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PubMed2001

Circadian coupling between pancreatic secretion and intestinal motility in humans.

Human interdigestive intestinal motility follows a circadian rhythm with reduced nocturnal activity, but circadian pancreatic exocrine secretion is unknown. To determine whether circadian changes in interdigestive pancreatic secretion occur and are associated with motor events, pancreatic enzyme outputs, proximal jejunal motility, and plasma pancreatic polypeptide concentrations were measured during consecutive daytime and nighttime periods (12 h each) in seven healthy volunteers using orojejunal multilumen intubation. Studies were randomly started in the morning or evening. Nocturnally, motility decreased (motor quiescence: 67 +/- 22 vs. 146 +/- 37 min; motility index: 3.59 +/- 0.33 vs. 2.78 +/- 0.40 mmHg/min; both P < 0.05) but amylase output increased (273 +/- 78 vs. 384 +/- 100 U/min; P < 0.05) and protease output remained unchanged (P > 0.05); consequently, enzyme/motility ratio increased. Amylase outputs were always lowest during phase I. Motor but not pancreatic circadian activities were associated with sleep. Pancreatic polypeptide plasma concentrations were unchanged. Consequently, intestinal motor and pancreatic exocrine functions may have different circadian rhythms, i.e., decreased motor and stable secretory activity during the night. However, the association between individual phases of interdigestive motor and secretory activity is preserved. The nocturnal increase in enzyme/motility ratio is probably not caused by increased cholinergic tone.

Amylases↗
PubMed1975

[Participation of the small intestine in carbohydrate metabolism].

Participation of the small intestine in the intermediate carbohydrate metabolism was pointed out by appearing of glucose in the small intestine secret within 2-3 hrs after carbohydrate uptake in the concentration comparable or even exceeding that in the blood. The glucose concentration in the blood drops just when it increases in the intestinal juice, while increase in the blood sugar coincided with reducing of the glucose concentration in the small intestine secret. This suggests that the small intestine lumen can serve as one of the depots for carbohydrates: a kind of temporary depot for monomeres.

Animals↗
PubMed1993

Functional coupling between the active transport of glucose and the secretion of intestinal neurotensin in rats.

1. In this study, the mechanisms involved in the release of neurotensin-like immunoreactivity (NTLI) by glucose were investigated with the isolated, vascularly perfused rat jejunoileum preparation. 2. Luminal infusion of glucose (1-250 mM) produced a sharp and sustained release of NTLI in the intestinal venous effluent. The first significant response was observed with 5 mM glucose and the release reached a maximum under 250 mM glucose with a plateau secretion at 500% of basal. 3. There was no significant difference in the ability of galactose and 3-O-methylglucose to release NTLI when compared to glucose, but alpha-methylglucose, mannose, 2-deoxyglucose and fructose did not stimulate NTLI release. 4. Luminal infusion of 5 mM phloridzin reduced the glucose-induced release of NTLI by 90%. Intra-arterial infusion of glucose (25 mM) or of phloretin (20 microM) had no significant effect on the glucose-evoked NTLI secretion. 5. Intra-arterial infusion of ouabain (1 mM) produced a dramatic increase (at about 1500% of basal) in portal NTLI although it drastically reduced intestinal absorption of glucose. 6. Intra-arterial infusion of tetrodotoxin (1 microM), atropine (10 microM), verapamil (50 microM) or nifedipine (50 microM) did not modify the glucose-induced NTLI secretion. 7. Intra-arterial infusion of forskolin (2-20 microM) evoked a prompt and well-sustained secretion of NTLI which was increased to a mean value of 800% of basal with the highest dose tested. 3-Isobutyl-1-methylxanthine (IBMX, 10-100 microM) also stimulated the secretion of NTLI (maximal increase at 725% of basal at 100 microM). In contrast, intra-arterial infusion of 4-beta-phorbol 12-myristate, 13-acetate (PMA, 0.05-0.5 microM) had no effect on NTLI release. 8. IBMX (10-100 microM) synergistically enhanced NTLI responses induced by 250 mM glucose; the integrated response of NTLI release was 3- to 5-fold higher than the sum of individual responses produced by the same stimulants given separately. 9. It is concluded that the carbohydrate-induced NTLI release is related to the active, sodium-dependent hexose transport, but not to the carbohydrate catabolic pathway. Furthermore, the intramural nerves and L-type calcium channels are not involved in the glucose-induced NTLI secretion. Finally, the secretory activity of the intestinal N cell seems to be mainly stimulated through a cAMP-dependent pathway.

