Electrolyte Secretion Research Articles

An Intriguing Tale of a Patient Passing Copious Amounts of Watery Stools

Introduction:C. difficile is one of the commonly diagnosed infectious causes of acute diarrhea in hospital settings. Other non-infectious causes of acute diarrhea often get overlooked especially when a diagnosis as common as C. difficile colitis has been made. Case Report: 78-year-old male with a history of HTN, hyperlipidemia, lung cancer s/p resection and metastatic gastric cancer (on chemotherapy) was transferred to our tertiary medical center for ICU care. He carried a diagnosis of first episode of fulminant C. difficile colitis and was suspected of harboring a hyper virulent strain at the outside facility. The patient had already finished 10 days of metronidazole therapy but still had high volume watery diarrhea with more than 20 bowel movements a day. This led to progressive dehydration, acute kidney injury and hemodynamic instability needing pressor support and Continuous venous hemofiltration (CVVH) for first few days in our ICU. Stool studies were redone besides other metabolic work-up. Abdominal imaging showed mildly dilated bowel loops. Oral vancomycin was added to his regimen besides aggressive IV hydration and supportive management. In spite of optimal medical support, the diarrhea persisted with clinical deterioration. We rescrutinized his recent medications to discover that he had finished recently his second cycle of chemotherapy (epirubicin, oxaliplatin and capecitabine) around three weeks ago for management of gastric cancer. The patient revealed further that he had milder self limiting episode of watery diarrhea after the first cycle of chemotherapy also. Keeping a possibility of chemotherapy induced diarrhea, we added octeotride to his regimen to achieve a rapid and gratifying response over next few days. The patient was finally transitioned to oral loperamide and discharged to home with complete remission of his diarrhea symptoms. Discussion: Chemotherapy-induced diarrhea (CID) has been described in cancer management with fluoropyrimidines (like 5-fluorouracil), capecitabine and irinotecan. The proposed mechanism of CID is direct toxicity to rapidly dividing crypt cells of the intestinal epithelium, and the destruction and/or augmentation of intestinal enzymes. This disrupts the balance between absorptive and secretory capacity, and alters the osmotic gradients in the gut, thereby leading to increased secretion of fluids and electrolytes in the stool. Despite the life threatening severity of CID, it is often under-recognized, as was the case in our patient.

Neuropeptide Y, peptide YY and pancreatic polypeptide in the gut–brain axis

The gut–brain axis refers to the bidirectional communication between the gut and the brain. Four information carriers (vagal and spinal afferent neurons, immune mediators such as cytokines, gut hormones and gut microbiota-derived signalling molecules) transmit information from the gut to the brain, while autonomic neurons and neuroendocrine factors carry outputs from the brain to the gut. The members of the neuropeptide Y (NPY) family of biologically active peptides, NPY, peptide YY (PYY) and pancreatic polypeptide (PP), are expressed by cell systems at distinct levels of the gut–brain axis. PYY and PP are exclusively expressed by endocrine cells of the digestive system, whereas NPY is found at all levels of the gut–brain and brain–gut axis. The major systems expressing NPY comprise enteric neurons, primary afferent neurons, several neuronal pathways throughout the brain and sympathetic neurons. In the digestive tract, NPY and PYY inhibit gastrointestinal motility and electrolyte secretion and in this way modify the input to the brain. PYY is also influenced by the intestinal microbiota, and NPY exerts, via stimulation of Y1 receptors, a proinflammatory action. Furthermore, the NPY system protects against distinct behavioural disturbances caused by peripheral immune challenge, ameliorating the acute sickness response and preventing long-term depression. At the level of the afferent system, NPY inhibits nociceptive input from the periphery to the spinal cord and brainstem. In the brain, NPY and its receptors (Y1, Y2, Y4, Y5) play important roles in regulating food intake, energy homeostasis, anxiety, mood and stress resilience. In addition, PP and PYY signal to the brain to attenuate food intake, anxiety and depression-related behaviour. These findings underscore the important role of the NPY-Y receptor system at several levels of the gut–brain axis in which NPY, PYY and PP operate both as neural and endocrine messengers.

