Effect of antacid treatment on endogenous prostaglandin synthesis in human antral and duodenal mucosa

Using¹⁴C-labeled arachidonic acid as precursor for in vitro prostaglandin synthesis, the effect of an antacid containing Al (OH)₃, Mg(OH)₂ and CaCO₃ on endogenous prostaglandin synthesis was investigated in antral and duodenal mucosa of healthy volunteers. After three weeks of treatment with a high-dose antacid, there was no detectable change in the total capacity of the mucosa for prostaglandin synthesis, but the prostaglandin profile was markedly altered. The relative amounts of PGE₂ and PGF₂ synthesized by antral and duodenal mucosa increased at the expense of the prostaglandinsA₂/B₂, thromboxane A₂, and prostacyclin. In a short-term study, this change was not observed following a single antacid dose within 1 hr after application. It is concluded that long-term antacid treatment may alter the prostaglandin pattern formed by gastroduodenal mucosa and this may be related to its therapeutic effect.     

Appearance of gastrin and somatostatin in the human fetal stomach, duodenum and pancreas.

The gestational time of appearance of gastrin and somatostatin in the human fetal stomach, duodenum and pancreas was examined. Immunoreactive gastrin (IRG) is detected in antral, duodenal and pancreatic extracts of a 7.0-cm (crown-heel length) fetus. More IRG is extracted from the duodenum than the antrum. Duodenal IRG concentration from fetuses of 16.0--26.0 cm are higher than younger fetal and adult concentrations. Antral IRG concentrations are one tenth of the adult contents. Very small IRG concentrations are present in the human fetal pancreas. Gastrin immunohistochemical staining is positive first in duodenal (6.5-cm fetus) and later in antral (12.5-cm fetus) mucosa; pancreatic tissue is negative for gastrin immunohistochemistry. Type IV cells are encountered in antral and duodenal mucosa of 4.0-cm fetuses; other endocrine cells appear with fetal growth. Not until much later in gestation (21.0 cm) do typical G cells appear. These results suggest that early in fetal life gastrin is produced by the type IV cell. Somatostatin immunohistochemical staining is positive in stomach, duodenum and pancreas in 6.5-cm fetuses. Immature D cells are found in antral and duodenal mucosa of 5.0-cm fetuses and mature D cells in 11.0-cm fetuses.     

Stimulation by human chorionic gonadotropin of prostaglandin synthesis by early human placental tissue

Successful establishment of pregnancy is dependent on inhibition of clotting and suppression of the maternal immune response at the feto-maternal interface. Early human placental production of prostacyclin (PGI2) and prostaglandin E2 (PGE2) may be important in this process. To examine the possible role of these PGs, we studied PGE and 6-keto-PGF1 alpha (stable metabolite of PGI2) synthesis in human placental (9-17 weeks gestation) organ cultures, and monolayer cultures of purified trophoblasts. PGE2 appeared to be the major protanoid formed. Other arachidonic acid metabolites identified in placental organ culture were 6-keto-PGF1 alpha, thromboxane B2, PGF2 alpha, leukotriene B4, 5(S)-hydroxyeicosatetraenoic acid (5-HETE), 12-HETE, and 15-HETE. The synthesis of PGE and 6-keto-PGF1 alpha altered with gestation and was maximal in the younger placentas. Arachidonic acid (33 microM) stimulated and indomethacin (28 microM) inhibited PG production. hCG, including physiological concentrations, stimulated PGE and 6-keto-PGF1 alpha synthesis in placental organ cultures. This effect was most striking in the 9-12 week placentas, compared to 15-17 week placentas. A similar hCG-induced stimulation of PGE production occurred in monolayer cultures of trophoblasts. The addition of TSH, FSH, and LH indicated that this effect was specific for hCG. These data suggest that hCG may have a biological role in the regulation of PG synthesis in early human placenta.     

Stimulation of prostaglandin E synthesis in cultured human umbilical vein smooth muscle cells.

Cultured human umbilical vein smooth muscle cells secreted 1.26 +/- 0.20 mug of immunoreactive prostaglandin E (iPGE) per mg of cell protein per 24 hr (mean +/- SEM). In indomethacin, an inhibitor of prostaglandin synthesis, abolished greater than 95% of this basal iPGE production (ID50 = 1.8 nM).     