1-Methyl-3-isobutylxanthine↗
PubMed2006

Bacteroides fragilis enterotoxin induces cyclooxygenase-2 and fluid secretion in intestinal epithelial cells through NF-kappaB activation.

Bacteroides fragilis produces an approximately 20-kDa heat-labile toxin (B. fragilis enterotoxin, BFT) which is known to be associated with diarrhea. To determine whether cyclooxygenase (COX)-2, via NF-kappaB activation, can contribute to BFT-induced diarrhea, the relationship between COX-2 expression and fluid secretion in BFT-stimulated human intestinal epithelial cells was examined. BFT stimulation increased the expression of COX-2, but not COX-1, in human intestinal epithelial cells. Suppression of the NF-kappaB signal significantly decreased COX-2 expression in response to BFT stimulation. Prostaglandin E2 (PGE2) levels were increased in parallel with COX-2 expression, and, conversely, PGE2 production was significantly inhibited when COX-2 or NF-kappaB activities were suppressed using COX-2 small interfering RNA (siRNA), p65 NF-kappaB subunit siRNA, or a retrovirus encoding the IkappaBalpha superrepressor. In addition, a selective COX-2 inhibitor, NS-398, significantly inhibited the increased cAMP level induced by BFT stimulation. Furthermore, a selective COX-2 inhibitor prevented BFT-induced PGE2 production and ileal fluid secretion in a mouse ileal loop model. These results suggest that the secretory response to BFT stimulation may be mediated by the production of PGE2, through NF-kappaB activation and the up-regulation of COX-2 in intestinal epithelial cells.

Animals↗
PubMed1978

Protective antitoxic cholera immunity in mice: influence of route and number of immunizations and mode of action of protective antibodies.

An adult mouse model has been elaborated for studies of experimental cholera (Vibrio cholerae enterotoxin-induced intestinal secretion) and protective antitoxic immunity in either ligated small bowel loops or intact small intestine. Mice of different inbred strains varied markedly in intestinal susceptibility to toxin, C57B1 being the most sensitive strain tested. Fluid accumulation started within 1 h after the inoculation of toxin and was maximal after 5 h, whereafter recovery gradually ensued. The dose-response curve was sigmoid, the ED50 of crude toxin being equivalent to about 0.1 microgram purified toxin/cm in the loops and 0.3 microgram/cm in the nonligated intestine. Two peroral (p.o.) immunizations induced significant protective immunity which increased markedly after two further immunizations by the same route. Additional p.o. immunizations did not appreciably enhance the protective immunity any further. Intravenous (i.v.) vaccination had to be repeated more than 5 times before intestinal immunity could be observed. No correlation between serum antitoxin titers and protective immunity was found. Electron microscopic examination revealed that whereas peroxidase-coupled cholera toxin bound tightly to intestinal microvilli from unimmunized or 5-times i.v. immunized mice it did not bind to the microvilli of p.o. immunized animals. The data thus suggest that the protective immunity is mediated exclusively by locally produced antibodies which prevent the binding to toxin to the gut epithelium.

Administration, Oral↗
PubMed2001

Bile salt-stimulated carboxyl ester lipase influences lipoprotein assembly and secretion in intestine: a process mediated via ceramide hydrolysis.

