Intestinal Water Transport Research Articles

Food-based solutions are a viable alternative to glucose-electrolyte solutions for oral hydration in acute diarrhoea—studies in a rat model of secretory diarrhoea

A survey of acute diarrhoea and its treatment, in 3 groups of villages in south India, revealed that use of the World Health Organization oral rehydration solution (WHO-ORS) was poor or virtually non-existent and that several liquid foods were given to children during acute diarrhoea. The effects of the most commonly used, boiled and cooled supernatants of these liquid foods [rice ( Oryza sativa)-water, ragi ( Eleusine coracana)-water, arrowroot ( Maranta arundinacea)-water], and tender coconut-water, and of the bicarbonate- and citrate-WHO-ORS on intestinal water transport were evaluated using a rat model of secretory diarrhoea. All solutions either decreased cholera toxin-induced net water secretion (arrowroot-water) or reversed it to net absorption. Ragi-water produced maximum net water absorption, significantly greater than the WHO oral rehydration solutions. WHO-ORS utilization is poor in some developing countries, and locally used food-based solutions could be used for maintaining hydration or correcting the dehydration due to acute diarrhoea once their effectiveness has been proved by clinical trials.

Effects of food containing betaine/amino acid additive on the osmotic adaptation of young Atlantic salmon, Salmo salar L.

One-year-old salmon ( Salmo salar L.) were reared in freshwater (FW) and fed with either control feed or an experimental feed containing 1.5% of betaine/amino acid additive. After 1 month of rearing in freshwater, some of the fish in each group were gradually acclimated to 39 ppt seawater (SW) over a week, then reared in it for 4 weeks. The rest of the fish were maintained in FW. Physiological samples were taken at the start of the experiment, after 4 weeks' rearing in FW and five successive times during the SW stage. In addition, a group of the FW fish were challenged with SW three times during the experiment using an abrupt change from FW to SW and a further stay of 48 h in SW. The surviving fish were sampled for physiological analyses. The betaine/amino acid additive induced some physiological changes in FW fish. The most marked were a lowered muscle water content and delayed desmoltification of the experimental fish. The additive somewhat improved the capacity to maintain the ionic and osmotic balance in SW but, due to the low number of experimental animals, the difference in SW survival was insignificant. The seawater challenge tests indicated that betaine may also help the fish to maintain the ionic and osmotic balance after abrupt transfer to SW. There seem to be several mechanisms of action: the gill ion extrusion is somewhat enhanced as expressed by elevated gill Na,K-ATPase activity, but the effects on the water and magnesium balance are more pronounced, indicating changes in the intestinal and renal ion and water transport.

Pathogenesis of Shigella diarrhea. XVI. Selective targetting of Shiga toxin to villus cells of rabbit jejunum explains the effect of the toxin on intestinal electrolyte transport.

To examine the mechanism by which Shiga toxin alters intestinal water and electrolyte transport, ligated loops of rabbit jejunum were incubated in vivo with purified toxin and then studied in vivo by single pass perfusion and in vitro by the Ussing chamber voltage-clamp technique. Toxin exposure led to accumulation of water in the jejunal lumen, associated with decreased active basal NaCl absorption. Glucose- and alanine-stimulated Na absorption were also reduced, while toxin had no effect on either basal short-circuit current or the secretory response to theophylline. These observations suggest that Shiga toxin selectively inhibits NaCl absorption without significantly altering active anion secretion. To localize the cellular site of toxin action, populations of villus and crypt cells from rabbit jejunum were isolated and studied. Villus cells had a greater content of the glycolipid Shiga toxin receptor, Gb3, had more toxin binding sites than did crypt cells, and were much more sensitive than crypt cells to toxin-induced inhibition of protein synthesis. These experiments demonstrate that purified Shiga toxin inhibits jejunal fluid absorption without affecting active fluid secretion by a preferential effect on villus cells. The results suggest that this is due to the differential distribution of toxin receptors on villus compared to crypt cells.

