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Biomedical subjects

L A Turnberg

Publications and source records attributed to L A Turnberg.

At least 37 records · Page 2Linked to original sources
PubMed1990

The small intestine: prospects for therapeutic approaches in secretory diarrhoeal diseases.

In many diarrhoeal diseases the intestinal mucosa is stimulated to secrete salt and water. This occurs in diarrhoea as a result of several bacterial toxins, is associated with inflammation and release of inflammatory mediators, and, in many instances, occurs when a neural element is evident. An understanding of the basic underlying mechanisms of secretion could lead to improvements in therapy. Development of vaccines against cholera is showing promise, and a knowledge of the complex field of inflammatory mediators, many of which provoke secretion, provides a foundation for development of more specific and selective anti-inflammatory agents. A detailed understanding of the complicated intracellular second-messenger systems, which are switched on by externally perceived signals, and of the ion transport responses, which are responsible for secretion, may lead to the development of specific anti-diarrhoeal drugs. Meanwhile, the message that oral rehydration therapy for severe diarrhoea, including cholera, is successful, should continue to be widely promulgated and taken up.

Acute-Phase Proteins↗
PubMed1989

Stimulation of Cl/HCO3 exchange in rat duodenal brush border membrane vesicles by cAMP.

Brush border membrane vesicles have been used to study the regulation of rat duodenal HCO3 secretion. When vesicles were loaded with cAMP and ATP SITS-sensitive Cl/HCO3 exchange (unidirectional 36Cl influx in response to an outward-facing OH/HCO3 gradient) was stimulated by approximately 25%. In contrast, there was no effect of cAMP upon SITS-insensitive 36Cl uptake. The stimulation of Cl/HCO3 exchange caused by cAMP was abolished in the presence of a specific heat-stable cAMP-dependent protein kinase inhibitor. These results suggest that Cl/HCO3 exchange, and hence HCO3 secretion, is regulated by cAMP via phosphorylation of some component of the membrane associated with the transport protein.

Animals↗
PubMed1989

An investigation of the role of possible neural mechanisms in cholera toxin-induced secretion in rabbit ileal mucosa in vitro.

1. Cholera toxin stimulates intestinal secretion in vitro by activation of mucosal adenylate cyclase. However, it has been proposed that cholera toxin promotes secretion in vivo mainly through an indirect mechanism involving enteric neural reflexes. 2. We examined this hypothesis further by studying the influence of neuronal blockade on cholera toxin-induced changes in fluid transport across rabbit ileum in vitro. Mucosa, stripped of muscle layers, was mounted in flux chambers and luminal application of crude cholera toxin (2 micrograms/ml) caused a delayed but sustained rise in the short-circuit current, electrical potential difference and Cl- secretion. Pretreatment with the nerve-blocking drug, tetrodotoxin (5 x 10(-6) mol/l serosal side), failed to influence the secretory response to cholera toxin, and addition of tetrodotoxin at the peak response to cholera toxin also had no effect. 3. That tetrodotoxin could block neurally mediated secretagogues was confirmed by the demonstration that the electrical responses to neurotensin (10(-7) mol/l and 10(-8) mol/l) were blocked by tetrodotoxin (5 x 10(-6) mol/l). Furthermore, the response to cholera toxin of segments of ileum, which included the myenteric, submucosal and mucosal nerve plexuses, was not inhibited by tetrodotoxin. 4. We conclude that cholera toxin-induced secretion in rabbit ileum in vitro is not mediated via a neurological mechanism.

Animals↗
PubMed1989

A microelectrode study of responses to secretagogues by epithelial cells on villus and crypt of rat small intestine.