Bile salt-stimulated carboxyl ester lipase (CEL), also called cholesterol esterase, is one of the major proteins secreted by the pancreas. The physiological role of CEL was originally thought to be its mediation of dietary cholesterol absorption. However, recent studies showed no difference between wild type and CEL knockout mice in the total amount of cholesterol absorbed in a single meal. The current study tests the hypothesis that CEL in the intestinal lumen may influence the type of lipoproteins produced. A lipid emulsion containing 4 mm phospholipid, 13.33 mm [(3)H]triolein, and 2.6 mm [(14)C]cholesterol in 19 mm taurocholate was infused into the duodenum of lymph fistula CEL(+/+) and CEL(-/-) mice at a rate of 0.3 ml/h. Results showed no difference between CEL(+/+) and CEL(-/-) mice in the rate of cholesterol and triglyceride transport from the intestinal lumen to the lymph. However, CEL(-/-) mice produced predominantly smaller lipoproteins, whereas the CEL(+/+) mice produced primarily large chylomicrons and very low density lipoprotein. The proximal intestine of CEL(-/-) mice was also found to possess significantly less ceramide hydrolytic activity than that present in CEL(+/+) mice. By using Caco2 cells grown on Transwell membranes as a model, sphingomyelinase treatment inhibited the secretion of larger chylomicron-like lipoproteins without affecting total cholesterol secretion. In contrast, the addition of CEL to the apical medium increased the amount of large lipoproteins produced and alleviated the inhibition induced by sphingomyelinase. Taken together, this study identified a novel and physiologically significant role for CEL, namely the promotion of large chylomicron production in the intestine. The mechanism appears to be mediated through CEL hydrolysis of ceramide generated during the lipid absorption process.

Amidohydrolases↗
PubMed1984

Alpha-2 receptors in the gastrointestinal system: a new therapeutic approach.

Alpha-2 receptor activation mediates the inhibition of a number of gastrointestinal functions including gastric and intestinal secretions. Alpha-2 receptors are located in the brain and presynaptically on cholinergic nerve terminals; activation of either inhibits vagus nerve activity. Intestinal secretions are inhibited by postsynaptic alpha-2 receptors located on intestinal epithelial cells. Agents which selectively activate alpha-2 receptors in the gut may therefore be beneficial in treating gastric ulcers and diarrheal states. Two such agents which activate alpha-2 receptors in the gut are WHR-1370A [1-n-butoxy-3-(2,6-dimethylphenylcarbamoyl) guanidine hydrochloride] and lidamidine. WHR-1370A is a potent gastric antisecretory and antiulcer agent which inhibits the release of acetylcholine from the vagus nerve. WHR-1370A's activity is blocked by yohimbine. Lidamidine is a clinically effective antidiarrheal agent. Lidamidine's response is partially inhibited by yohimbine in animal diarrheal models. Alpha-2 agonists represent a new class of drugs which have a promising future in the treatment of gastrointestinal disorders.

Adrenergic alpha-Agonists↗
PubMed1980

Non-gastrin, intestinal-phase secretion. Experimental confirmation in the dog.

Four mongrel dogs were prepared with a Heidenhain pouch, a gastric fistula, and a 90-cm-long Thiry-Vella loop. After recovery, dose-response curves were obtained with different doses of pentagastrin, and the maximal acid output was determined. The jejunal loop was perfused for 3 h with either 5% liver extract or with 0.15 M NaCl at a rate of 114 ml/h. To verify that the stomach could release gastrin and that the assay could detect that change, antral perfusion with liver extract was performed. Serum gastrin levels and acid output were measured every 30 min. Perfusion of the jejunal loop with liver extract resulted in a significant increase in acid output from the Heidenhain pouch and the gastric fistula, whereas perfusion with saline solution failed to show any changes. The magnitude of acid response from the Heidenhain pouch and gastric fistula was 11% and 18%, respectively, as compared with maximal pentagastrin stimulation. The serum gastrin levels remained unchanged during both liver extract and saline perfusion of the jejunal loop, in contrast to the marked increase in serum gastrin level after antral perfusion. The results confirm the existence of the intestinal phase of gastric acid stimulation in dogs as an entity and show that the magnitude of this phase is significantly lower than has been suggested by results of earlier studies. Furthermore, the results suggest that the intestinal phase of gastric secretion in dogs is most probably elicited through a humoral agent other than gastrin.