COLONIC WATER ABSORPTION IS IMPAIRED DURING SMALL INTESTINAL SECRETION DUE TO CHOLERA TOXIN (CT)

The effects of CT on small intestinal transport of water and electrolytes are well characterized. However, it is not known whether ion and water transport are altered in the colon when CT is present only in the small intestine. Aiming at defining the role of the colon in handling of water and electrolyte transport in such circumstances, we have measured water and ion transport in vivo in rat jejunal and colonic separate loops. Two groups of rats were investigated: in one, CT (1 ug/ml) was instilled in the jejunal loop two hours before separate perfusion of both loops for the ensuing 3 hours with a modified Ringer solution; the other (control) was likewise handled, but without any previous instillation of CT. Results: In CT animals, water transport in the jejunum was significantly (p<0.01) shifted toward secretion (-0.77±2.0 ul/min g wet weight vs. 13.19±1.9 in the controls). Similarly, in CT animals, the simultaneously measured water transport to the colon was also significantly (p<0.01) shifted toward secretion (0.6±2,4 vs. 6.7±1.6 in the controls). Ha net transport paralleled these changes. In conclusion: our data shows that the colon contributes to the overall intestinal secretion seen in cholera infection, even when CT does not interact with its mucosa. It remains to be seen whether such observation relates only to CT-elicited small intestinal secretion or it represents a general pattern linking small and large intestinal transport.

Immune system control of rat and rabbit colonic electrolyte transport. Role of prostaglandins and enteric nervous system.

The role of the immune system in controlling intestinal electrolyte transport was studied in rat and rabbit colon in Ussing chambers. A phagocyte stimulus, the chemotactic peptide FMLP, and a mast cell stimulus, sheep anti-rat IgE, caused a brief (less than 10 min) increase in short-circuit current (Isc). Products of immune system activation, platelet-activating factor (PAF) and reactive oxygen species (ROS), caused a sustained, biphasic increase in the Isc. Ion replacement and flux studies indicated that these agonists stimulated electrogenic Cl secretion and inhibited neutral NaCl absorption; responses that were variably inhibited by the cyclooxygenase blockers indomethacin and piroxicam. Lesser degrees of inhibition by nordihydroguaiaretic acid could be accounted for by decreased prostaglandin synthesis rather than by lipoxygenase blockade. Tetrodotoxin, hexamethonium, and atropine also inhibited immune agonist-stimulated Isc, but had no effect on immune agonist-stimulated production of PGE2 or PGI2. These results indicate that immune system agonists alter intestinal epithelial electrolyte transport through release of cyclooxygenase products from cells in the lamina propria with at least 50% of the response being due to cyclooxygenase product activation of the enteric nervous system. The immune system, like the enteric nervous system and the endocrine system, may be a major regulating system for intestinal water and electrolyte transport in health and disease.

Intravenous atrial natriuretic peptide does not affect water and ion transport in the human small intestine

Atrial natriuretic peptide (ANP) increases renal sodium and water excretion in several species including man. In rats ANP was also found to influence water and electrolyte transport in the small intestine. In the present study we investigated whether ANP can alter transport in the jejunum and ileum of healthy volunteers using a triple-lumen perfusion technique. The small intestine was perfused under steady-state conditions with a plasma-like electrolyte solution using polyethylene glycol as a nonabsorbable volume marker. After an initial control period with intravenous saline infusion ANP was administered intravenously at a dose of 400 pmol kg-1 h-1. This dose led to a significant (P less than 0.05) increase in the plasma levels of ANP (up to 22-fold) and cGMP (up to 15-fold), and of urine volume. Intestinal water and electrolyte transport were, however, not affected by ANP. Our results suggest that circulating ANP does not play a role in the regulation of mucosal water and ion transport in the human small intestine.