Transport and interaction of cosmetic product material within the ocular surface: Beauty and the beastly symptoms of toxic tears

Eye cosmetics such as mascara, eye shadow and eyeliner are used extensively to highlight the eyes, and are normally applied external to the ocular surface. Adverse reactions of cosmetics within the ocular surface include mild discomfort, eyelid dermatitis, pre-corneal tear film instability, and keratitis. These are attributed mainly to the preservative (benzalkonium chloride (BAC)) constituent of cosmetic product material (CPM). Transport of CPM from an external environment to any location on the ocular surface, essentially precedes the adverse interactions occurring at the location, and the control of these transport modes is therefore of clinical relevance. The inter-transport of CPM across the TF occurs due to both diffusion and drift processes. Diffusion of neutral species is driven by concentration gradients, and the drift of cationic BAC is influenced by the inherent electric field; determined by the distribution of the various ions secreted into the aqueous layer, and the negative glycocalyx charge at the mucin layer. In the presence of mucin deficiency, the corneal epithelium is exposed to invasion by both incident BAC and lipophilic species. The transport of cationic BAC across the TF may be controlled by regulating the secretion of various electrolytes at the lacrimal gland. This is of clinical significance in reducing corneal epithelial adverse effects. However, the risks of adverse effects at the corneal surface due to invasion by the lipophilic species remain. Patients with mucin deficiency, and especially those on eye ointment/drops medication, should be discouraged from using cosmetics in a way likely to contaminate the TF.

Safety evaluation of lubiprostone in the treatment of constipation and irritable bowel syndrome

Introduction: Lubiprostone is approved in the United States for the treatment of chronic idiopathic constipation and constipation predominant irritable bowel syndrome (IBS-C). Lubiprostone causes secretion of fluid and electrolytes in the small bowel, through the activation of chloride channels, and thereby induces laxation and improvement of bowel functions. It is generally considered to be safe and effective. Common side effects of lubiprostone include nausea, diarrhea, abdominal pain and bloating, and the rare side effect dyspnea. Likely mechanisms for these side effects may be related to lubiprostone's primary action on small bowel secretion and the associated intestinal distension, as well as smooth muscle contraction.Areas covered: This article reviews the pharmacokinetic and safety profile of lubiprostone, with particular relevance to the two FDA-approved dosages.Expert opinion: Lubiprostone acts topically in the gut lumen and is almost completely metabolized in the gut lumen. Lubiprostone's M3 metabolite can be detected in low concentrations in the serum and may be responsible for some of its side effects. However, the exact mechanisms by which the side effects are produced are currently unknown.

Airway epithelial cells—Functional links between CFTR and anoctamin dependent Cl− secretion

Airways consist of a heterogeneous population of cells, comprising ciliated cells, Clara cells and goblet cells. Electrolyte secretion by the airways is necessary to produce the airway surface liquid that allows for mucociliary clearance of the lungs. Secretion is driven by opening of Cl− selective ion channels in the apical membrane of airway epithelial cells, through either receptor mediated increase in intracellular cAMP or cytosolic Ca2+. Traditionally cAMP-dependent and Ca2+-dependent secretory pathways are regarded as independent. However, this concept has been challenged recently. With identification of the Ca2+ activated Cl− channel TMEM16A (anoctamin 1) and with detailed knowledge of the cAMP-regulated cystic fibrosis transmembrane conductance regulator (CFTR), it has become possible to look more closely into this relationship.

Chronic Diarrhea in Children

Chronic Diarrhea in Children

Calcium-sensing receptor inhibits secretagogue-induced electrolyte secretion by intestine via the enteric nervous system

Bacterial toxins such as cholera toxin induce diarrhea by both direct epithelial cell generation of cyclic nucleotides as well as stimulation of the enteric nervous system (ENS). Agonists of the extracellular calcium-sensing receptor (CaSR) can reduce toxin-stimulated fluid secretion in ENS-absent colonic epithelial crypts by increasing phosphodiesterase-dependent cyclic-nucleotide degradation. Here we show that the CaSR is also highly expressed in tetrodotoxin (TTX)-sensitive neurons comprising the ENS, suggesting that CaSR agonists might also function through neuronal pathways. To test this hypothesis, rat colon segments containing intact ENS were isolated and mounted on Ussing chambers. Basal and cyclic nucleotide-stimulated electrolyte secretions were monitored by measuring changes in short-circuit current (I(sc)). CaSR was activated by R-568 and its effects were compared in the presence and absence of TTX. Consistent with active regulation of anion secretion by the ENS, a significant proportion of I(sc) in the proximal and distal colon was inhibited by serosal TTX, both at basal and under cyclic AMP-stimulated conditions. In the absence of TTX, activation of CaSR with R-568 significantly reduced basal I(sc) and cyclic AMP-stimulated I(sc); it also completely reversed the cAMP-stimulated secretory responses if the drug was applied after the forskolin stimulation. Such inhibitory effects of R-568 were either absent or significantly reduced when serosal TTX was present, suggesting that this agonist exerts its antisecretory effect on the intestine by inhibiting ENS. The present results suggest a new model for regulating intestinal fluid transport in which neuronal and nonneuronal secretagogue actions are modulated by the inhibitory effects of CaSR on the ENS. The ability of a CaSR agonist to reduce secretagogue-stimulated Cl(-) secretion might provide a new therapeutic approach for secretory and other ENS-mediated diarrheal conditions.