Animals↗
PubMed1999

Insulin secretion and intestinal peptides during lactation in sheep.

Intravenous infusions of glucose and/or glucagon-like peptide-1(7-36)-amide (GLP) or somatostatin-28 (S28) were administered to dry and lactating sheep and changes in plasma glucose and serum insulin were followed before, during and after infusion. Basal serum insulin concentrations were significantly lower in lactating sheep but there was no significant difference in plasma glucose concentrations. During glucose infusion, changes in serum insulin concentrations were diminished by comparison with those in dry animals. GLP stimulated insulin secretion during hyperglycaemia in both dry and lactating sheep but, proportionately, the response was significantly greater in the lactating animals. S28 inhibited glucose-stimulated insulin secretion in both dry and lactating sheep and there was no significant difference in the extent of the inhibition between the two physiological states. S28 infusion also inhibited the secretion of GLP from the intestinal tract and this effect was significantly greater in the lactating animals. The results demonstrate a difference in response in the lactating animal to GLP compared with S28. A possible explanation of the difference is a decreased sensitivity (i.e. increased Km) of the pancreas to the insulinotropic effects of GLP but an increased sensitivity to the inhibitory effects of S28 at tissues other than the pancreas in lactation.

Animals↗
PubMed2001

Dietary cholesterol is secreted in intestinally derived chylomicrons during several subsequent postprandial phases in healthy humans.

BACKGROUND: The process of intestinal absorption and chylomicron resecretion of dietary cholesterol in humans is poorly understood. OBJECTIVE: The present study aimed to test the hypothesis that dietary cholesterol ingested during a given meal is resecreted into chylomicrons (and plasma) during several subsequent postprandial periods. DESIGN: Seven healthy subjects ingested 3 comparable mixed test meals (at 0, 8, and 24 h) containing a given amount of fat (49 g) and cholesterol (157 mg); blood samples were taken 3 and 6 h after each test meal and 48 and 72 h after the beginning of the experiment. Heptadeuterated dietary cholesterol was present in the first test meal only, enabling its specific determination with use of gas chromatography-mass spectrometry. Chylomicrons, LDL, and HDL were isolated and lipids were quantified. RESULTS: In apolipoprotein B-48-containing chylomicrons, deuterated cholesterol concentrations were moderate after the first meal (1.3 x 10(-4) mmol/L), reached a maximum after the second meal (2.4 x 10(-4) mmol/L), and were still elevated after the third meal (1.7 x 10(-4) mmol/L). In plasma, LDL and HDL cholesterol enrichment in deuterated cholesterol was lower than in chylomicrons and plateaued after 24--48 h. Estimates of newly secreted exogenous deuterated cholesterol in chylomicrons indicate that 30.7%, 55.2%, and 14.1% of the total was secreted after the first, second, and third meals, respectively. CONCLUSION: Ingested dietary cholesterol is secreted by the small intestine in chylomicrons into the circulation during > or =3 subsequent postprandial periods in healthy humans. This likely results from a complex multistep intestinal processing of cholesterol with dietary fat as a driving force.

Adult↗
PubMed2000

Immune activation in the intestinal mucosa before the onset of colitis in Galphai2-deficient mice.