Luminal adrenergic agents modulate intestinal transport

Intestinal transport is controlled by luminal solutes, neural pathways, and paracrine or humoral agents. The current study investigated the effect of luminally administered adrenergic agents on the intestinal transport of water and electrolytes. Dogs with 25-cm jejunal Thiry-Vella loops were studied. The loops were luminally perfused with an isotonic solution containing [ 14C]PEG, and the fluxes of H 2O, Na +, and Cl − were calculated. Each experiment consisted of three 1-hr periods: basal, luminal agent infusion, and recovery. Luminal adrenergic agents did not alter heart rate. Norepinephrine ( α 1 > α 2 and β adrenergic agonist) and phenylephrine ( α 1 adrenergic agonist) caused significant absorption of water and sodium. Clonidine ( α 2 adrenergic agonist) and isoproterenol (β adrenergic agonist) caused significant secretion of water, sodium, and chloride. Luminally administered adrenergic agents can influence small intestinal water and electrolyte transport. Alpha 1 agonists have a proabsorptive effect, while α 2 and β agonists have a secretory effect. Luminally administered proabsorptive adrenergic agents may prove useful in pathologic secretory states such as diabetic diarrhea, small bowel transplantation, or diarrhea-associated endocrinopathies.

Central μ-, δ- and κ-opioid influences on intestinal water and electrolyte transport in dogs

The effects of intracerebroventricular (i.c.v.) administration of opioid peptides with μ- (DAGO), μ- and δ- (DALAMIDE, DADLE) and κ- (dynorphin) properties on normal and stimulated (cholera toxin) net fluxes of water, Na + and K + through a jejunal Thiry-Vella loop were investigated in conscious dogs. Basal net water absorption was slightly, but significantly ( P < 0.05) increased during i.c.v. infusion of DALAMIDE or DAGO (0.5 ng/kg/min) but not DADLE and dynorphin-(1–13) at the same rate; DALAMIDE and DAGO also markedly reduced (by 72.3 and 79.5% respectively) the secretory effects of cholera toxin (0.4 μg/ml). Similar effects were obtained with DALAMIDE and DAGO when injected i.c.v. as a bolus (100 ng/kg) prior to cholera toxin infusion; they were suppressed after i.v. pretreatment with naltrexone (0.3 mg/kg) but also with propranolol (0.2 mg/kg). In contrast, i.v. phentolamine (0.2 mg/kg) and bilateral truncal vagotomy, were unable to block their effects. These results suggest that Met-enkephalin can act centrally to affect intestinal transport of (i) water and (ii) electrolytes in dogs. They act probably at central μ-receptors which are involved in the regulation of intestinal secretion mediated through a central or peripheral β-adrenergic pathway.

The effect of norepinephrine on intestinal transport and perfusion pressure in the isolated perfused rabbit ileum

Norepinephrine (NE) is an autonomic neurotransmitter and a potent vasoactive agent, with putative effects on intestinal absorption and secretion. To characterize the effects of NE on intestinal water and ion transport, independent of changes in intestinal blood flow, we studied the effects of three doses of NE (0.1, 0.4, and 2.0 μg/min) on the isolated, vascularly perfused rabbit ileum at a constant vascular perfusion rate. Twenty-centimeter segments of New Zealand white rabbit distal ileum ( n = 21) were vascularly perfused at a fixed rate of 1.5 ml/min using a modified Krebs buffer solution (37°C) containing washed human red blood cells with a hematocrit of 15–20%. The intestinal lumen was perfused at 2 ml/min with a warm buffered isotonic electrolyte solution containing 10 μCi[ 14C]PEG as a nonabsorbable volume marker. Net fluxes of H 2O, Na +, and Cl − were calculated during 20-min basal, NE infusion, and recovery periods. Perfusion pressure was monitored continuously. NE caused statistically significant graded increases in vascular resistance, as reflected by perfusion pressure, with increasing doses. NE stimulated absorption of H 2O, Na +, and Cl − with a less distinct response to increasing dose. These data suggest that the separate effects of NE on absorption and hemodynamics may be mediated through different pathways or different receptors in the intestine.

Unconjugated bilirubin and the bile from light exposed Gunn rats inhibit intestinal water and electrolyte absorption.

