PubMed Health⌕ Search

Biomedical subjects

W Schepp

Publications and source records attributed to W Schepp.

At least 91 records · Page 5Linked to original sources
PubMed1989

Leukotrienes C4 and D4 potentiate acid production by isolated rat parietal cells.

The effects of leukotrienes (LTs) B4, C4, and D4 on acid production by enriched (80%-85%) rat parietal cells were investigated. Acid production was indirectly measured by [14C]aminopyrine uptake into the cells. Leukotriene B4 (10(-10)-10(-6) mol/L) had no effect on basal or prestimulated [14C]aminopyrine uptake. Leukotriene C4 and LTD4 (10(-10)-10(-6) mol/L) also did not change basal acid production but potentiated prestimulated [14C]aminopyrine uptake. Maximal effects were observed with 1 x 10(-7) mol/L LTC4 or with 3 x 10(-7) mol/L LTD4. At these concentrations LTC4 and LTD4 induced the indicated increases above the responses to the following prestimulants (= 100%): 10(-4) mol/L histamine (71% and 74%, respectively), 10(-5) mol/L forskolin (54% and 106%), 10(-4) mol/L dibutyryl cyclic adenosine monophosphate (34% and 81%), and 10(-4) mol/L carbamylcholine (160% and 116%). Yet, adenosine triphosphate (2.5-5 x 10(-3) mol/L)-induced [14C]aminopyrine uptake in digitonin-permeabilized parietal cells was not further increased by LTC4 or LTD4. At 10(-5) mol/L the selective LTD4 antagonist L-660,711 (MK-571) reduced the effect of 3 x 10(-7) mol/L LTD4 by 74% but had no effect on the potentiation by LTC4. We conclude that the sulfidopeptide LTs C4 and D4, but not LTB4, exert a direct effect on rat parietal cells, and that this effect seems to be mediated by separate specific receptors. Leukotriene C4 and LTD4 potentiate prestimulated H+ formation by interacting with an intracellular mechanism that is commonly activated upon occupation of histamine H2- as well as muscarinic receptors, and that is also activated by the postreceptor stimuli forskolin and dibutyryl cyclic adenosine monophosphate; yet, this mechanism seems to be localized proximal to the H+,K+-adenosine triphosphatase.

Animals↗
PubMed1989

Effect of amino acids on H+ production by isolated rat parietal cells.

We investigated the hypothesis of a direct effect of amino acids on gastric parietal cells. [14C]aminopyrine uptake into isolated enriched rat parietal cells served as a quantitative index of H+ production. Cells were incubated in media containing 1 mM Ca2+ in the absence or presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX), or 3 mM Ca2+ without IBMX. Under these different conditions, L-arginine, L-phenylalanine and L-tryptophan (10(-6) M to 3 X 10(-2) M) failed to alter basal [14C]aminopyrine uptake as well as the response to submaximal stimulation by histamine, forskolin, N6O2-dibutyryladenosine-3',5'-(cyclic)-phosphate (db cAMP) or carbachol. Pentagastrin failed to elicit an appreciable response in the presence and absence of 10(-3) M of all three amino acids studied. It is concluded that in vivo the potent stimulation of gastric acid secretion by L-arginine, L-phenylalanine and L-tryptophan is mediated by other than direct mechanisms.

Amino Acids↗
PubMed1989

Omeprazole in the acute treatment of gastric ulcer.

Antisecretory drugs are known to be valuable in the treatment of gastric ulcer. Recent studies have shown that this also holds true for omeprazole, the most effective antisecretory drugs currently available. At 30-40 mg once daily omeprazole provides cumulative healing rates of up to 100% after 4-8 weeks. In one study, omeprazole, 20 mg, and ranitidine, 150 mg b.d., produced similar healing rates in the acute treatment of gastric ulcer, though there was a tendency towards more rapid healing with omeprazole. In a more recent multicentre study including more than 600 patients, significantly more ulcers healed after 4 weeks with omeprazole, both 20 mg and 40 mg once daily, than with ranitidine, 150 mg b.d. Omeprazole was also superior to ranitidine with respect to relief of night-time pain and in gastric ulcer healing during concomitant therapy with non-steroidal anti-inflammatory drugs. After omeprazole therapy, the proportion of patients in remission during the following half-year period was higher than after ranitidine, arguing against the hypothesis that rapid ulcer healing following more effective inhibition of acid secretion might be of lower quality. During acute therapy, no drug-specific serious side-effects occurred. Omeprazole is a valuable alternative in modern treatment of gastric ulcer, being superior to histamine H2-receptor antagonists.