The cellular origin of the response to secretagogues in small bowel epithelium was investigated by recording the effect of 5-hydroxytryptamine (5-HT, 10(-4) mol/l), acetylcholine (10(-4) mol/l), and prostaglandin E2 (PGE2, 10(-5) or 10(-4) mol/l) on apical membrane potentials (Va) of crypt and villus cells of rat ileum and jejunum in vitro using intracellular microelectrodes. Experiments were performed under visual control; addition of secretagogues and other manipulations were carried out during single impalements. Under basal conditions, apical membrane potential differences were consistently higher in jejunum than ileum (-72 +/- 1 vs. -47 +/- 2 mV, respectively, for villus impalements; -61 +/- 2 mV vs. -57 +/- 1 mV, respectively, for crypt impalements), and in jejunum villous membrane potentials exceeded those in the crypt. In the ileum, this crypt-villus gradient was reversed. The three secretagogues increased transmural potential difference and transiently reduced Va in cells in both crypt and villus regions by 8 mV or more. Fractional apical membrane resistance (FR) declined in ileum by approximately 30% in response to 5-HT and PGE2, whereas little change in FR was observed in jejunal recordings. PGE2 was ineffective in crypt and villus when Cl- was replaced by gluconate in both the luminal and serosal perfusates but depolarized the apical membrane in both regions after serosal restoration of Cl- from -76 +/- 4 to -56 +/- 8 mV in villus and from -58 +/- 4 to -45 +/- 6 mV in crypt. Rapid luminal Cl- substitution depolarized Va on the villus from -77 +/- 2 to -74 +/- 3 mV, but this effect was enhanced in the presence of PGE2, reducing Va from -65 +/- 8 to -43 +/- 12 mV. Prior to PGE2 addition, Va was -81 +/- 4 mV for this group of experiments. FR rose in the nominal absence of luminal Cl- from 0.69 +/- 0.09 to 0.77 +/- 0.06. It is concluded that because a Cl(-)-dependent depolarization of apical membrane potentials occurs in villi and crypts, net secretion in the small bowel is probably not confined to the crypts and may also occur from villous epithelium.

Acetylcholine↗
PubMed1989

Cl-HCO3 exchange and anion conductance in rat duodenal apical membrane vesicles.

Transport mechanisms for Cl and HCO3 anions in the apical membrane of rat duodenal enterocytes have been characterized using brush-border membrane vesicles. 36Cl uptake was stimulated by outwardly directed gradients of OH, HCO3, and Cl anions. The anion exchanger was sensitive to inhibition by 4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonic acid (SITS) (Ki, 1.3 mmol/l), 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), and furosemide. The process was electroneutral, since voltage clamping the membrane potential to 0 mV or applying a large inside-positive potential had no effect on the magnitude of uptake. The kinetic properties of the exchanger were measured and an apparent Km of 9.8 mM Cl and a Vmax of 134 nmol.mg protein-1.4 s-1 were found. In addition, an electrogenic conductive component of 36Cl uptake was found. This component was dependent on an inside-positive membrane potential and was inhibited by the Cl channel blocker diphenylamine-2-carboxylate. SITS, DIDS, and furosemide had no effect on the electrogenic component of 36Cl uptake. An apparent anion selectivity of SCN greater than I greater than Br greater than Cl greater than HCO3 greater than SO4 greater than Glu greater than PO4 was found. These results support the presence of both Cl-HCO3 exchange and a conductive anion channel in the apical membrane of rat duodenal enterocytes.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1988

Effect of cold-induced pain on salt and water transport in the human jejunum.

The possibility that the central and autonomic nervous systems might be involved in the control of intestinal absorption was assessed by measuring the effect of physical stress (cold-induced pain) on jejunal transport in 13 healthy subjects. Using a triple-lumen perfusion technique to determine jejunal absorption, cold pain significantly reduced net water absorption from 34.9 to 15.7 ml/30 cm.50 min (p less than 0.005), net sodium absorption from 2.6 to 0.2 mEq/30 cm.50 min (p less than 0.005), and net chloride absorption from 2.2 to 0.6 mEq/30 cm.50 min (p less than 0.02). These changes were associated with an elevation of blood pressure and plasma norepinephrine during cold pain. During the period following cold pain, systolic blood pressure remained significantly elevated and net jejunal water absorption significantly reduced. These results suggest that physical stress can influence jejunal absorption of salt and water in humans and support the possibility that the central and autonomic nervous systems have a physiologic role in the control of intestinal function.