Jaundiced babies undergoing phototherapy often develop diarrhoea. The cause of it is still uncertain. Increasing evidence supports a role of a secretory mechanism for the diarrhoea. We therefore studied the effects of bile from congenitally jaundiced rats undergoing phototherapy and of unconjugated bilirubin on rat small intestine in vivo and in vitro. Results suggest that: (1) the bile from homozygous Gunn rats under phototherapy has an anti-absorptive effect when tested in the perfused jejunum of normal Wistar rats; (2) unconjugated bilirubin has a dose dependent secretory effect on the intestinal transport of water and electrolytes, when tested in the same system. Alteration of cyclic AMP or cyclic GMP, known intracellular mediators of secretion, was not observed. We conclude that free bilirubin is an intestinal secretagogue acting by an as yet unknown mechanism, that may mediate the secretory type of diarrhoea in jaundiced neonates undergoing phototherapy.

Effects of auranofin and myochrysine on intestinal transport and morphology in the rat.

Auranofin (SKF-D 39162) is an oral gold preparation for the treatment of rheumatoid arthritis. One of its major side effects is diarrhoea. To determine one possible mechanism for this we compared the effects of auranofin and myochrysine on intestinal water and solute transport in the rat. Jejunal perfusion with 2 mM auranofin (n = 5) induced fluid and electrolyte secretion and inhibited glucose absorption (p less than 0.01). Auranofin (0.2 mM) induced fluid secretion in the jejunum (n = 5; p less than 0.01) and colon (n = 6; p less than 0.01). In contrast, 2 mM myochrysine enhanced jejunal water and electrolyte absorption (n = 6; p less than 0.02). Both compounds enhanced absorption of mannitol (p less than 0.01). Perfusion of 0.2 mM auranofin for two hours had no significant effect on mucosal c-AMP levels (n = 4). After perfusion for two hours with 2 mM auranofin the jejunal mucosa showed severe injury by light and scanning electronmicroscopy while myochrysine had no apparent effect. The damage after perfusion with 0.2 mM auranofin for two hours was less severe. Auranofin was more rapidly absorbed than myochrysine (p less than 0.05). These effects provide an explanation for the diarrhoea associated with auranofin therapy.

Effect of bisacodyl on intestinal electrolyte and water net transport and transit. Perfusion studies in men.

The effect of bisacodyl on intestinal electrolyte, glucose, and water transport, and transit was studied in 6 healthy volunteers by intestinal perfusion. A 5-lumen tube with an occluding balloon allowed constant perfusion (10 ml/min) of 30 cm of the upper jejunum and a rapid collection of the perfusate free of contaminants. A phenol red bolus was injected into the tube and its passage through the test segment was calculated by dye dilution formula. A 1-hour control period was followed by a test period with 6 mg/h bisacodyl and followed by 2 other 1-hour control periods. Net absorption of Na+ (0.35 +/- 0.08 mmol/min) and water (1.7 +/- 0.6 ml/min) changed to net secretion (Na+ -0.93 +/- 0.3 ml/min; water -6.6 +/- 1.9 ml/min), glucose absorption decreased from 25.4% +/- 1.1 to 6.3 +/- 0.5 mg/min and K secretion was enhanced. 62 +/- 2.1% of bisacodyl was absorbed in the 30-cm jejunal segment. Mean transit time decreased from 8.5 +/- 1 to 4.4 +/- 0.7 min and mean flow rate increased from 8.4 +/- 0.6 16.6 +/- 1.9 ml/min. There was an inverse linear relationship between mean transit time and mean flow rate. All the effects of bisacodyl were fully or at least partially reversible. Volume and calculated radius of the test segment remained constant and did not change under bisacodyl. It is concluded, that the secretory effect of bisacodyl is mainly responsible for the decreased mean transit time rather than a direct effect on motility.

Central regulation of intestinal basal and stimulated water and ion transport by endogenous opiates in dogs.

