Distinct mechanisms for stimulation of intestinal secretion by vasoactive intestinal peptide (VIP) and glucagon.
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Animals↗
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[Water and electrolytes intestinal secretion (author's transl)].
This paper reviews methods used for studying intestinal secretion in man and animals, fasting and post prandial intestinal secretion, as well as that induced by bacterial enterotoxins, hormonal stimuli, some endocrine tumours and various intraluminary agents; finally the possible mechanisms and sites of intestinal secretion are discussed. That the intestine secretes fluid under physiological conditions is not proven but seems very likely. Several mechanisms seem to be involved in the production of fluid by the intestine. The adenylate-cyclase-cyclic adenosine monophosphate (AMPc) system is currently thought to play a major role in endotoxins and some hormone-induced secretions. The site of intestinal secretion remains a matter of discussion: both crypts and villi seem to participate in the secretory process.
Adenylyl Cyclases↗
Intestinal secretion induced by vasoactive intestinal polypeptide. A comparison with cholera toxin in the canine jejunum in vivo.
The effect of vasoactive intestinal polypeptide (VIP) on intestinal water and electrolyte transport and transmucosal potential difference was investigated in the dog jejunum in vivo and compared to secretion induced by cholera toxin. Isolated jejunal loops were perfused with a plasma-like electrolyte solution. VIP (0.08 mug/kg per min) was administered directly into the superior mesenteric artery by continuous infusion over 1 h. From a dye dilution method, it was estimated that a mean plasma VIP concentration of 12,460 pg/ml reached the loops. VIP caused secretion of water and electrolytes; for example, chloride: control, 8 mueq/cm per h absorption; VIP, 92 mueq/cm per h secretion. A marked increase in transmucosal potential difference (control, -1.0 mV; VIP, -5.9 mV, lumen negative) occurred within 1 min after starting VIP infusion. Analysis of unidirectional fluxes showed increased plasma-to-lumen flux of sodium and chloride and decreased lumen-to-plasma flux of sodium. Chloride and bicarbonate were actively secreted against an electrochemical gradient. Although sodium secretion occurred down an electrochemical gradient, flux ratio analysis suggested a component of active sodium secretion. VIP caused a slight increase in protein output into the loops; light microscopy revealed capillary dilatation and closed intercellular spaces. The effect of VIP was readily reversible. Except for the delayed onset of secretion, the effect of cholera toxin was qualitatively similar to VIP; however, capillary dilatation and increased protein output were not noted with cholera toxin.
Animals↗
Mechanism of production of intestinal secretion by elevated venous pressure.
A study was carried out to elucidate the physiological mechanisms responsible for the intestinal secretion produced by venous pressure elevation. In dogs, measurements were made of the rate and composition of small intestinal secretion, rate of flow and composition of intestinal lymph, plasma composition, and mucosal water content, all in response to elevations of intestinal venous pressure. Venous pressure elevations above a threshold value of 30-35 cm H2O produce secretion at a rate of approximately proportional to the value of the pressure minus the threshold value. Above the threshold value, there were large increases in the rates of lymph flow and net sustained transcapillary filtration. These rates were also roughly proportional to the incremental venous pressure. It is concluded that intestinal secretion produced by elevated venous pressure is almost surely secretory filtration, a passive process with the driving force for secretion an increase in mucosal tissue fluid pressures to values of only some 4-6 cm H2O. The increased tissue fluid pressure not only provides the driving force but also produces an increase in the hydraulic permeability of the epithelium without which the driving force would be ineffective. The transepithelial channels are large enough to permit insulin to pass freely and even plasma protein to pass in large amounts, and hence are most probably intercellular. Secretory filtration probably represents a general pathophysiological response of transporting epithelia to elevated tissue fluid pressure. It is proposed that the threshold value for secretion and associated changes is explained by dilution of the tissue fluid protein colloid osmotic pressure in a small subepithelial, juxtacapillary compartment.
Animals↗
Difference between the antisecretory mechanisms of opioids and the somatostatin analogue octreotide in cholera toxin-induced small intestinal secretion in the rat.