Guanylin and functional coupling proteins in the hepatobiliary system of rat and guinea pig

Guanylin, a bioactive intestinal peptide, is involved in the cystic fibrosis transmembrane conductance (CFTR)-regulated electrolyte/water secretion in various epithelia. In the present work we report on the expression and cellular localization of guanylin and its affiliated signaling and effector proteins, including guanylate cyclase C (Gucy2c), Proteinkinase GII (Pkrg2), CFTR and the solute carrier family 4, anion exchanger, member 2 (Slc4a2) in the hepatobiliary system of rat and guinea pig. Localization studies in the liver and the gallbladder revealed that guanylin is located in the secretory epithelial cells of bile ducts of the liver and of the gallbladder, while Gucy2c, Pkrg2, CFTR, and Slc4a2 are confined exclusively to the apical membrane of the same epithelial cells. Based on these findings, we assume that guanylin is synthesized as an intrinsic peptide in epithelial cells of the hepatobiliary system and released luminally into the hepatic and cystic bile to regulate electrolyte secretion by a paracrine/luminocrine signaling pathway.

Review article: the pathophysiological roles of the renin–angiotensin system in the gastrointestinal tract

SummaryBackgroundThe renin‐angiotensin system (RAS) is a homeostatic pathway widely known to regulate cardiovascular and renal physiology; however, little is known about its influence in gastrointestinal tissues.AimTo elicit the anatomical distribution and physiological significance of the components of the RAS in the gastrointestinal tract.MethodsAn extensive online literature review including Pubmed and Medline.ResultsThere is evidence for RAS involvement in gastrointestinal physiology and pathophysiology, with all the components required for autonomous regulation identified throughout the gastrointestinal tract. The RAS is implicated in the regulation of glucose, amino acid, fluid and electrolyte absorption and secretion, motility, inflammation, blood flow and possibly malignant disease within the gastrointestinal tract. Animal studies investigating the effects of RAS blockade in a range of conditions including inflammatory bowel disease, functional gut disorders, gastrointestinal malignancy and even intestinal ischaemia have been encouraging to date. Given the ready availability of drugs that modify the RAS and their excellent safety profile, an opportunity exists for investigation of their possible therapeutic role in a variety of human gastrointestinal diseases.ConclusionsThe gastrointestinal renin‐angiotensin system appears to be intricately involved in a number of physiological processes, and provides a possible target for novel investigative and therapeutic approaches.

Cannabinoid receptors in submandibular acinar cells: functional coupling between saliva fluid and electrolytes secretion and Ca2+ signalling

Cannabinoid receptors (CBRs) belong to the G protein-coupled receptor superfamily, and activation of CBRs in salivary cells inhibits agonist-stimulated salivation and modifies saliva content. However, the role of different CBR subtypes in acinar cell physiology and in intracellular signalling remains unclear. Here, we uncover functional CB(1)Rs and CB(2)Rs in acinar cells of rat submandibular gland and their essential role in saliva secretion. Pharmacological activation of CB(1)Rs and CB(2)Rs in the submandibular gland suppressed saliva outflow and modified saliva content produced by the submandibular gland in vivo. Using Na(+)-selective microelectrodes to record secretory Na(+) responses in the lumen of acini, we observed a reduction in Na(+) transport following the activation of CBRs, which was counteracted by the selective CB(1)R antagonist AM251. In addition, activation of CB(1)Rs or CB Rs caused inhibition of Na(+)-K(+) 2 -ATPase activity in microsomes derived from the gland tissue as well as in isolated acinar cells. Using a Ca(2+) imaging technique, we showed that activation of CB(1)Rs and CB(2)Rs alters [Ca(2+)](cyt) signalling in acinar cells by distinct pathways, involving Ca(2+) release from the endoplasmic reticulum (ER) and store-operated Ca(2+) entry (SOCE), respectively. Our data demonstrate the expression of CB(1)Rs and CB(2)Rs in acinar cells, and their involvement in the regulation of salivary gland functioning.