Cimetidine↗
PubMed1989

Cholinergic stimulation of isolated rat parietal cells: role of calcium, calmodulin and protein kinase C.

We studied the cholinergic stimulation of isolated and enriched rat parietal cells. H+ production was indirectly measured by the uptake of 14C-aminopyrine into the parietal cells. Stimulation by carbachol required the presence of extracellular Ca2+ not only in the initial phase but also during the sustained phase of a 100-min incubation period. The response to carbachol was prevented by the Ca2+ entry blocker lanthanum IC50: 1.5 X 10(-7) mol/l). Furthermore, the dependence on Ca2+ influx of cholinergic stimulation was demonstrated by a 269% increase in total intracellular Ca2+ in response to carbachol, as determined by optical emission spectrometry. The naphthalene sulfonamides W7 and W5 which bind calmodulin and thus block the intracellular transduction of Ca2+ effects also inhibited a carbachol-induced H+ production. In the following experiments we studied the effect of agents which activate the protein kinase C, an enzyme which is supposed to play a key role in intracellular signal transduction of Ca2+-dependent effects. Phospholipase C is supposed to activate protein kinase C via induction of the phosphoinositol breakdown. In our preparation of isolated rat parietal cells, phospholipase C (4-100 mU/ml) exerted inhibition instead of amplification of the response to 10(-4) mol/l carbachol. Similarly, the direct activation of protein kinase C by 12-O-tetradecanoylphorbol-13-acetate or by 1-oleoyl-2-acetyl-sn-glycerol (both tested at 10(-7) to 10(-5) mol/l) reduced the submaximal and maximal response to 10(-5) or 10(-4) mol/l carbachol. We conclude that the cholinergic stimulation of rat parietal cells is dependent on the influx of extracellular Ca2+. Calmodulin seems to mediate intracellular Ca2+ effects during cholinergic stimulation. The activation of protein kinase C impairs carbachol-induced H+ production instead of augmenting the response. This might be due to an already maximal activation of protein kinase C by carbachol alone or to autoregulatory down-regulation by the protein kinase C of muscarinic parietal-cell receptors.

Aminopyrine↗
PubMed1988

Modulation of rat gastric mucosal prostaglandin E2 release by dietary linoleic acid: effects on gastric acid secretion and stress-induced mucosal damage.

We studied chronic intake of diets deficient in or supplemented with linoleic acid to determine whether it affects gastric acid secretion, release of prostaglandin E2, and stress-induced lesions. For 8-10 wk rats were fed three dietary regimens supplying 3.5% (control group), 0.3%, and 10% of total calories as linoleic acid. We found that diets deficient in linoleic acid (0.3%) reduced release of prostaglandin E2 into the gastric lumen (-77%) and increased basal (+133%) and pentagastrin-stimulated acid secretion (+93%) and the area of cold restraint-induced gastric mucosal lesions (+280%), when compared with the control group. Diets supplemented with linoleic acid (10%) increased prostaglandin E2 release into the gastric lumen (+106%) and reduced basal (-44%) and pentagastrin-stimulated acid secretion (-78%) and the area of cold restraint-induced mucosal.lesions (-80%). Prevention of these lesions by the 10% linoleic acid diet was confirmed by quantitative histology. Pretreatment with indomethacin (8 mg/kg intraperitoneally) abolished the effects of the 10% linoleic acid diet on prostaglandin formation, acid secretion, and mucosal injury. We conclude that in rats chronic intake of dietary linoleic acid reduces acid secretion and prevents cold restraint-induced mucosal lesions, possibly because of augmented synthesis of endogenous prostaglandins in the gastric mucosa.

Animals↗
PubMed1988

Effect of somatostatin on skin lesions and concentrations of plasma amino acids in a patient with glucagonoma-syndrome.