Adult↗
PubMed1988

Comparison of delayed-release 5-aminosalicylic acid (mesalazine) and sulfasalazine as maintenance treatment for patients with ulcerative colitis.

To assess the safety and efficacy of delayed-release mesalazine (5-aminosalicylic acid) as maintenance treatment for patients with ulcerative colitis, 100 patients with quiescent colitis were randomly grouped to receive either delayed-release mesalazine or an equivalent dose of enteric-coated sulfasalazine in a 48-wk trial. Groups were comparable for age, sex, and duration and extent of disease. Relapse rates at 48 wk were as follows: sulfasalazine 38.6% (95% confidence limits, 24%-54%) and mesalazine 37.5% (95% confidence limits, 24%-53%), chi 2 = 0.01, p greater than 0.90. Mean time to relapse, cumulative relapse rate, and relapse severity were similar in the two groups. Headaches and upper gastrointestinal symptoms--common at trial entry--improved to a greater extent in patients receiving mesalazine. Delayed-release mesalazine is an effective treatment for maintaining ulcerative colitis remission and is associated with fewer side effects than equivalent doses of enteric-coated sulfasalazine.

Adult↗
PubMed1988

Comparison of delayed release 5 aminosalicylic acid (mesalazine) and sulphasalazine in the treatment of mild to moderate ulcerative colitis relapse.

Oral formulations of 5-aminosalicylic acid (mesalazine) appear less toxic than sulphasalazine. We have therefore compared sulphasalazine, low dose mesalazine and high dose mesalazine in the treatment of mild to moderate relapse of ulcerative colitis. Sixty one patients (32 men, aged 20-78 years) were randomly allocated to sulphasalazine 2 g daily, mesalazine 800 mg daily, or mesalazine 2.4 g daily in a double blind, double dummy, four week trial. Groups were comparable for age, sex, extent of disease, and pretrial sulphasalazine intake. Four patients were unable to complete the study because of treatment failure (two taking sulphasalazine and two high dose mesalazine). A further two patients taking sulphasalazine developed side effects necessitating withdrawal. Within treatment comparisons revealed significant improvement of: sigmoidoscopic grade in the sulphasalazine group; rectal bleeding, sigmoidoscopic and histological grade in the low dose mesalazine group; stool frequency, rectal bleeding and sigmoidoscopic grade in the high dose mesalazine group. Greater improvement in rectal bleeding (p less than 0.05) and sigmoidoscopic appearances (p less than 0.05) occurred in patients taking high dose mesalazine than in those taking sulphasalazine. In two patients taking high dose mesalazine minor rises of plasma creatinine concentrations occurred, suggesting the need to monitor renal function.

Adult↗
PubMed1988

Effect of moderate exercise on salt and water transport in the human jejunum.

The effect of moderate exercise on jejunal absorption was examined in seven healthy subjects using a triple lumen perfusion technique. Moderate exercise on a bicycle ergometer significantly reduced net absorption of water from 32.0 (4.0) to 16.2 (6.1) ml/30 cm/50 min (p less than 0.02), sodium from 2.4 (0.4) to 0.5 (0.9) mmol/30 cm/50 cm (p less than 0.05), chloride from 2.0 (0.4) to 0.3 (0.7) mmol/30 cm/50 min (p less than 0.05), and potassium from 0.20 (0.02) to 0.01 (0.04) mmol/30 cm/50 min (p less than 0.01). After exercise, water, sodium, and chloride absorption returned towards basal values, but potassium absorption remained significantly decreased. These results suggest that moderate exercise can influence jejunal absorption of salt and water in man. They support the possibility that the autonomic nervous system has a physiological role in the control of intestinal transport, although other mechanisms may be involved.