Enteroendocrine and Neuronal Mechanisms in Pathophysiology of Acute Infectious Diarrhea

While enterocyte secretion is the predominant mechanism considered responsible for secretory diarrhea in response to acute enteric infections, there are several lines of evidence that support alternative mechanisms controlling fluid and electrolyte secretion in diarrhea. To review enteroendocrine and neuronal mechanisms that participate in the development of acute infectious diarrhea. Acute infectious diarrheas due to bacterial toxins (e.g., cholera, E. coli heat-stable enterotoxin, C. difficile) and rotavirus are all associated with secretion of transmitters from enteroendocrine cells (e.g., 5-HT) and activation of afferent neurons that stimulate submucosal secretomotor neurons. The latter secrete acetylcholine (which binds to muscarinic receptors on epithelial cells) and VIP. Involvement of nerves was demonstrated by inhibition of bacterial toxin-induced secretion by hexamethonium (nicotinic), tetrodotoxin (Na(+) channel blocker), and lidocaine (visceral/mucosal afferents). Nicotinic receptors are present on secretomotoneurons and these are activated by release of acetylcholine from enteric interneurons or extrinsic efferent fibers. Specific organisms also modify other mechanisms that may contribute to development of acute diarrhea. Thus, mucin secretion, activation of motor mechanisms, increased mucosal permeability and inhibition of bile acid absorption have been reported in specific types of acute infectious diarrhea. New therapies targeting neural and transmitter mediation including 5-HT, VIP, NPY, as well as toxin receptors and channels activated during acute infectious diarrhea could usher in a novel approach to enhancing glucose-electrolyte solutions used in the treatment of acute diarrhea.

Characterization of Cholix Toxin-induced Apoptosis in HeLa Cells

Cholix toxin (Cholix) is a novel ADP-ribosylating cytotoxin produced by Vibrio cholerae, which utilizes eukaryotic elongation factor 2 as a substrate and acts by a mechanism similar to that of diphtheria toxin and Pseudomonas exotoxin A. First it was found that Cholix-treated HeLa cells exhibited caspase-dependent apoptosis, whereas intestinal cells such as Caco-2, HCT116, and RKO did not. Here we investigated Cholix-induced cell death signaling pathways in HeLa cells. Cholix-induced cytochrome c release into cytosol was initiated by specific conformational changes of pro-apoptotic Bak associated with Bax. Silencing of bak/bax genes or bak gene alone using siRNA significantly suppressed cytochrome c release and caspase-7 activation, but not activation of caspases-3 and -9. Although pretreatment with a caspase-8 inhibitor (Z-IETD-FMK) reduced Cholix-induced cytochrome c release and activation of caspases-3, -7, and -9, cytotoxicity was not decreased. Pretreatment with Z-YVAD-FMK, which inhibits caspase-1, -4, and -5, suppressed not only cytochrome c release, activation of caspase-3, -7, -8, or -9, and PARP cleavage, but also cytotoxicity, indicating that caspase-1, -4, and -5 activation is initiated at an early stage of Cholix-induced apoptosis and promotes caspase-8 activation. These results show that the inflammatory caspases (caspase-1, -4, and -5) and caspase-8 are responsible for both mitochondrial signals and other caspase activation. In conclusion, we showed that Cholix-induced caspase activation plays an essential role in generation of apoptotic signals, which are mediated by both mitochondria-dependent and -independent pathways.

Bile acid malabsorption investigated by selenium-75-homocholic acid taurine ( 75SeHCAT) scans: Causes and treatment responses to cholestyramine in 298 patients with chronic watery diarrhoea