G-protein subunit Galphai2-deficient mice spontaneously develop an inflammatory bowel disease that clinically and histopathologically resembles ulcerative colitis in humans. The aim of this study was to determine whether immunological changes precede the development of colitis in Galphai2-deficient mice. Therefore, Galphai2-deficient mice with no clinical or histopathological signs of colitis were compared with Galphai2-deficient mice with established colitis and wild-type animals, concerning immunological parameters. Healthy Galphai2-deficient mice displayed an increased frequency of CD4+ T cells and a decreased frequency of CD19+ B lymphocytes in the intestinal mucosa compared with control mice. The CD4+ population was characterized by a memory phenotype, i.e. increased expression of CD44 and decreased expression of CD45RB and CD62L, as well as increased expression of the mucosal homing receptors integrins alpha4beta7 and alphaEbeta7. Production of pro-inflammatory cytokines, interleukin (IL)-1beta and interferon (IFN)-gamma, were increased in Galphai2-deficient mice before clinical signs of disease were evident. In addition, total immunoglobulin (Ig)G and IgA levels in large intestinal secretions were increased significantly compared with wild-type mice, and antibodies specific for the normal intestinal flora in large intestinal secretions were present in Galphai2-deficient mice several weeks before the onset of colitis. In contrast, antibodies against tropomyosin, a putative autoantigen in human ulcerative colitis, were not found in Galphai2-deficient mice before the onset of colitis, although they were present in animals with established disease. In conclusion, activation of the intestinal immune system precedes histopathological and clinical signs of inflammation in Galphai2-deficient mice, suggesting that immune abnormalities play an important role in the induction of colitis.

Animals↗
PubMed1983

Escherichia coli heat-stable enterotoxin: biochemical and physiological effects on the intestine.

E. coli which elaborate suckling mouse active small MW heat-stable enterotoxin (STa), are important causes of diarrhea in animals and man. These STa's share the property of causing intestinal secretion and diarrhea by virtue of inhibiting the absorption of sodium and chloride and possibly stimulating the secretion of chloride. STa's seem to act in the colon as well as the small intestine and the alterations in intestinal ion and water transport are probably mediated by the guanylate cyclase-cyclic GMP system. Glucose transport is unaffected. STa also causes alterations in the myoelectrical activity of the small intestine which may result in the loss of normal peristaltic activity. STa binds in a reversible fashion to specific receptors on the surface of small intestinal and colonic epithelial cells. The mechanisms whereby occupation of the STa receptors lead to activation of the guanylate cyclase system and intestinal secretion are unknown but may involve influx of calcium through calcium channels, stimulation of prostaglandin synthesis and release of free radicals.

Action Potentials↗
PubMed1996

Beta-adrenergic regulation of cholecystokinin secretion in STC-1 cells.

Previously, it has been shown that an increase in adenosine 3',5'-cyclic monophosphate (cAMP) levels stimulates intestinal secretion of cholecystokinin (CCK); however, the mechanisms for increasing intracellular cAMP levels are not known. Using the CCK-secreting intestinal cell line, STC-1, we evaluated whether beta-adrenergic receptors (beta-ARs) might be present on STC-1 cells and whether they stimulated CCK release through increases in cAMP. Photoaffinity labeling of beta-ARs from solubilized STC-1 cell membranes revealed photoincorporation of the agonist [125I]iodocyanopindolol into an approximately 75-kDa band. Addition of the beta-AR agonist, isoproterenol, in the presence of 3-isobutyl-1-methylxanthine, produced a concentration-dependent increase in both cAMP levels and CCK release. Blockade of beta 1- and/or beta 2-ARs significantly inhibited isoproterenol-stimulated increases in cAMP production and CCK release. With the use of fura 2-loaded cells to measure changes in intracellular Ca2+ concentration ([Ca2+]i), isoproterenol stimulation was found to increase cytosolic Ca2+ levels. To evaluate whether this increase in [Ca2+]i was due to release of Ca2+ or influx of Ca2+, cells were treated with the L-type calcium channel blocker, diltiazem, which inhibited isoproterenol-stimulated CCK secretion. Furthermore, in patch-clamp studies with inside-out membrane patches, addition of the catalytic subunit of protein kinase A activated diltiazem-sensitive Ca2+ channels. It is concluded that beta-ARs are present on STC-1 cells and are coupled to the production of cAMP, which may increase CCK release through a calcium-dependent process.

Adrenergic beta-Agonists↗
PubMed2005

Trichuris suis excretory secretory products (ESP) elicit interleukin-6 (IL-6) and IL-10 secretion from intestinal epithelial cells (IPEC-1).