The antisecretory effect of morphine and the somatostatin analogue octreotide was studied on cholera toxin-induced secretion in anaesthetized rats. Small intestinal secretion was induced with cholera toxin. Morphine (6 mg/kg b.wt.) and the somatostatin analogue octreotide (3 micrograms/kg b.wt.) reduced the cholera secretion in rats whose intestines had been subjected to sympathetic denervation. This was in contrast to the secretion elicited by helodermin which was unaffected by octreotide and morphine in the presence of nicotinic ganglionic blockade. The alpha-adrenergic receptor blocker phentolamine (1-2 mg/kg b.wt. i.v.) and the inhibitor of sympathetic transmitter release guanethidine (5 mg/kg b.wt. i.v.) abolished the antisecretory effect of morphine on the cholera secretion in contrast to the antisecretory effect of somatostatin which was unaffected by the alpha-blockade. It is proposed that the antisecretory effect of morphine and octreotide on cholera toxin-induced secretion was conducted at a step prior to the activation of the secretory epithelium and that the antisecretory effect of morphine was mediated indirectly by interaction with sympathetic nerve terminals in the intestine. The findings are consistent with a model where octreotide and morphine inhibit the nervous secreto-motor reflex activated by the cholera toxin.
Animals↗
Prostaglandin E in cholera toxin-induced intestinal secretion. Lack of an intermediary role.
Prostaglandin E1 (PGE1) and cholera enterotoxin stimulate small-intestine mucosal adenylate cyclase and intestinal secretion of water and electrolytes. The previous suggestion that PGE may mediate cholera-toxin effects was explored in these studies. Closed rabbit jejunal loops were injected in vivo with cholera toxin and compared to similar loops in the same animal injected with buffer. Loop mucosal homogenates and intestinal secretions were analyzed by radioimmunoassay for cAMP and PGE concentrations. Cholera toxin produced significant increases in mucosal and intestinal fluid cAMP; however, there were no significant increases in PGE in the toxin-treated loops when compared to the control loops. In addition, there was no correlation between cAMP and PGE in the same samples. These studies indicate that cholera toxin stimulates intestinal cAMP anc secretion independent of PGE synthesis and provide evidence against a specific role for PGE in mediating cholera-toxin effects.
Animals↗
Antibody response in the intestinal secretions of volunteers immunized with various cholera vaccines.
The efficacy of various cholera vaccines in eliciting an intestinal antibody response was assessed in human volunteers who received oral live, oral killed, or parenteral cholera vaccines, or placebo. The intestinal immune response in terms of antibacterial and antitoxin antibodies was determined 2 and 4 weeks after immunization. By means of the mouse peritoneum opsonization assay and the infant mouse protection test, antibacterial activity could be detected in the intestinal secretions of volunteers who had been immunized either orally or by the parenteral route. Significant protective activity and duration of immunity were observed with the oral killed vaccine. The bacteriological data indicated the absence of significant intestinal colonization of the live attenuated strain after oral administration, and probably explains the observed lack of effectiveness of the oral vaccine compared with that of the killed vaccine. The predominant immunoglobulin class of intestinal antibody was found to be IgA. None of the vaccines used in the study elicited significant antitoxin activity in the intestinal secretions, as determined by the skin permeability neutralization test.
Adult↗
Ion transport changes during calcitonin-induced intestinal secretion in man.
Previous studies have shown that synthetic salmon calcitonin (SCT) infused intravenously causes secretion of water and electrolytes in the jejunum of normal human subjects. The present experiments were carried out to learn more about the nature of this intestinal secretory process. During SCT- or synthetic human calcitonin (HCT)-induced intestinal secretion, the following observations were made: (1) There was no change in potential difference; (2) Cl was secreted against an electrochemical gradient; (3) unidirectional Na flux out of the lumen was decreased while the opposite flux was normal; (4) luminal pCO2 fell; (5) addition of glucose to the jejunal contents stimulated Na abdsorption, and this in turn counteracted the secretory effect of calcitonin. These findings suggest that calcitonin induces active Cl secretion and inhibits active Na absorption, and that HCO3 absorption is reduced by virtue of OH secretion; furthermore, jejunal glucose absorption and glucose-stimulated Na absorption are intact during calcitonin-induced secretion. Intravenous infusion of HCT caused intestinal secretion only when blood levels were much higher than occur physiologically; therefore, calcitonin is probably not a mediator of spontaneous variations of intestinal transport in normal people. However, because calcitonin induces secretion in the ileum as well as in the jejunum, hypercalcitonemia (within the range commonly found in patients with medullary carcinoma of the thyroid) could be a cause of severe secretory diarrhea.
Action Potentials↗
Diquat-induced intestinal secretion in the anaesthetized rat.
