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At least 199 records · Page 11Linked to original sources
PubMed2004

Prevention of toxin-induced intestinal ion and fluid secretion by a small-molecule CFTR inhibitor.

BACKGROUND & AIMS: The cystic fibrosis transmembrane conductance regulator (CFTR) provides an important apical route for Cl(-) secretion across intestinal epithelia. A thiazolidinone-type CFTR blocker (CFTR(inh)-172) reduced cholera toxin-induced fluid accumulation in mouse intestinal loops. Here, we characterize the efficacy and pharmacodynamics of CFTR(inh)-172 in blocking cAMP and cGMP induced Cl(-)/fluid secretion in rodent and human intestine. METHODS & RESULTS: CFTR(inh)-172 inhibited cAMP and cGMP agonist induced short-circuit current by >95% in T84 colonic epithelial cells (K(I) approximately 3 micromol/L) and in mouse and human intestinal sheets (K(I) approximately 9 micromol/L). A single intraperitoneal injection of CFTR(inh)-172 (200 microg) blocked intestinal fluid secretion in a rat closed-loop model by >90% for cholera toxin and >70% for STa Escherichia coli toxin. In mice, CFTR(inh)-172 (20 microg) inhibited cholera toxin-induced intestinal fluid secretion by 90% (persistence t(1/2) approximately 10 hours, K(I) approximately 5 microg) and STa toxin by 75% (K(I) approximately 10 microg). Tissue distribution and pharmacokinetic studies indicated intestinal CFTR(inh)-172 accumulation facilitated by enterohepatic circulation. An oral CFTR(inh)-172 preparation reduced fluid secretion by >90% in a mouse open-loop cholera model. CONCLUSIONS: A small molecule CFTR blocker markedly reduced intestinal ion and fluid secretion caused by cAMP/cGMP-dependent bacterial enterotoxins. CFTR inhibition may thus reduce fluid secretion in infectious secretory diarrheas.

Administration, Oral↗
PubMedDate not supplied

Cytosolic Ca2+ gradients triggering unidirectional fluid secretion from exocrine pancreas.

Exocrine gland cells secrete Cl(-)-rich fluid when stimulated by neurotransmitters or hormones. This is generally ascribed to a rise in cytosolic Ca2+ concentration ([Ca2+]i), which leads to activation of Ca2(+)-dependent ion channels. A precise understanding of Cl- secretion from these cells has been hampered by a lack of knowledge about the spatial distribution of the Ca2+ signal and of the Ca2(+)-dependent ion channels in the secreting epithelial cells. We have now used the whole-cell patch-clamp method and digital imaging of [Ca2+]i to examine the response of rat pancreatic acinar cells to acetylcholine. We found a polarization of [Ca2+]i elevation and ion channel activation, and suggest that this comprises a novel 'push-pull' mechanism for unidirectional Cl- secretion. This mechanism would represent a role for cytosolic Ca2+ gradients in cellular function. The cytosolic [Ca2+]i gradients and oscillations of many other cells could have similar roles.

Acetylcholine↗
PubMed1996

An ammonium pulse inhibits fluid secretion.

Exposing perfused mandibular salivary glands to a 5-min pulse of NH4Cl almost totally inhibited fluid secretion evoked by acetylcholine. Recovery from exposure to 0.5 mM NH4Cl occurred within 10 min, but after exposure to 20 mM NH4Cl recovery was not complete even after 30 min. The inhibition could not be explained by changes in intracellular pH as there was no acidosis measurable after the 0.5 mM NH4Cl pulse. NH4Cl did not inhibit intracellular calcium release by acetylcholine so that receptor inhibition could not be the explanation for the inhibition of secretion. These observations indicate that data obtained from ammonium pulse experiments should be interpreted with caution.

Acetates↗
PubMed1996

Ketoconazole activates chloride and fluid secretion by Necturus gallbladder at low pH.