The influence of intracerebroventricular (ICV) vs intravenous (IV) administration of (D-Ala2, Met5) enkephalinamide (Dalamide) on normal and stimulated (cholera toxin) jejunal fluxes of water, Na+, and K+ were investigated in dogs prepared with a Thiry-Vella (TV) loop. Intestinal transport in the TV loop and concomitant transit time were measured during an infusion (2 ml/min) of an isotonic electrolyte solution alone, or containing 0.4 micrograms/ml of cholera toxin (CT). Basal net water absorption was slightly, but significantly (P less than 0.05), increased during an ICV infusion of Dalamide at 0.5 ng/kg/min, while the secretory effects of cholera toxin were markedly reduced by nearly 75%. Similar effects were observed for Na+ and K+ movement. In contrast, Dalamide infused intravenously at a five times higher dose, ie, 2.5 ng/kg/min did not affect the control and CT-stimulated water and electrolyte movements. The jejunal loop transit times were halved during CT infusion. Similar values were observed under Dalamide ICV administration as well as during a five times higher dose of Dalamide administered intravenously. It was concluded that (1) Dalamide administered into the CNS, but not peripherally, increased the absorption of water, Na+, and K+, causing a net reduction in their secretion induced by cholera toxin; and (2) these effects did not result from changes in transit time. These results also suggest that Met-enkephalin can act in the brain to affect the intestinal transport of water and electrolytes in dogs.

Human intestinal motor activity and transport: Effects of a synthetic opiate

Effects of opiates on intestinal motor activity and transport of water and electrolytes have been studied separately in previous investigations. The aim of these experiments was to evaluate simultaneously the effects of a synthetic opiate, loperamide, on motor activity and transport in the human intestine. Jejunal, ileal, and colonic perfusions were performed in 9 healthy volunteers. After application of loperamide (12 mg), cyclically recurring migrating motor complexes in the small intestine occurred at a significantly higher frequency than after application of placebo. This was primarily due to a decrease in the duration of irregular motor activity (phase II). Loperamide increased the transit time in the jejunum but not in the ileum or in the colon. Transport rates of water and electrolytes and transmural electrical potential differences were not significantly affected by the drug. These results suggest that opiates exert their constipating effect by inhibiting phase II-related irregular motor activity.

The effects of severe zinc deficiency on intestinal permeability: an ultrastructural study.

Evidence suggests that intestinal transport of water and electrolytes may be altered in zinc deficiency. We examined the structural features of intestinal epithelial cells of zinc-deficient rats using electron microscopy and assessed the integrity of the junctional complexes using a heavy metal tracer, lanthanum hydroxide. The absorptive cells, as well as Paneth cells and chromaffin cells, were not found to have ultrastructural changes of a consistent nature in zinc deficiency. Moreover, the integrity of the junctional complexes was found to be preserved. These findings suggest that the abnormalities in intestinal transport previously reported are not secondary to increased tight junction permeability in zinc deficiency.

Age-related changes in rat intestinal transport of D-glucose, sodium, and water.

Experiments were performed with everted sacs of jejunum and ileum and brush-border membrane vesicles from four different age groups of rats: very young, young, adult, and old. The changes with age in several parameters, such as cell electrolyte and D-glucose concentrations, cell volume, net D-glucose, Na+ and water transport, and D-glucose uptake into vesicles, were studied. Differences in transport activities in the four age groups of animals were observed. In the jejunum the greatest transport was found in young rats and less in adult, very young, and old rats. In the ileum, the greatest transport activity was found in very young and young rats, while in adult and old animals transport activity was negligible. The cell volume of the enterocyte was significantly smaller in old rats. Changes in cell electrolytes (increased Na+ and decreased K+) were observed only in the jejunum of old rats. The overshoot of D-glucose in brush-border membrane vesicles varied considerably in the four different age groups of animals. In other words, the capacity for sugar uptake into vesicles is greater in young rats than in very young or adult animals. In old rats there was no overshoot, and a slow linear increase of sugar entry was observed. The results indicate that the changes in D-glucose transport with age might be explained in part by the changes in the amount of sugar that crosses the brush-border membrane of the enterocyte.