1. Diquat (1,1'-ethylene-2,2'-bipyridilium) is a non-selective desiccant herbicide which, when administered orally to mammalian species, causes significant secretion of fluid into the lumen of the gastrointestinal tract. In order to characterize this secretory response in more detail the effect of sublethal doses of diquat dibromide (DQBr2) on intestinal secretion was investigated in vivo in the jejunum of anaesthetized rats. 2. Ligated segments of jejunum (10 cm) which were prepared in groups of up to five animals were filled with 500 microliters of isosmotic DQBr2 solutions with concentrations ranging from 1-100 mM and maintained in the anaesthetized rat for 1, 2 or 3 h; in control experiments a solution of 100 mM NaBr was used. 3. It was found that while all of the fluid instilled into the segments was absorbed in the control experiments, there was both a dose- and time-dependent secretory response to DQBr2. Maximal fluid secretion occurred after treatment with 50 mM DQBr2 for 3 h. 4. Histological assessment of the jejunum revealed an increase in cell exfoliation and evidence of luminal distension after incubation with DQBr2. However, no structural damage to the mucosa could be seen to account for the fluid secretion. 5. The model described provides a quantitative means of evaluating intestinal secretion and may be used for elucidating the mechanism by which diquat alters fluid transport processes.
Animals↗
Methylxanthine induced small intestinal secretion.
Methylxanthines, being potent phosphodiesterase inhibitors, produce increased intestinal cyclic AMP levels and would be predicted to produce increased net intestinal fluid secretion. Their effect when presented to the intestinal lumen, which would be analogous to human ingestion, had not been previously determined. Isolated loops of rat jejunum were perfused with solutions of caffeine and theophylline in vivo. There was a decrease in net fluid absorption in both neonatal and mature animals exposed to theophylline. Mature animals exposed to caffeine developed a prompt secretory response, comparable to thax induced by cholera toxin. The data indicate that methylxanthines are potent intestinal secretagogues when administered intraluminally and suggest that secretory stimulation could be important in the gastrointestinal symptomatology elicited in man by these compounds.
Animals↗
[Hemagglutinating antibodies in the serum and intestinal secretions of rats infested by Nippostrongylus brasiliensis].
Nippostrongylus brasiliensis infected rats responded with the formation of hemagglutinating antibodies in both serum and intestinal secretions. After the first infection seric antibody titers were quite weak but increased sharply after challenge. Intestinal secretion hemagglutinines remained at constant level after both infections. This result represents a new approach in our understanding of the immune mechanism towards this parasite in rats.
Agglutinins↗
Importance of the intestinal inflammatory reaction in salmonella-mediated intestinal secretion.
The ability of Salmonella typhimurium to invade the intestinal epithelium is essential to the pathogenesis of salmonella-induced intestinal secretion. This invasion is accompanied by an intense acute inflammatory reaction. The present study tests the hypothesis that the acute inflammatory reaction may have a role in the pathogenesis of salmonella-induced secretion. Two groups of rabbits infected with S. typhimurium were studied: normal animals and animals pretreated with nitrogen mustard. Nitrogen mustard depletes the polymorphonuclear leukocyte pool and thereby prevents the formation of an acute inflammatory reaction. In vivo ligated ileal loops were constructed and infected 72 h after nitrogen mustard administration when polymorphonuclear leukocytes were undetectable. Nitrogen mustard treatment markedly inhibited salmonella-induced secretion. Ileal histology in normal animals infected with S. typhimurium revealed an intense acute inflammatory reaction, while in animals pretreated with nitrogen mustard only a rare polymorphonuclear leukocyte was seen. The antisecretory effect of nitrogen mustard was not merely a nonspecific effect since nitrogen mustard treatment did not inhibit cholera toxin-induced secretion and did not alter either ileal morphology nor the activities of various intestinal enzymes in normal animals. Nitrogen mustard also did not alter the virulence of the inoculated S. typhimurium. These data suggest that the mucosal inflammatory reaction induced by salmonella invasion may be important to the pathogenesis of the salmonella secretory process. The mechanism by which the inflammatory reaction stimulates secretion is not known.
Animals↗
Ionic composition of small intestinal secretion induced by PGE2.