Immune responses to gastrointestinal helminth infections have received increasing attention due to similarities to allergen-induced responses. In fact, the whipworm parasite of swine, Trichuris suis, has been used in beginning clinical trials as an antidote to inflammatory bowel disease. This strategy was based on this similarity and the recognition that other worms have been documented to induce anti-inflammatory responses in the host. In an effort to understand the basis for this response, we hypothesized that the proteins and peptides secreted by T. suis stimulate local intestinal epithelial cells to produce anti-inflammatory cytokines. To test this hypothesis in a correlate system of the natural swine host, T. suis excretory secretory products (ESP) were used to treat both differentiated and undifferentiated intestinal pig epithelial cells (IPEC-1) in vitro as a model for the effect on villus tip and crypt epithelial cells in the vicinity of the worms. IPEC-1 were exposed to low-level doses (0.3mg/ml) of T. suis ESP, and IL-4, IL-6 and IL-10 cytokine responses were measured by an enzyme-linked immunosorbant assay (ELISA). IL-6 was the predominant cytokine produced, accompanied by moderate IL-10 secretion from both differentiated and undifferentiated cells. As expected, IL-4 was not produced by IPEC-1. Additionally, IL-6 and IL-10 cytokines were produced within 24h, suggesting that these two cytokines form part of the primary host response to T. suis infections. These data suggest that T. suis ESP could enhance host immune responses and modulation through the induction of enteric IL-6 and IL-10.

Animals↗
PubMed1992

Transforming growth factor-beta enhances interleukin-6 secretion by intestinal epithelial cells.

Recent reports have suggested that transforming growth factor-beta (TGF-beta) may have an important role in IgA immune responses, e.g. induction of surface IgM+ B cells to commit to IgA. TGF-beta is also an important regulatory cytokine for the maturation of intestinal epithelial cells. Using the IEC-6 rat intestinal epithelial cell line as a model system, TGF-beta 1 was found to enhance interleukin-6 (IL-6) secretion by the IEC-6 cells. The IL-6 was produced in a dose-dependent manner and secretion could be specifically inhibited by an anti-TGF-beta 1 antibody. IL-6 production by the IEC-6 cells was confirmed by using a rabbit anti-mouse IL-6 antibody which completely neutralized the IL-6 present in the IEC-6 cell supernatant. The enhancement of IL-6 secretion was found to involve a low-level enhancement in the expression of RNA for IL-6. The induction of IL-6 secretion was also reversible when TGF-beta was removed. These results suggest that the action of TGF-beta on intestinal epithelial cells may play an important role in immune responses at the intestinal mucosa.

Animals↗
PubMed1995

Systemic and mucosal antibody responses to group B streptococci following immunization of the colonic-rectal mucosa.

The cervico-vaginal mucosa is poorly designed for inducing a mucosal immune response, but it can effect such a response evoked at other mucosal sites. This study was undertaken to determine whether colonic-rectal immunization with group B streptococci (GBS) might induce a local cervico-vaginal immune response. Mice were immunized with either fragmented GBS rectally, whole GBS rectally, or whole GBS subcutaneously. Cholera toxin (CT) was used as an adjuvant for the rectal immunizations. Following colonic-rectal immunization with whole GBS, the mean anti-GBS IgA antibody level in vaginal secretions was 735 kU/ml, with individual values reaching 3480 kU/ml. Corresponding levels of IgA antibodies never exceeded 10 kU/ml in serum and intestinal secretions, or 90 kU/g in feces. In vaginal secretions IgA antibodies to GBS also constituted a much larger fraction of total IgA than in serum, intestinal secretions and feces. Immunizations with fragmented GBS produced much lower IgA responses. Anti-GBS IgA response at the inductive site in the colon-rectum was not significant, as opposed to a strong anti-CT IgA response. Except in serum, the anti-GBS IgG responses to colonic-rectal immunizations were generally low, or absent. The results may provide a basis for the development of mucosal vaccines against GBS-infection.

Administration, Rectal↗
PubMed1997

Acetorphan prevents cholera-toxin-induced water and electrolyte secretion in the human jejunum.