Background The liver produces and secretes bile acids into the small intestine. In the small intestine, most of the bile acids are absorbed in the distal ileum with portal vein transportation back to the liver and resecretion (enterohepatic recycling). Increased spillover of bile acids from the small intestine into the colon (bile acid malabsorption) may affect the secretion of colonic water and electrolytes and result in watery diarrhoea. The aim of this study was to investigate the frequency of bile acid malabsorption and treatment responses to cholestyramine with 75SeHCAT scanning among patients suffering from chronic watery diarrhoea. Methods This was a retrospective study that included all patients who received a 75SeHCAT scan over a five-year period (2004–2009). Results In total, 298 patients (198 females, 100 men) with a median age of 42 years (range 16–82 years) were investigated. Bile acid malabsorption ( 75SeHCAT retention < 15% after seven days) was identified in 201 patients (68%, 95% confidence interval (CI): 62%–73%). Bile acid malabsorption due to ileal dysfunction (Type I) was found in 77 patients, idiopathic bile acid malabsorption (Type II) was found in 68 patients and 56 patients with other conditions had bile acid malabsorption (Type III). Of the 150 patients who were able to take cholestyramine continuously, 108 patients (71%, CI: 63%–78%) reported a positive effect on their bowel habits. Conclusions Bile acid malabsorption is a frequent problem in patients with chronic watery diarrhoea. Treatment with bile acid binders was effective regardless of type and severity.

Matrigel-Induced Tubular Morphogenesis of Human Eccrine Sweat Gland Epithelial Cells

Human eccrine sweat glands are tubule-structured glands of the skin that are vital in thermoregulation, secretion, and excretion of water and electrolytes. A study of tubular morphogenesis in vitro would facilitate the development of a tissue engineering model for eccrine sweat glands and other tubule-structured glands. Matrigel, a basement membrane matrix, has been shown to promote differentiation and morphogenesis of many different cell types, including tubular cells. This study investigated the growth, differentiation, and tubular morphogenesis of human eccrine sweat gland epithelial cells cultured in Matrigel. Human eccrine gland epithelial cells were isolated and cultured in vitro. The cell growth in Matrigel was evidenced by the formation of cell clusters, which were observed under an inverted microscope. The internal structure of the cell clusters was further investigated by hematoxylin-eosin (HE) staining and confocal laser scanning microscopy (CLSM) of propidium iodide-stained nuclei. The results demonstrated that although on a plastic surface or in a collagen gel the cells could not form tubular structures, they formed tubular structures when cultured in Matrigel. Consequently, we conclude that Matrigel can promote tubular morphogenesis of human eccrine sweat gland epithelial cells.

Glia and NO nicotine: a perfect harmony for secretory control

Glia and NO nicotine: a perfect harmony for secretory control

CFTR induces extracellular acid sensing in Xenopus oocytes which activates endogenous Ca2+-activated Cl- conductance

The cystic fibrosis transmembrane conductance regulator (CFTR) produces a cyclic adenosine monophosphate (cAMP)-dependent Cl⁻ conductance of distinct properties that is essential for electrolyte secretion in human epithelial tissues. However, the functional consequences of CFTR expression are multifaceted, encompassing much more than simply supplying a cellular cAMP-regulated Cl⁻ conductance. When we expressed CFTR in Xenopus oocytes, we found that extracellular acidic pH activates a Ca²⁺-dependent outwardly rectifying Cl⁻ conductance that does not reflect CFTR activity. The proton-activated Cl⁻ conductance showed biophysical and pharmacological features of a Ca²⁺-dependent Cl⁻ conductance, most likely mediated by Xenopus TMEM16A. In contrast to the effects of extracellular acidification, intracellular acidification did not activate an endogenous Cl⁻ conductance. Proton/CFTR-mediated activation of human TMEM16A was also detected in HEK293 cells. The gating mutant G551D-CFTR conferred proton sensitivity, while deltaF508-CFTR enabled proton activation of TMEM16A only in Xenopus oocytes, which, unlike HEK293 cells, allow deltaF508-CFTR to be trafficked to the cell membrane. Activation of TMEM16A by lysophosphatidic acid was enhanced in the presence of CFTR but was additive with activation by extracellular protons. Because expression of CFTR-E1474X did not confer proton sensitivity, we propose that CFTR translocates a proton receptor to the plasma membrane via its PDZ-binding domain.