Small intestinal fluid secretion induced by oral prostaglandin E2 in fasted rats was analyzed for various ionic components. Rat intestinal fluid had elevated calcium and potassium as well as decreased sodium and chloride concentrations relative to plasma electrolytes. Either low dose prostaglandin (0.15 mg/kg) or 1 ml of intragastric mannitol (5%) induced accumulation in the small intestine of fluid that had elevated chloride and depressed calcium and sodium concentrations compared to vehicle-treated controls. Higher doses of prostaglandin (1.0 mg/kg) led to secretions with increased sodium and chloride concentrations with respect to mannitol-induced fluid. Electrolyte concentrations in fluid induced by low dose prostaglandin appear to be similar to those in fluid caused by osmotically-induced changes. Higher doses of prostaglandin E2 induce additional electrolyte alterations which may result from modified gut transport of water and ions.
Animals↗
Effects of indomethacin on intestinal secretion, prostaglandin E and cyclic AMP: evidence against a role for prostaglandins in cholera toxin-induced secretion.
The effects of indomethacin on intestine mucosal cAMP, intestinal fluid secretion, and mucosal and fluid PGE were studied in rabbits in vivo following challenge with cholera toxin. Indomethacin had no effect on cholera toxin-induced fluid secretion or cAMP accumulation. Inhibition of PGE synthesis was achieved by the administration of two but not one injection of indomethacin. These studies provide evidence against a role for PGE in mediating cholera toxin-induced secretion and point out the need to measure prostaglandin levels when using prostaglandin synthetase inhibitors in vivo.
Animals↗
Failure to reverse cholera toxin induced intestinal secretion by agents which decrease mucosal cAMP.
The feasibility of reducing intestinal secretion by the use of agents which decrease intestinal mucosal cAMP concentration has been investigated in the weanling pig and the rabbit. Three different agents for decreasing mucosal cAMP concentration were studied. The cyclic nucleotide phosphodiesterase activator, imidazole, significantly reduced mucosal cAMP concentrations only in the weanling pig. Intraluminal 2'-deoxyadenosine-3'AMP inhibited adenylate cyclase and caused a decrease in mucosal cAMP concentration in both the pig and the rabbit. The introduction of the heat-stable enterotoxin of Escherichia coli into pig jejunal segments also gave lowered mucosal cAMP concentrations. While these three agents effectively reduced cAMP concentrations in intestinal mucosa, they were ineffective in reducing the net fluid secretory effects of cholera toxin. Secretion caused by cholera toxin apparently persists independent of the temporary changes in cAMP concentration which can be induced by pharmacological agents.
Adenylyl Cyclases↗
Antibodies in the intestinal secretions of rats. Primary and secondary responses to polymeric flagellin.
The antibody responses in serum and secretions obtained from the mucosal surfaces of the small intestine of rats immunized by a parenteral and intestinal route have been compared. Though no significant differences in the mean serum titres were found, the responses of animals immunized via the latter route to large doses of antigen were far less uniform. Apart from the first few days of the primary response, antibody activity was found in three major immunoglobulin classes (IgG2, IgA and IgM), irrespective of the route of immunization. Significant antibody activity appeared in the intestinal surface secretions only after two injections of antigen. In rats immunized parenterally the activity was found only in the IgG2 component. Whilst activity was found in both IgG2 and IgA fractions of the secretions obtained from intestinally immunized rats, it was predominantly of the IgG2 class. The possible significance of this observation is discussed.
Animals↗
Opiates and intestinal secretion.
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Codeine↗
Inhibition of macrophage migration by normal guinea pig intestinal secretions.
The incubation fluid from 24-hr cultures of normal guinea pig small intestines was found to contain activity capable of inhibiting the migration of normal guinea pig peritoneal macrophages. Each of three different culture fluids showed macrophage inhibitory activity in the 25,000-55,000 mol wt range when subjected to Sephadex G-100 gel filtration. One of these three preparations also contained inhibitory activity in the excluded volume. The low molecular weight activity was nondialyzable and heat stable to 56 degrees for 30 min. It was destroyed by boiling for 1 hr, and its activity was reversed by 10(-4)M epinephrine. Based upon these properties it is suggested that this activity was due to migration inhibitory factor (MIF). The high molecular weight inhibitor was stable to heating and its activity was not reversed by epinephrine. This material was most likely endotoxin. The presence of MIF, which may be associated with T-cell activity in the intestine, suggests that cell-mediated immunity (CMI) could play a role in local protection against gut infections. Furthermore, its presence in normal intestinal secretions suggests that some MIF-producing cells are always being stimulated by normal flora. The question is thus raised whether further specific stimulation of local CMI in the gut could be successful.
Animals↗