Necturus gallbladder epithelium, normally a reabsorptive epithelium, was stimulated to secrete chloride and fluid by the combined effects of ketoconazole and a reduction in perfusate pH to 7.0. The reversal in the direction of net fluid transport was accompanied by inhibition of the conductance of the apical cell membrane to sodium, potassium, and a striking stimulation of the conductance to chloride. The results are consistent with a previously unidentified mechanism for regulation of the apical cell membrane transport properties of reabsorptive epithelia.

Animals↗
PubMed2005

Fluid secretion and the Na+-K+-2Cl- cotransporter in mouse exorbital lacrimal gland.

We have previously suggested that fluid flow in the mouse exorbital lacrimal gland is driven by the opening of apical Cl- and K+ channels. These ions move into the lumen of the gland and water follows by osmosis. In many tissues, the Na+-K+-2Cl- cotransporter (NKCC1) replaces the Cl- and K+ ions that move into the lumen. We hypothesize that mouse exorbital lacrimal glands would have NKCC1 co-transporters and that they would be important in fluid transport by this gland. We used immunocytochemistry to localize NKCC1-like immunoreactivity to the membranes of the acinar cells as well as to the basolateral membranes of the duct cells. We developed a method to measure tear flow and its composition from mouse glands in situ. Stimulation with the acetylcholine agonist carbachol produced a peak flow followed by a plateau. Ion concentration measurements of this stimulated fluid showed it was high in K+ and Cl-. Treatment of the gland with furosemide, a blocker of the NKCC1 cotransporter, reduced the plateau phase of fluid flow by approximately 30%. Isolated cells exposed to a hypertonic shock shrank by approximately 20% and then showed a regulatory volume increase (RVI). Both the RVI and swelling were blocked by treatment with furosemide. Cells isolated from these glands shrink by approximately 10% in the presence of carbachol. Blocking NKCC1 with furosemide reduced the amount of shrinkage by approximately 50%. These data suggest that NKCC1 plays an important role in fluid secretion by the exorbital gland of mice.

Animals↗
PubMed1997

Effect of ganglionic blocking compounds on in-vivo fluid secretion in the rat small intestine.

It is well-known that enteric, secreto-motor nerves mediate cholera toxin-induced fluid secretion in the rat small intestine. This notion is, in part, derived from experiments on anaesthetized animals in which the response to cholera toxin was antagonized by the ganglionic nicotinic receptor antagonist, hexamethonium. In the current study, such anti-secretory action of ganglionic blocking compounds was analysed in an experiment designed to minimize any possible negative effect of general anaesthesia on intestinal secretion. Rats were anaesthetized with ether for 5-10 min, during which time a jejunal loop (10-12 cm) was constructed. The loop was challenged with one of the secretagogues, cholera toxin, prostaglandin E1 (PGE1) or okadaic acid. Saline (control) or either of the ganglionic blockers, hexamethonium and chlorisondamine, was administered intravenously. The rats were killed 5 h (cholera toxin) or 1.5 h (PGE1 and okadaic acid) after challenge, and the amount of fluid accumulated in the loops was determined. Cholera toxin-induced secretion was unchanged by hexamethonium but reduced by approximately 80% by chlorisondamine. The difference in effect between the two blockers might relate to the duration of ganglionic blockade. Chlorisondamine blocked secretion induced by either PGE1 or okadaic acid by approximately 60%. It is suggested that the anti-secretory effect of ganglionic blocking compounds might be a result of blockade of secreto-motor nerves but other mechanisms, for example interference with haemodynamic factors, cannot be ruled out.

Alprostadil↗
PubMed1997

A synthetic peptide derived from glycine-gated Cl- channel induces transepithelial Cl- and fluid secretion.

