluxes in untreated animals showed that cholera toxin caused an increase in the plasma-to-lumen flux and a decrease in the lumen-to-plasma flux. Both effects were abolished by pretreating the animals with nicotinic acid. These studies indicate that nicotinic acid prevents cholera toxin-induced secretion by restoring the unidirectional fluxes to control levels.

R51619, an agent reported to release endogenous acetylcholine, increased the potential difference and short-circuit current across non-stripped, but not stripped sheets of rat mid-intestine. The response was abolished by both hexamethonium and atropine. R51619 stimulated fluid accumulation by intestinal loops in-vivo suggesting its predominant effect is to stimulate anion secretion. These results are consistent with R51619 releasing endogenous acetylcholine within the myenteric plexus to activate postganglionic cholinergic fibres which stimulate intestinal secretion via muscarinic cholinoreceptors.

The actions of secoverine and atropine on bethanechol-induced intestinal secretion, hypermotility and transintestinal potential difference were investigated in the rat jejunum in-vivo. Both secoverine (10(-7) mol kg-1) and atropine (1.2 X 10(-9) mol kg-1) inhibited motility at doses that did not affect secretion or transintestinal potential difference. However, secoverine was a less potent antagonist of all the bethanechol-induced changes than atropine. Increases in transintestinal potential difference were more closely related to production of fluid secretion than to increases in motility.

Three patients with external fistulas from the gastrointestinal tract were treated with somatostatin, a peptide which inhibits pancreatic, gastric and intestinal secretion. Although somatostatin reduced fistula output in two patients and possibly prevented haemorrhage in one, it did not induce fistula closure in any; moreover on withdrawal of somatostatin one patient developed life threatening gastrointestinal haemorrhage and a transient fistula hypersecretion occurred in the others. This experience of somatostatin treatment was less favourable than that previously reported in other small series. Positive nitrogen balance was probably not maintained during treatment in the three patients reported here and in one patient in a previous study in whom somatostatin was ineffective; the peptide may only promote fistula closure in adequately nourished patients.

Ethacrynic acid (EA) has been reported to reduce cholera toxin-induced intestinal fluid secretion in the intact animal. We explored the nature of this inhibition in vitro by measuring unidirectional, transmural fluxes of (22)Na and (36)Cl across isolated rabbit ileal mucosa. Under control conditions (short-circuited mucosa bathed in bicarbonate-Ringer), there was net absorption of Na and Cl. Theophylline (10 mM), cyclic AMP (5 mM), and cholera toxin (added in vivo) abolished net Na flux and produced net Cl secretion. In the presence of either theophylline or cAMP, addition of 0.1 mM EA to the serosal bathing solution abolished net Cl secretion and restored net Na absorption. Cholera toxin-treated mucosa was exposed to 0.05 and 1.0 mM EA. The lower concentration restored net Na absorption but did not significantly reduce Cl secretion. The higher concentration abolished net transport of both Na and Cl. Short-circuit current and Na flux measurements in the presence and absence of glucose indicated that 0.1 mM EA does not inhibit glucose-coupled Na transport. Short-circuit current measurements in the presence of 1.0 mM EA suggested that even this concentration of EA does not inhibit glucose-coupled Na transport. Thus EA appears to specifically inhibit Cl (or NaCl) secretion without inhibiting the absorptive Na "pump." The anti-secretory effect of 0.1 mM EA does not appear to result from inhibition of adenylate cyclase since secretion stimulated by addition of 5 mM cAMP was abolished. Furthermore, 0.1 mM EA did not significantly reduce theophylline-augmented and cholera toxin-augmented cAMP levels in ileal mucosa. We conclude that EA interacts specifically with the active Cl (or NaCl) secretory mechanism of the small intestine at a step beyond generation of cAMP.