Vipoma syndrome: Effect of a somatostatin analogue on intestinal water and ion transport

Vipoma syndrome: Effect of a somatostatin analogue on intestinal water and ion transport

Influence of Morphine Tolerance and Withdrawal on Intestinal Salt and Water Transport in the Rat In Vivo and In Vitro

Intestinal water and electrolyte transport was investigated in vivo and in vitro in rats made tolerant to morphine and subsequently withdrawn with naloxone. Rats were rendered tolerant by injection of a slow-release emulsion containing morphine (75 mg/rat over 48 h), and when challenged with naloxone, they exhibited a characteristic withdrawal syndrome that included acute diarrhea. Morphine tolerance did not influence water absorption from ileal or colonic loops in vivo but naloxone-induced withdrawal provoked a rapid and sustained reduction in absorption. Naloxone did not affect absorption in control animals. In further experiments, sodium and chloride fluxes were measured in isolated stripped ileal mucosa derived from animals made tolerant to morphine and withdrawn with naloxone. Net sodium and chloride absorption was markedly reduced in mucosa derived from withdrawn animals compared with that derived from tolerant animals (Na+: 1.12 +/- 0.76 vs. 5.52 +/- 0.46, and Cl-: 0.60 +/- 0.52 vs. 4.70 +/- 0.80 microEq/cm2 X h, in withdrawn and tolerant animals, respectively; n = 8; p less than 0.001 and p less than 0.005). When an attempt was made to induce withdrawal by adding naloxone in vitro to isolated mucosa derived from tolerant animals, no effect on transport was detected whether the mucosa was stripped of muscle layers or not. Thus naloxone had to be given in vivo to produce withdrawal effects in mucosa studied subsequently in vitro. Naloxone also had an effect in control rats when a 50% reduction in net chloride absorption was observed in isolated ileal mucosa derived from these animals. Net sodium absorption was unaffected. These data support a role for endogenous opiates in the control of intestinal transport and provide a mechanism for the diarrhea associated with opiate withdrawal.

Effect of 13-norleucin motilin on water and ion transport in the human jejunum

Passage of the interdigestive migrating myoelectric complex through the proximal small bowel is associated with elevated plasma motilin levels and an increase in transmucosal potential difference suggesting altered ion transport. The aim of the present study was to investigate whether motilin may have an effect on intestinal water and ion transport. Steady state jejunal perfusion studies were carried out in healthy volunteers while either saline (control) or synthetic motilin (256 pmol/kg · h) was infused via peripheral vein. Plasma motilin levels rose from a mean of 31 to a plateau of 832 pmol/L. Motilin infusion significantly reduced absorption of water, sodium, potassium, and chloride when a plasmalike electrolyte solution was perfused. During perfusion with a bicarbonate-free salt solution, motilin significantly enhanced secretion of water, potassium, and chloride. Chloride secretion was active inasmuch as it occurred against both an electrical and chemical gradient. Motilin infusion had no effect on transit time during perfusion of the 30-cm jejunal test segments. We conclude that motilin can act as an intestinal secretagogue in the human jejunum.

Effect of Senokot on rat intestinal electrolyte transport: Evidence of Ca++ dependence

The mechanism of action of Senokot, a widely used laxative, has not been established. Senokot was given orally to rats 8–14 h before intestinal water and electrolyte transport were studied. Senokot significantly decreased colonic and jejunal water absorption measured in vivo by the single-pass perfusion technique. The Senokot changes were not associated with changes in jejunal or colonic histology or adenylate cyclase activity or colonic cyclic adenosine monophosphate content. Senokot also altered active electrolyte transport in rat descending colon as measured by the Ussing chamber-voltage clamp technique. These changes consisted of an increase in short-circuit current and a decrease in active Na and Cl transport that was due to a decrease in the mucosal-to-serosal fluxes. The changes in active electrolyte transport were dependent on Ca++ in the serosal but not the mucosal bathing solution. In contrast, addition of 10−4 M verapamil to the serosal surface did not alter the Senokot effect. In spite of a dependence on serosal Ca++, Senokot did not alter 45Ca++ entry across the colonic serosal surface. The phospholipase A2 inhibitor quinacrine (10−4 M) also did not alter the effect of Senokot on colonic Na and Cl transport. Senokot alters active colonic Na and Cl transport via a presently unknown mechanism that is dependent on serosal Ca++.