M2GlyR is a synthetic 23-amino acid peptide that mimics the second membrane-spanning region of the alpha-subunit of the postsynaptic glycine receptor. This peptide has been shown to form an anion-selective channel in phospholipid bilayers. We have investigated the possibility that the peptide may incorporate into the apical membrane of secretory epithelia and induce the secretion of Cl- and water. We improved the solubility of this peptide by adding four lysine residues to the carboxy terminus, C-K4-M2GlyR, and assayed its channel-forming activity using a subculture of Madin-Darby canine kidney (MDCK) cells. The addition of 100 microM C-K4-M2GlyR to the apical surface of MDCK monolayers significantly increased short-circuit current (Ise), hyperpolarized transepithelial potential difference, and induced fluid secretion. The increase in Ise was inhibited by 100 microM bumetanide and by Cl- channel inhibitors. The effectiveness of the channel blockers followed the sequence niflumic acid > or = 5-nitro-2-(3-phenylpropylamino)benzoate > diphenylamine-2-carboxylate (DPC) > glibenclamide. The effect of the peptide was not inhibited by 4.4'-diisothiocyanostilbene-2-2'-disulfonic acid. Removing Cl from the bathing solutions also inhibited the effect of the peptide. The Cl- efflux pathway induced by C-K4-M2GlyR differs from the native pathway activated by the adenosine 3',5'-cyclic monophosphate (cAMP) agonist, forskolin. First, intracellular cAMP levels were unaffected. Second, the concentration of DPC required to inhibit the effect of the peptide was much lower than that needed to block the forskolin response (100 microM vs. 3 mM). These results support the hypothesis that the synthetic peptide C-K4-M2GlyR can from Cl -selective channels in the apical membrane of secretory epithelial cells and can induce sustained transepithelial secretion of Cl- and fluid.

Amino Acid Sequence↗
PubMed1984

Effects of Na+ depletion on fluid secretion and levels of phosphorus compounds as measured by 31P-NMR in perfused canine mandibular gland.

The dependency of fluid secretion on extracellular Na+ and the levels of phosphorus compounds were studied in the perfused canine mandibular gland (using 31P-NMR). During control perfusion, the resting levels of creatine phosphate (CP) and ATP were 0.62 +/- 0.05 mmol . kg-1 gland and 0.42 +/- 0.04 mmol . kg-1 (mean +/- S.E., n = 9), respectively. Acetylcholine (Ach; 1 mumol . l-1 for 3 min) induced a salivary secretion and decreased the CP level. When Na+ in the perfusate was completely replaced with Li+, Ach induced only a minimal salivary secretion and no change in the ATP and CP levels. Restitution of Na+ to the perfusion, even without added Ach, caused a decrease in ATP and CP, and a small increase in salivary secretion. These results suggest that the activity of Na+/K+ ATPase is increased inversely via a rise of the intracellular Na+ concentration and that the salivary secretion is induced not only by added secretagogues but by an increase in the Na+ entry without added secretagogues.

Adenosine Triphosphate↗
PubMed1986

Tetrodotoxin inhibits directly acting stimulants of intestinal fluid secretion.

Intravenous injection of tetrodotoxin (20 micrograms kg-1) to anaesthetized rats blocks PGE1- and inhibits VIP-induced fluid secretion from the mucosa of the jejunum without affecting the physiological rates of net water and glucose absorption. It is suggested that the toxin might release an endogenous inhibitor of secretion or that it might possess direct antisecretory activity on the epithelial cells of the jejunum. It is further suggested that results where tetrodotoxin has been used to investigate secretagogue action should be treated with caution.

Alprostadil↗
PubMed2002

Regulation of mucin and fluid secretion by conjunctival epithelial cells.