A randomised controlled trial was conducted to investigate the ability of chlorpromazine to reduce intestinal secretion in cholera. Chlorpromazine had reduced loss of intestinal fluid in animals with diarrhoea induced by cholera toxin, and in a preliminary study the drug had reduced purging in patients with cholera. Forty-six adults with cholera were included in the randomised trial. Of these, 34 were treated with chlorpromazine (1 mg/kg or 4 mg/kg either by mouth or intramuscularly) and 12 served as controls. After treatment with the drug there was a significantly greater reduction in the rate of fluid loss in the treated patients than in the controls during the first (p less than 0.005), second (p less than 0.05), and fourth (p less than 0.01) eight-hour periods, but not during the third eight-hour period; the dose of 4 mg/kg was only marginally more effective than 1 mg/kg. The effect of chlorpromazine was strikingly biphasic, with one peak during the first eight hours and another 24-32 hours after administration. Chlorpromazine also significantly reduced the duration of diarrhoea, frequency of vomiting, and amount of intravenous fluid required. The drug induced mild sedation and no hypotension in these well-hydrated patients. These findings confirm the effectiveness of chlorpromazine in reducing fluid loss in cholera. A sedative effect, however, especially in children, may limit its usefulness and requires further study.

Inactivation of botulinum toxins type B-L, B-M, C-L and E in the digestive juices of man and ducks was determined. Botulinum toxins of the M size (B-M and E) lost their toxicity completely in the gastric juices of both man and ducks, but toxins of the L size (B-L and C-L) lost their toxicity only partially. The toxins were hardly affected by duodenal fluid even after exposure to gastric juice. The toxins were not inactivated by cecal fluid from ducks. Since human digestive juices and those from ducks appeared to have comparable effects on the inactivation of toxin, differences in susceptibilities of the animal species to orally acquired toxins are in all probability not caused by digestive action of those species.

In an effort to demonstrate a physiologic role of vasoactive intestinal peptide, awake dogs with either Heidenhain pouches or Thiry-Vella loops and duodenal cannulas with duodenoduodenostomies to prevent obstruction were stimulated with meat meals given by mouth and infusions of various substances given intraduodenally, including hypertonic saline solution or 0.16 normal hydrochloric acid. Stimulated Heidenhain pouch secretion was significantly inhibited by concomitant intraduodenal administration of hydrochloric acid. Plasma vasoactive intestinal polypeptide was highest in the animals who received hydrochloric acid intraduodenally among all the intraduodenal stimuli. These findings support a role for vasoactive intestinal polypeptide as a physiologic inhibitor of gastric secretion, at least in dogs.

The effect of heat stable and heat labile Escherichia coli enterotoxins or cholera toxin in combination with theophylline on net water, sodium and chloride and unidirectional sodium and chloride fluxes was examined in acute isolated loops of jejunum of weanling swine. The effect of heat stable enterotoxin in combination with theophylline was determined in loops located in the proximal jejunum, while combinations of theophylline and either heat labile enterotoxin or cholera toxin were studied in the distal jejunum. In each situation the addition of theophylline resulted in an additive rather than a synergistic increment of intestinal secretory activity. This study implies that the intestinal adenyl cyclase system and enterotoxin induced intestinal secretion may not be directly related in the swine small intestine.

Dietary fibres (Plantago ovata seeds, P. ovata husks, wheat bran, alfalfa, pectin, xylan) were incubated in vitro with gastrointestinal enzymes (pepsin, trypsin, chymotrypsin, lipase, alpha-amylase, maltase, lactase) in buffer solutions at concentrations of 1-5% for 10-30 min at 37 degrees C. All fibres induced sometimes pronounced changes in enzyme activity, but the effect of the different fibres on the various enzymes varied individually and was not predictable. Both P. ovata preparations had no (pepsin, trypsin, alpha-amylase) or only stimulating (chymotrypsin, lipase, lactase) actions whereas all other fibres showed inhibiting as well as stimulating influences. Wheat bran induced the most pronounced alterations increasing lipase, maltase and lactase activity and inhibiting alpha-amylase activity. Pectin and xylan were comparable in decreasing lipase and pepsin activity and in increasing chymotrypsin activity but had opposite effects on maltase activity. Alfalfa was able to stimulate lactase and lipase activity but depressed trypsin and alpha-amylase activity. The inactivation of enzymes by dietary fibres can, at least partly, be explained by adsorption to the fibre or by the presence of enzyme inhibitors especially in natural compounds. The reasons for activation processes are unknown. As enzyme activities are decisive for food digestion, the properties of the individual fibres should be carefully considered when used as dietary supplement in physiological or pathological conditions.

For detection of cholera enterotoxin activity, suckling hamster, mouse, and rat models were compared. It was found that not only suckling mice but also suckling rats and hamsters were sensitive to cholera enterotoxin. Among these models, suckling hamsters were the most sensitive and gave positive results with about 1/100 the cholera toxin seen in suckling mice and rats.