A case of glucagonoma syndrome in a 58-year-old male patient who had the typical skin lesions associated with severe hypoaminoacidemia is described. The decrease in amino acids has been proposed to be causally related to the dermatosis. Furthermore, it has been shown previously that somatostatin rapidly improves skin lesions in glucagonoma patients. Therefore, plasma amino acid levels were determined before and during an infusion of somatostatin prior to surgical removal of the tumor in the tail of the pancreas. During somatostatin infusion in combination with total parenteral nutrition, 10 out of 22 amino acids were in the normal range. Thus it seems unlikely that normalization of amino acid levels is responsible for the rapid improvement in skin lesions in glucagonoma patients. On the other hand it cannot be excluded that partial normalization of amino acids contributed to the observed healing process. Nevertheless, somatostatin administered prior to surgery is a useful therapeutic regimen in these patients.

Adenoma, Islet Cell↗
PubMed1987

A calmodulin antagonist inhibits histamine-stimulated acid production by isolated rat parietal cells.

The role of calmodulin in the regulation of histamine-stimulated parietal cell function was studied in isolated rat parietal cells using [14C]aminopyrine uptake as a quantitative index of acid production. In enriched (77-87%) intact parietal cells the calmodulin antagonist naphthalene sulfonamide W 7 dose-dependently inhibited the response to 10(-4) M histamine (IC50: 2 X 10(-6) M). The mechanism of this inhibition was examined further with two other stimuli of H+-production: forskolin which directly activates the parietal cell adenylate cyclase without interacting at the histamine H2-receptor and dbcAMP which mimics the biological action of cAMP without preceding activation of adenylate cyclase. W 7 effectively inhibited the responses to 10(-4) M forskolin (IC50: 6 X 10(-7) M), 10(-3) M dbcAMP (IC50: 10(-6) M) and to 10(-2) M K+ (IC50: 3 X 10(-6) M). The action of W 7 followed non-competitive kinetics since the antagonist reduced the entire range of the concentration-response curves without shifting them rightwards towards higher concentrations of the respective stimulants. The effect of W 7 was reversed by washing the cells. ATP-induced [14C]aminopyrine uptake into digitonin-permeabilized oligomycin-inhibited parietal cells reflects H+-production independent of oxidative phosphorylation and was also inhibited by W 7 (IC50: 10(-5) M). Inhibition of K+-stimulated H+/K+-ATPase activity required even higher W 7-concentrations (IC50: 1.4 X 10(-4) M). Our data suggest that calmodulin might be involved in the intracellular mediation of the response to histamine. Between histamine-induced cAMP-generation and the H+-secreting tubulovesicular system W 7 seems to inhibit an intracellular step that finally activates the H+/K+-ATPase. Yet, direct inhibition of the ATPase requires W 7 concentrations of questionable specificity and is unlikely to be the mechanism behind the action of W 7 on the parietal cell response to histamine.

Adenosine Triphosphatases↗
PubMed1987

[Calcium, phospholipase C and protein kinase C stimulate prostaglandin secretion of isolated gastric mucosa cells of the human].

We studied PGE2-release from isolated human gastric mucosal cells. Mucosa was obtained at surgery and cells were dispersed by collagenase and pronase. Centrifugation with Percoll yielded a fraction of light density cells (70-75% parietal cells; 2-4% mast cells) revealing maximal rates of PGE2-release. A radioimmunoassay was used to measure PGE2-release into the incubation medium. Calcium ionophore A23187 which aids calcium transport across membranes caused a 3.5-fold increase of PGE2-release; this effect was abolished in calcium-free incubation medium. PGE2-release was also stimulated by phospholipase C (100 mU/ml) which is known to induce phosphoinositol breakdown, as well as by 1-oleyl-2-acetyl-sn-glycerol (OAG; 10 microM) and by 12-O-tetradecanoyl-13-acetate (TPA; 10 microM) which cause direct activation of protein kinase C without preceding induction of phosphoinositol breakdown. The response to TPA was potentiated by A23187. The calmodulin antagonist naphthalene sulfonamide W 7 reduced PGE2-release in response to A23187 and TPA (IC50: 1 microM). Our data indicate that PGE2-release of human gastric mucosal cells is stimulated by calcium influx as well as by indirect (phospholipase C) and direct (OAG, TPA) activation of protein kinase C. Stimulation of PGE2-release involves calmodulin-mediated mechanisms.

Calcium↗
PubMed1986

Effect of glucagon on adenylate cyclase activity and acid production of isolated human parietal cells.