Tears play a vital role in the health and protection of the cornea and conjunctiva. The tear film consists of multiple layers and different glands secrete each layer. Because of many and varied requirements of the ocular surface cells, the volume, composition and structure of the tear film must be exquisitely controlled. If any layer of the tear film is disrupted or altered, the entire tear film is affected, often with deleterious effects. This chapter reviews the current knowledge of the neural and growth factor regulation of electrolyte, water and protein secretion from the goblet and stratified squamous cells of the conjunctiva as well as the mechanisms used for fluid secretion. The evidence presented in this review suggests that parasympathetic nerves stimulate goblet, but not stratified squamous, cell secretion. Sympathetic nerves stimulate stratified squamous, but not goblet, cell secretion, while P2Y(2) agonists stimulate secretion from both cell types. Growth factors regulate goblet cell secretion, but their effects on stratified squamous cell secretion are unknown.

Animals↗
PubMed1999

Cyclosporin A increases tear fluid secretion via release of sensory neurotransmitters and muscarinic pathway in mice.

Cyclosporin A, an immunosuppressant, has the potential to increase tear fluid secretion through mechanisms which are not yet well understood. To gain insight into this question, we investigated the effect of cyclosporin A containing eyedrops on lacrimation in normal mice. Topical application of 0.1% cyclosporin A eyedrops for 3 days significantly increased lacrimation. This response was completely blocked by pre-exposure to 1% capsaicin. Immunohistochemical analysis revealed that capsaicin treatment depleted substance P from the lacrimal gland. Furthermore, following 1% atropine treatment, which completely blocks pilocarpine-stimulated (500 micrograms kg-1, i.p.) lacrimation, application of 0.1% cyclosporin A eyedrops significantly increased lacrimation. However, this increase was less than the response seen with 0.1% cyclosporin A in the absence of atropine. Interestingly, substance P-induced tear secretion was also partially inhibited in atropine treated mice. These results suggest that cyclosporin A accelerates tear secretion by releasing neurotransmitters from sensory nerve endings which interacts with the parasympathetic nerves.

Administration, Topical↗
PubMed1982

The influence of calcium on the control of fluid secretion in the cockroach salivary gland.

When cockroach salivary glands are bathed in calcium-free medium the basal rate of fluid secretion increases from about 1 nl/min to about 10 nl/min; maintained dopamine stimulation elicits a further rise in secretory rate which gradually declines. Evidence is presented which indicates that magnesium is unable to substitute for calcium in this system. When calcium is returned to the bathing solution after a period of calcium deprivation there is a transient increase in secretory rate. Stimulation of the glands in certain conditions which inhibit the secretory response leads to some kind of calcium-dependent active state in the secretory cells which can outlast the interaction of the agonist with its receptors. It is concluded that stimulus-secretion coupling in this gland involves a calcium-dependent second messenger system.

Animals↗
PubMed1977

Effect of intestinal distention on levels of cyclic AMP and fluid secretion.

The effect of distention on levels of intestinal cyclic AMP has been examined in rabbit jejunal loops under conditions of distention causing fluid secretion. Cyclic AMP levels were not significantly changed when compared with control loops. Histologic examination of the distended loops showed no significant changes from normal. The data indicate that the secretion in response to distention can occur in absence of morphological alteration and is not mediated by the cyclic AMP system.

Animals↗
PubMed2005

Escherichia coli heat stable (STa) enterotoxin and the upper small intestine: lack of evidence in vivo for net fluid secretion.

Heat stable (STa) enterotoxin from E. coli reduced fluid absorption in vivo in the perfused jejunum of the anaesthetized rat in Krebs-phosphate buffer containing lactate and glucose (nutrient buffer), in glucose saline and in glucose free saline. Bicarbonate ion enhanced fluid absorption of 98 +/- 7 (6) microl/cm/h was very significantly (P < 0.0001) reduced by STa to 19 +/- 4 (6) microl/cm/h, but net secretion was not found. When impermeant MES substituted for bicarbonate ion, net fluid absorption of 29 +/- 3 (6) microl/cm/h was less (P < 0.01) than the values for phosphate buffer and bicarbonate buffer. With STa in MES buffer, fluid absorption of 3 +/- 2 (6) microl/cm/h was less than (P < 0.001) that in the absence of STa and not significantly different from zero net fluid absorption. E. coli STa did not cause net fluid secretion in vivo under any of the above circumstances. Neither bumetanide nor NPPB when co-perfused with STa restored the rate of fluid absorption. In experiments with zero sodium ion-containing perfusates, STa further reduced fluid absorption modestly by 20 microl/cm/h. Perfusion of ethyl-isopropyl-amiloride (EIPA) with STa in zero sodium ion buffers prevented the small increment in fluid entry into the lumen caused by STa, indicating that the STa effect was attributable to residual sodium ion and fluid uptake that zero sodium-ion perfusates did not eradicate. These experiments, using a technique that directly measures mass transport of fluid into and out of the in vivo proximal jejunum, do not support the concept that E. coli STa acts by stimulating a secretory response.