Adult↗
PubMed1988

Activation of protein kinase C attenuates prostaglandin E2 responses in a colonic cell line.

We examined the possibility that the protein kinase C pathway may interact with the adenosine 3',5'-cyclic monophosphate (cAMP) pathway in intestinal epithelium by studying the influence of phorbol esters on the response to prostaglandin E2 (PGE2) in a colonic epithelial cell line. Pretreatment of T84 cells with 4 beta-phorbol 12,13-dibutyrate (PDB) markedly attenuated the rise in short-circuit current provoked by PGE2, a receptor-mediated cAMP agonist. The EC50 of this effect was 52 nM PDB with a half time of 4-6 min. The responses to nonreceptor-mediated agonists, forskolin and dibutyryl cAMP, were unaffected by phorbol ester. PDB also reduced the ability of PGE2 to stimulate adenylate cyclase activity in these cells. The accumulation of cAMP in response to PGE2 was inhibited by PDB (EC50 38 nM), an effect mimicked by the diacylglycerol analogue 1-oleoyl-2-acetyl-sn-glycerol. In addition, PGE2 stimulation of adenylate cyclase in membranes from PDB-treated cells was reduced by 30-40%. Inhibition was not mediated via the catalytic or regulatory subunit of the adenylate cyclase, implying an action involving desensitization of PGE2 receptors. These results provide evidence of a complex interrelationship between protein kinase C- and cAMP-mediated pathways that might be important in regulating the cellular response to secretagogues.

Animals↗
PubMed1987

Glucose depolarizes villous but not crypt cell apical membrane potential difference: a micropuncture study of crypt-villus heterogeneity in the rat.

Brush-border membrane potentials and fractional resistances have been recorded from enterocytes at different points along the crypt-villus axis of rat ileum in vitro. Microelectrode impalements were obtained under visual control and brush-border membrane potentials were higher in crypt than in villous cells (-57 +/- 1.6 against -50 +/- 1.6 mV referred to the mucosal side). Replacing mannitol with D-glucose in the mucosal perfusate resulted in a rise in transmural potential difference (0.5 +/- 0.17 to 1.0 +/- 0.21 mV (n = 37)) and apical membrane potential was depolarized. This occurred consistently only in the upper two-thirds of the villus (-54 +/- 1.7 to -47 +/- 2.3 mV (n = 17)) and not in crypt cells (-56 +/- 2.6 to -57 +/- 2.4 mV (n = 10) or at the crypt-villus junction. The glucose-induced apical membrane depolarization in villous enterocytes was blocked by phlorizin, a competitive inhibitor of sodium-dependent glucose uptake (-50 +/- 2.1 to -53 +/- 2.8 mV (n = 9) in the presence of phlorizin and glucose). Transmural resistance, Rt, and fractional resistance, FR, were unaltered by glucose (61 +/- 3.4 to 61 +/- 3.5 omega X cm2 (n = 50] and (0.60 +/- 0.06 to 0.57 +/- 0.06 (n = 17]. This micro-puncture technique provides direct evidence for functional differentiation along the crypt-villus axis and indicates that active electrogenic accumulation of glucose is confined to villous epithelium.

Animals↗
PubMed1987

Effect of psychological stress on salt and water transport in the human jejunum.