The direct effect of glucagon on human parietal cell function in vitro was tested by measuring adenylate cyclase (AC) activity and H+ production in homogenates of human gastric mucosa obtained during surgery or at biopsy. Cells isolated from mucosa obtained during surgery showed an increase in AC with histamine and glucagon. In parietal cell enriched fractions (75%) glucagon and histamine stimulated AC much more effectively than in parietal cell depleted fractions (15% and 7%). In contrast, glucagon did not affect basal or histamine stimulated 14C amino pyrine uptake. In homogenates of mucosal biopsy specimens 2 X 10(-7) mol/l glucagon enhanced AC activity by 76% (corpus) and 20% (antrum). In the same homogenates 10(-4) mol/l histamine caused a stimulation by 161% (corpus) and 38% (antrum). In fundic biopsy specimens glucagon displayed a biphasic concentration response curve with an increase at 10(-10) mol/l (46% above basal AC activity) and a maximum at 2 X 10(-7) mol/l (97%). Histamine elicited the maximal response (192%) at 10(-3) mol/l. Increasing histamine and glucagon concentrations caused additive stimulation of AC. Ranitidine did not change AC in response to glucagon but abolished the effect of histamine. Data suggest that the glucagon action is mediated by separate (glucagon?) receptors. As H+ production was not affected by glucagon, the coexistence of two AC systems in the human parietal cell is postulated: One that is activated via histamine H2-receptors and which stimulated H+ production; another that is activated by glucagon and is directed towards other, possibly metabolic effects.

Adenylyl Cyclases↗
PubMed1986

[Isolated human gastric mucosa cells--studies on physiologic and pharmacologic regulatory mechanisms].

Cells were isolated by use of collagenase, EDTA and pronase form human gastric mucosa obtained at peptic ulcer surgery (n = 61) or at Whipple's operations (n = 6). Enriched parietal cell fractions were prepared by isopycnic centrifugation with Percoll. H+ production, intracellular instrinsic factor and histamine content were maximal in the low density fraction containing 75% parietal cells and--among other nonparietal cell types--mast cells. H+ production, intrinsic factor secretion and adenylate cyclase-activity responded to histamine stimulation in a concentration dependent manner. Response was blocked by histamine H2 receptor antagonists (rantidine, famotidine). Dibutyryl cAMP and the phosphodiesterase inhibitor IMX were the most powerful stimuli whereas carbachol, hexoprenaline and pentagastrin were less effective. Prostaglandin E2 and 6-keto-PGF2 alpha occurred in the highest concentrations in the low density cell fraction. PG production increased linearly for 15 min and seemed to be influenced by the intracellular calcium level.

Adenylyl Cyclases↗
PubMed1986

Effects of glucagon and histamine on human parietal cells.

Since in vivo pancreatic glucagon inhibits gastric acid secretion it was of interest to test its direct effect on human parietal cell function in vitro by measuring adenylate cyclase (AC) activity and H+ production. Cells were isolated from human gastric mucosa obtained at surgery for peptic ulcer. In enriched (75%) parietal cells glucagon and histamine stimulated AC much more effectively than in the parietal cell depleted (15%, 7%) fractions. In contrast basal and histamine-stimulated [14C] aminopyrine uptake, an indirect measure of parietal cell H+ production, was not affected by glucagon. In homogenates of mucosal biopsy specimens 2 X 10(-7) mol/l glucagon enhanced AC activity by 76% (corpus) and 20% (antrum), respectively; in the same homogenates 10(-4) mol/l histamine caused a stimulation by 161% (corpus) and 38% (antrum). In fundic biopsy specimens glucagon displayed a biphasic concentration response curve with an increase at 10(-10) mol/l (46% above basal AC activity) and a maximum at 2 X 10(-7) mol/l (97%); histamine elicited the maximal response (192%) at 10(-3) mol/l. Histamine (10(-5), 10(-4), 10(-3) mol/l) and glucagon (10(-10) to 10(-6) mol/l) caused additive stimulation of AC. Ranitidine did not change AC in response to glucagon but abolished the effect of histamine. Our data demonstrate that glucagon stimulates an AC bound to the parietal cells. This response is not blocked by ranitidine suggesting that the glucagon action is mediated by a separate receptor, possibly by a glucagon-receptor. Furthermore we have shown that glucagon in contrast to its effects on AC does not affect H+ production.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗
PubMed1986

[14C]-aminopyrine accumulation by isolated human parietal cells.