Animals↗
PubMed1975

Association of race, age, menopausal status, and cerumen type with breast fluid secretion in nonlactating women, as determined by nepple aspiration.

Biologic and physiologic factors associated with the availability of breast secretions by a nipple aspiration technique were investigated in 606 normal, non-lactating women. Data obtained on race, age, menstrual status, parity, contraceptive pill use, hormone use, and cerumen type indicated that availability of secretions was related to race, age, and menopause, and to genetic factors associated with apocrine bland function. Fluid aspirates were obtained most often from Caucasians (70.2% success), least often from Chinese (24.1% success). The percentage of successful aspirations declined in women over 50 years of age in all racial groups, but distinctly less so in Caucasians. Chinese and Japanese women with dry-type cerumen had a lower percentage of successful aspirations than those with wet type, which suggested that genetic factors may be associated with breast fluid secretion in nonlactating women.

Age Factors↗
PubMed1983

Leukotriene C4 and dimethylphenylpiperazinium-induced responses in canine airway tracheal muscle contraction and fluid secretion.

Leukotrienes have been implicated as putative mediators in several air way diseases. In previous canine studies it was shown that leukotriene C4 (LTC4) enhanced fluid secretion over baseline values and this enhancement could be blocked by hexamethonium. This indicates that leukotrienes have as one of their actions, stimulation of ganglionic motor neurons. In the present study, we determined that LTC4 acts at a similar site as the specific nicotinic receptor agonist dimethylphenylpiperazinium (DMPP). Both LTC4 and DMPP when given alone enhanced mucus secretion and induced tracheal muscle contraction over control baseline (p less than 0.05). When added to DMPP, LTC4 enhanced the DMPP effect of muscle contraction at 5 and 8 micrograms by a synergistic amount, while the secretion was only additive. The slopes of the dose-response curves for DMPP + LTC4 did not differ by a statistically significant amount. LTC4 and DMPP act on a similar, if not the same, ganglionic receptor.

Animals↗
PubMed1997

Anti-diuresis in the blood-feeding insect Rhodnius prolixus Stål: the peptide CAP2b and cyclic GMP inhibit Malpighian tubule fluid secretion.

Rhodnius prolixus eliminates NaCl-rich urine at high rates following its infrequent but massive blood meals. This diuresis involves stimulation of Malpighian tubule fluid secretion by diuretic hormones released in response to distention of the abdomen during feeding. The precipitous decline in urine flow that occurs several hours after feeding has been thought until now to result from a decline in diuretic hormone release. We suggest here that insect cardioacceleratory peptide 2b (CAP2b) and cyclic GMP are part of a novel mechanism of anti-diuresis. Secretion rates of 5-hydroxytryptamine-stimulated Malpighian tubules are reduced by low doses of CAP2b or cyclic GMP. Maximal secretion rates are restored by exposing tubules to 1 mmol l-1 cyclic AMP. Levels of cyclic GMP in isolated tubules increase in response to CAP2b, consistent with a role for cyclic GMP as an intracellular second messenger. Levels of cyclic GMP in tubules also increase as urine output rates decline in vivo, suggesting a physiological role for this nucleotide in the termination of diuresis.

Animals↗