Toll-Like Receptor 4 Potentiates Ca2+-Dependent Secretion of Electrolytes from Swine Tracheal Glands

Airway surface fluids are mainly secreted from submucosal glands, and play important roles in the defense of airways via the up-regulation of mucociliary transport, resulting in an exclusion of many microbes or foreign substances. Although there are many articles concerning the importance of Toll-like receptors (TLRs) in airway immune systems, whether TLRs directly cooperate with tracheal submucosal glands to increase secretion remains unknown. We investigated the effects of ligands of the three TLR subtypes (TLR2, TLR3, and TLR4) on the physiologic secretion of electrolytes by using a patch-clamp technique. Among these TLRs, only the TLR4 ligand, LPS, showed potentiating effects on acetylcholine (ACh)-induced ionic currents in a dose-dependent manner. These potentiating effects were completely abolished by pretreatment with a specific TLR4 antagonist or the anti-TLR4 antibody. LPS per se exerted no appreciable effect on baseline currents. Next, we demonstrated the abundant expression of TLR4 in submucosal gland acinar cells by using immunofluorescent staining and RT-PCR. Furthermore, we revealed that both nitric oxide synthase inhibitors and cyclic guanosine monophosphate (cGMP)-dependent protein kinase (cGK) inhibitors abolished the LPS-induced potentiating effects completely. Analyses of fluorescence intensities, using an intracellular nitric oxide (NO) indicator, demonstrated that LPS could further increase the ACh-induced synthesis of NO. These findings suggest that TLR4 takes part in airway mucosal defense systems as a unique exogenous potentiator of electrolyte-water secretion from submucosal gland acinar cells, and that NO/cGMP/cGK signaling is involved in this rapid TLR4 signaling pathway.

Dissection of Calcium Signaling Events in Exocrine Secretion

The secretion of fluid and electrolytes by salivary gland acinar cells requires the coordinated regulation of multiple ion channel and transporter proteins, signaling components, and water transport. Importantly, neurotransmitter stimulated increase in the cytosolic free [Ca(2+)] ([Ca(2+)](i)) is critical for the regulation of salivary gland secretion as it regulates several major ion fluxes that together establish the sustained osmotic gradient to drive fluid secretion. The mechanisms that act to modulate these increases in [Ca(2+)](i) are therefore central to the process of salivary fluid secretion. Such modulation involves membrane receptors for neurotransmitters, as well as mechanisms that mediate intracellular Ca(2+) release, and Ca(2+) entry, as well as those that maintain cellular Ca(2+) homeostasis. Together, these mechanisms determine the spatial and temporal aspects of the [Ca(2+)](i) signals that regulate fluid secretion. Molecular cloning of these transporters and channels as well as development of mice lacking these proteins has established the physiological significance of key components that are involved in regulating [Ca(2+)](i) in salivary glands. This review will discuss these important studies and the findings which have led to resolution of the Ca(2+) signaling mechanisms that determine salivary gland fluid secretion.

Stimulation of PGE2 synthesis and water and electrolyte secretion by senna anthraquinones is inhibited by indomethacin.

The effect of dried senna pod extract, containing 10% sennoside B, on colonic electrolyte and fluid transport was examined in the anaesthetized rat in-situ. Oral administration of senna pod extract dose-dependently (17.5-30 mg kg-1, calculated as sennoside B) reversed net absorption of water, sodium and chloride to net secretion and increased potassium secretion. Senna pod extract stimulated the output of prostaglandin E2 into the colonic lumen. Inhibition of prostaglandin biosynthesis by pretreatment of the rats with indomethacin (10 mg kg-1) significantly inhibited the effects of senna pod extract (17.5-30 mg kg-1) both on net fluid transport and on prostaglandin E2 synthesis. The inhibitory effect of indomethacin on net fluid transport induced by senna pod extract (30 mg kg-1) was dose-dependent. It is concluded that anthraquinones exert their laxative action at least partially via stimulation of colonic fluid and electrolyte secretion, and that this secretion is mediated by stimulation of endogenous prostaglandin E2 formation.

Involvement of prostaglandins in histamine-induced fluid and electrolyte secretion by rat colon.

Histamine increased the transmural potential difference across rat colon in-vivo and induced a net secretion of fluid. Both effects were inhibited by indomethacin. Histamine increased the potential difference and short-circuit current, and reduced tissue resistance in colonic sheets in-vitro. This response was reduced in the absence of chloride in the bathing medium or in the presence of serosal frusemide, suggesting that histamine stimulated electrogenic chloride secretion by the colon. The rise in short-circuit current induced by histamine was calcium-dependent since it was reduced in the absence of serosal calcium or in the presence of serosal verapamil. Indomethacin, a cyclo-oxygenase inhibitor, and mepacrine, a phospholipase inhibitor, both caused a dose-dependent inhibition of the electrical response of colonic sheets to histamine, without affecting the rise in short-circuit current induced by prostaglandin E2. The stimulation of chloride secretion induced by histamine in rat colon therefore appears to be mediated by an increased production of prostaglandins.