The possibility that the central and autonomic nervous system might be involved in the control of intestinal absorption was assessed by measuring the effect of psychological stress, induced by dichotomous listening, on jejunal transport in 15 healthy subjects. Using a triple-lumen perfusion technique to determine jejunal absorption, dichotomous listening significantly reduced mean net water absorption from 31.2 to 8.7 ml X 30 cm-1 X h-1 (p less than 0.005) and changed mean net sodium and chloride absorption to secretion (sodium +1.14 to -1.2 mEq X 30 cm-1 X h-1, p less than 0.01; and chloride +1.5 to -0.9 mEq X 30 cm-1 X h-1, p less than 0.02). During the hour following dichotomous listening these changes were maintained. Jejunal water, sodium, and chloride absorption measured in 9 subjects during three consecutive stress-free periods did not change significantly. Mean transit time over the 30-cm test segment, measured by a dye dilution technique, in 7 subjects was not significantly different during control and dichotomous listening periods, being 2.8 and 4.0 min, respectively. During the hour following dichotomous listening there was a significant increase in mean transit time to 6.4 min (p less than 0.02). In 7 subjects who received a constant intravenous infusion of atropine throughout the control, dichotomous listening, and recovery periods, jejunal sodium, chloride, and water absorption did not change significantly. These results suggest that psychological stress can influence jejunal absorption of salt and water and that this effect may be mediated by a cholinergic parasympathetic nervous mechanism.

Atropine↗
PubMed1987

pH of the microclimate lining human gastric and duodenal mucosa in vivo. Studies in control subjects and in duodenal ulcer patients.

Measurements of pH in the microclimate on gastric and duodenal mucosa were made during gastrointestinal endoscopy in 21 normal subjects and 9 duodenal ulcer patients. In controls luminal and juxtamucosal mean pH (+/- SEM) of 3.29 +/- 0.3 and 4.48 +/- 0.25 were recorded respectively in distal esophagus, 2.01 +/- 0.17 and 4.84 +/- 0.37 in gastric fundus, 1.82 +/- 0.12 and 5.5 +/- 0.15 in body, 3.52 +/- 0.34 and 5.42 +/- 0.29 in antrum, 6.89 +/- 0.21 and 7.16 +/- 0.13 in duodenal cap, and 6.84 +/- 0.19 and 7.03 +/- 0.19 in proximal duodenal loop. When the lumen of esophagus and duodenum were perfused with acid (pH 2) luminal and mucosal pH values were 2.18 +/- 0.11 and 4.08 +/- 0.41 in esophagus, 2.57 +/- 0.15 and 6.74 +/- 0.13 in duodenal bulb, and 2.44 +/- 0.14 and 6.39 +/- 0.2 in duodenal loop. Juxtamucosal pH in fundus, body, and duodenum remained near neutral when luminal pH was 1.5, but in distal esophagus and antrum it fell sharply at luminal pH values below 3. In duodenal ulcer patients juxtamucosal pH in the cap was significantly lower than that in normals at luminal pH values below 3. These studies support the hypothesis that a "mucus-bicarbonate" barrier inhibits mucosal acidification in humans and that duodenal mucosa in ulcer patients is less able to maintain a neutral zone adjacent to it in the face of luminal acid.

Adult↗
PubMed1987

Inhibition of the effect of serotonin on rat ileal transport by cisapride: evidence in favour of the involvement of 5-HT2 receptors.

Cisapride is a synthetic drug which binds, in vitro, to type 2 serotonin receptors. We examined the influence of serotonin and cisapride on ion transport across intestinal mucosa in vitro and studied the effect of cisapride on the response to serotonin. Segments of ileum of male Sprague-Dawley rats were stripped of muscle layers and mounted in flux chambers. The addition of serotonin (10(-8) to 10(-4) M) to the serosal aspect of the mucosa caused a rapid, dose-dependent rise in short circuit current and transmural potential difference. Cisapride alone (5 X 10(-5) M), when added to the mucosal and serosal surfaces, had no effect on the short circuit current, transmural potential difference, resistance, or sodium and chloride fluxes across the mucosa. It did, however, inhibit the response of the mucosa to serotonin (10(-5) M) in a dose dependent manner and blocked it completely at a concentration of 5 X 10(-5) M. Serotonin (5 X 10(-5) M) increased serosal to mucosal flux of chloride from 12.6 +/- 0.8 to 15.2 +/- 0.6 mumol/cm2/h (p less than 0.025), thus reducing net chloride absorption from 4.65 +/- 0.81 to 1.49 +/- 1.04 mumol/cm2/h (p less than 0.05). This effect was completely blocked by cisapride (5 X 10(-5) M). In summary, cisapride inhibits the effect of serotonin on rat ileal ion transport, probably by blocking type 2 serotonin receptors.