OBJECTIVES: Acetorphan is an orally administered inhibitor of enkephalinase in the wall of the digestive tract. It prevents inactivation of endogenous opioid peptides released by submucosal and myenteric neurons. The aim of this study was to examine the effect of acetorphan on jejunal water and electrolyte transport in healthy volunteers under basal conditions and in a state of intestinal secretion induced by a bacterial enterotoxin. DESIGN: Ten volunteers in two groups were studied in an open trial. For the experimental design an intestinal perfusion technique was used. METHODS: Cholera toxin was used to induce intestinal secretion in a model employing segmental perfusion of the human proximal jejunum. Acetorphan was given orally prior to intrajejunal administration of cholera toxin; its effect on intestinal transport was measured over a period of four hours after exposure to cholera toxin. Serum levels of methylthioether of thiorphan as the main metabolite were measured throughout three experiments to assure sufficient drug absorption. RESULTS: Acetorphan had no influence on basal water and electrolyte absorption (133 vs. 140 ml/30 cm x h). In a control group with cholera toxin alone, significant water secretion was induced (131 ml/30 cm x h). Acetorphan completely prevented this secretion by leaving an absorption rate of 27 ml/30 cm x h. Intestinal electrolyte transport was also significantly changed towards absorption by acetorphan. CONCLUSION: Acetorphan can prevent jejunal water and electrolyte secretion induced by cholera toxin. Enkephalins may thus protect the small intestine from enterotoxin-induced secretion.

Adult↗
PubMed1997

Inhibition of intestinal Cl- secretion by clotrimazole: direct effect on basolateral membrane K+ channels.

We evaluated the effects of clotrimazole and clofibrate on Ca(2+)- and adenosine 3',5'-cyclic monophosphate (cAMP)-mediated Cl- secretion in the colonic cell line, T84. We used 1-ethyl-2-benzimidazolinone (1-EBIO) to activate the Ca(2+)-dependent K+ channel (KCa) in these cells to induce a sustained Cl- secretory current (Isc). Clotrimazole potently inhibited the KCa-dependent Isc, with an inhibition constant (Ki) of 0.27 +/- 0.02 microM. Clofibrate also inhibited the 1-EBIO-induced Isc albeit with lower affinity (Ki = 6.5 +/- 1.2 microM). Clotrimazole (10 microM) inhibited the Isc response to the Ca(2+)-mediated agonist, carbachol, by 82%. Similarly, both clotrimazole and clofibrate inhibited cAMP-mediated Cl- secretion, with Ki values of 5.2 +/- 1.0 and 6.7 +/- 1.1 microM, respectively. We used nystatin to permeabilize the apical or basolateral membrane to determine the effects of clotrimazole and clofibrate on the basolateral K+ (IK) and apical Cl- (ICl) currents following stimulation by either 1-EBIO or forskolin. Both clotrimazole and clofibrate inhibited the 1-EBIO- and forskolin-induced IK without affecting ICl. We determined the effects of clotrimazole and clofibrate on KCa using 86Rb+ uptake studies into membrane vesicles. Both clotrimazole and clofibrate inhibited the 1-EBIO-induced 86Rb+ uptake, with Ki values of 0.31 +/- 0.08 and 10.8 +/- 5.5 microM, respectively. Similarly, clotrimazole inhibited the Ca(2+)-induced 86Rb+ uptake with a Ki of 0.51 +/- 0.15 microM. Charybdotoxin inhibited both the 1-EBIO- and Ca(2+)-induced 86Rb+ uptakes with similar affinities (Ki values of 0.57 +/- 0.07 and 0.47 +/- 0.08 nM, respectively), suggesting 1-EBIO and Ca2+ activate the same channel (KCa) in this assay. In excised, single-channel recordings both clotrimazole and clofibrate inhibited KCa, demonstrating a direct inhibition of the channel by these compounds. We demonstrate that clotrimazole blocks the intestinal KCa, thereby inhibiting Cl- secretion. These results suggest that clotrimazole may be useful as an antidiarrheal.

Benzimidazoles↗