Gastric mucosal cells were isolated from resected fundic mucosa of peptic ulcer patients and used to determine H+ production by [14C]-aminopyrine (AP) uptake. H+ production was stimulated by histamine linearly for 40 min and in a concentration-dependent manner reaching a maximum of 228% of basal at 10(-4) mol/l histamine. This response was reduced by the histamine H2-receptor antagonist ranitidine (IC50 = 3 X 10(-6) mol/l). Pentagastrin and carbachol induced a small but significant increase at 10(-7) and 10(-4) mol/l, respectively. At low histamine concentrations the response to carbachol plus histamine was nearly additive. The phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) was a powerful stimulant of basal AP uptake but failed to augment the histamine effect. IBMX-induced AP uptake was reduced by ranitidine suggesting that, at least in part, the response to IBMX is mediated by release of endogenous histamine. Isopycnic centrifugation with Percoll resulted in fractions with 7 and 72% parietal cells, respectively. Basal AP uptake amounted to 203 cpm/10(6) cells in the parietal cell depleted fraction whereas in the enriched preparation the basal rate (4,787 cpm/10(6) cells) exceeded the uptake which was to be expected due to 10-fold parietal cell enrichment. When calculated as percentage of the basal H+ production the histamine-stimulated AP uptake was less in the enriched fraction than in the parietal cell depleted or in the nonfractionated preparation. Basal AP uptake was reduced by ranitidine more effectively in the enriched fraction suggesting background stimulation by endogenous histamine which might impair the response to exogenous stimulants. This functional evidence was paralleled by electron microscopical identification of mast cells copurified in the enriched parietal cell fraction.

1-Methyl-3-isobutylxanthine↗
PubMed1986

Calcium, calmodulin, and cyclic adenosine monophosphate modulate prostaglandin E2 release from isolated human gastric mucosal cells.

We studied prostaglandin E2 (PGE2) release from isolated cells of the human gastric mucosa. Mucosal cells were enzymatically isolated from biopsy specimens of human fundic mucosa. The results from these crude cell preparations were compared to those obtained in fractions with enriched (65-80%) or depleted parietal cell content (3-7%) which were prepared from gastric mucosa obtained at surgery. PGE2 release in the enriched parietal cell fractions exceeded that from crude or parietal cell depleted preparations 3- and 13-fold, respectively. However, despite this quantitative difference, all preparations responded similarly to the test agents. Newly synthesized PGE2 was not stored intracellularly but was released into the incubation medium. Release increased linearly for 30 min. Addition of the calcium ionophore A23187 enhanced PGE2 release 4- to 5-fold. The effect of A23187 required the presence of extracellular Ca2+ (10(-3) mol/liter). Assuming that A23187 alters Ca2+ flux in gastric cells as it does in other cell systems our data indicate that increased Ca2+ influx enhances PGE2 release. Since calmodulin is of importance for intracellular Ca2+ action, the calmodulin antagonists trifluoperazine and W7 were tested. Both antagonists inhibited PGE2 release by 65-85%, trifluoperazine being slightly more effective. Activation of the adenylate cyclase system by forskolin or direct addition of (Bu)2cAMP, a stable cAMP-analog, also inhibited PGE2 release. We conclude that PGE2 is released from parietal and from nonparietal cells of the human gastric mucosa, although the major quantity is released from the light density fraction that is enriched in parietal cells. In parietal and nonparietal cells Ca2+ is of importance in the regulation of gastric mucosal PGE2 release and calmodulin seems to mediate this intracellular action of Ca2+. cAMP inhibits PGE2-release from gastric cells.

Bucladesine↗
PubMed1986

A rare source of occult gastrointestinal bleeding: jejunal filiae secondary to metastatic lung carcinoma.

A case of occult gastrointestinal bleeding due to jejunal metastases of a primary lung carcinoma in a 53-year-old man is reported. When after healing of a large gastric ulcer melena persisted, a subsequently performed double contrast enema of the small bowel revealed evidence of several jejunal tumors. This was confirmed by angiography of the superior mesenteric artery and computed tomography of the abdomen. After resection of the tumor-bearing jejunal loop, histological evaluation revealed metastases secondary to a large-cell bronchogenic carcinoma which had been resected 1 year previously.

Carcinoma, Bronchogenic↗