Action Potentials↗
PubMed1987

Sulphasalazine induced seminal abnormalities in ulcerative colitis: results of mesalazine substitution.

Seminal abnormalities are commonly found during sulphasalazine treatment. Although these changes appear reversible after drug withdrawal this may result in colitis relapse. Animal studies suggest that 5-aminosalicylic acid, the active component of sulphasalazine, does not impair fertility. Sixteen patients with quiescent ulcerative colitis were studied. Each patient produced three samples of semen at weekly intervals. Of the 48 samples analysed 39.6% showed oligospermia, 41.7% showed an increased number of abnormal forms and 91.7% showed impaired motility. Nine patients substituted enteric coated mesalazine (5-aminosalicylic acid) for sulphasalazine for a minimum period of three months. During this time one patient developed a salmonella associated colitis relapse; the others remained well. Improvement in sperm count (p less than 0.02), motility (p less than 0.001) and morphology (p less than 0.02) occurred in all cases. To date, four successful pregnancies have resulted, three in couples complaining of long term infertility. Treatment with enteric-coated mesalazine allows the recovery of seminal abnormalities induced by sulphasalazine in patients with colitis.

Adult↗
PubMed1987

Site and mechanisms of action of kinins in rat ileal mucosa.

Kinin-induced secretion in the intestine is accompanied by marked increases in mucosal adenosine 3', 5'-cyclic monophosphate (cAMP) and prostanoids that undoubtedly contribute to the overall secretory response. The cellular site at which these effects are initiated is unclear although a recent hypothesis has suggested the epithelial cell as the target for kinin action (6). We have investigated the effects of kallidin on the phospholipase-prostanoid-cAMP pathway in whole ileal mucosa and in epithelial cells isolated from the same tissue in the rat. Kallidin (1 microM) stimulated a marked rise (24 to 30-fold) in PG (prostaglandin) E2 release from the serosal surface of stripped ileal mucosa within 1-2 min, which correlated closely with the rise in mucosal short-circuit current. Mucosal cAMP levels were also increased two to threefold by kallidin. However, kinins were unable to elicit effects under the same conditions in suspensions of viable epithelial cells. PGE2 release was unaffected by kallidin or bradykinin at concentrations up to 100 microM, whereas cAMP levels could be stimulated by forskolin and PGE2 but not by kinin. Studies of intestinal phospholipase A2 (PLA2) activity also suggest a nonepithelial site for kinin action. This enzyme is responsible for liberating arachidonic acid from cellular phospholipids and has been shown to be activated by kinins in several tissues. In the intestine, PLA2 activity was found to be concentrated within the subepithelium with significantly lower levels in the epithelium itself. In addition, kallidin was unable to influence phospholipid labeling (an indirect measure of PLA2 activity) in cells incubated with [14C]arachidonic acid.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Gastric mucus, bicarbonate and pH gradients in mucosal protection.

The evidence is reviewed that mucus has the capacity to delay diffusion of acid across it. It may provide an environment adjacent to the gastric mucosa in which the relatively small amounts of bicarbonate secreted by the epithelium are able to nullify acid diffusing towards the mucosa. This combination creates a near-neutral zone immediately adjacent to the epithelium. Evidence in favour of this hypothesis is supports the idea that mucus and bicarbonate may together afford a first-line defence against luminal acid and pepsin, but equally it seems likely that this "barrier" can provide only part of the complete picture of mucosal protection.

Bicarbonates↗