Stimulation of gastric prostaglandin synthesis by refeeding in the rat

The purpose of the present study was to determine whether feeding stimulates prostaglandin (PG) synthesis in the gastric mucosa and whether this might play a role in the defensive mechanism of the gastric mucosa. The effect of refeeding on the formation of gastric lesions induced by nonsteroidal antiinflammatory drugs and on the generation of prostaglandin in the gastric mucosa was investigated. In the fasted rat aspirin and indomethacin produced many lesions in the corpus, but few or no lesions in the antrum. Refeeding of chow pellets before aspirin or indomethacin significantly decreased the corpus lesions, but provoked lesions in the antrum. When each drug was given before the refeeding, the protection against corpus lesions by refeeding was reduced and the lesions in the antrum were significantly increased. Mucosal generation of 6-keto-PGF 1 alpha (a stable metabolite of PGI2) and PGF2 alpha was measured ex vivo by the method of Whittle. The generation of 6-keto-PGF1 alpha and PGF2 alpha in the fasted rat deprived of food for 24 hr was 1761 +/- 170 and 217 +/- 7 ng/min/g tissue in the corpus mucosa, and 2958 +/- 217 and 453 +/- 33 ng/min/g tissue in the antral mucosa, respectively. Refeeding of chow pellets significantly increased the generation of both prostaglandins in the antral mucosa and of PGF2 alpha in the corpus mucosa, but did not affect the generation of PGI2 in the corpus mucosa.(ABSTRACT TRUNCATED AT 250 WORDS)     

Stimulation of glycoprotein and protein synthesis in isolated pig gastric mucosal cells by prostaglandins.

The purpose of this study is to evaluate the effects of different prostaglandin derivatives on protein and glycoprotein synthesis and secretion in isolated and enriched pig gastric mucous cells, as measured by the incorporation of [3H]L-leucine and N-acetyl-[14C]D-glucosamine respectively into acid insoluble macromolecules (AIM). PGE2 and 16,16-dimethyl-PGE2 enhanced the incorporation of the amino sugar into cellular (EC50 8 and 75 nmol/l) and secreted (EC50 30 and 270 nmol/l) AIM in a concentration dependent manner during a 20 hours incubation. After incubation for eight hours or more they also stimulated the incorporation of [3H]L-leucine into cellular AIM. PGF2 alpha was considerably less potent (EC50 greater than 1 mumol/l) than the E-type prostaglandins. Iloprost, a stable prostacyclin analogue, was ineffective.     

Exogenous prostaglandin protects against acid-induced deep mucosal injury by stimulating alkaline secretion in rat duodenum

In the anesthetized rat, exogenous acid (0.1–0.3 N HCl) perfused through the duodenum produced a dose-related increase in the severity of duodenal villous injury. Increasing the duration of perfusion of the 0.1 N HCl also increased the severity of the injury. The increase in the severity of the lesion score was due to an increase in the percentage of villi with damage extending to the lower half of the villus. 16,16-Dimethyl prostaglandin E₂ (dm PGE₂, 5 g/kg) administered subcutaneously significantly increased duodenal mucosal alkaline secretion and significantly reduced the duodenal villous injury produced by 0.1 N HCl. The reduction in the severity of the lesion score was due to a decrease in the percentage of villi with the deeper type of damage. These data indicate: (1) perfusion of the rat duodenum with 0.1 N HCl at 0.1 ml/min for 30 min provides a valid model for assessing deep duodenal villous injury, (2) exogenous prostaglandin enhances the resistance of the duodenal mucosa against acid induced deep villous injury, and (3) the enhanced resistance may be mediated at least in part by stimulation of duodenal alkaline secretion. The results support the hypothesis that stimulated duodenal alkaline secretion may play a role in defense of the duodenal mucosa against acid-induced deep villous injury.     

Stimulation of renal prostaglandin synthesis by the pressor activity of vasopressin

Renal prostaglandin E2 (PGE2) synthesis is enhanced by exogenous vasopressin (AVP). To determine whether the pressor or the antidiuretic activities of AVP are related to its effect on PGE2 synthesis, AVP and the nonpressor analog, 1-deamino-8-D-arginine vasopressin (dD'AVP), were administered to the isolated perfused rabbit kidney, PGE2 was measured in the renal venous effluent by RIA and validated by bioassay. AVP in doses of 20, 200, and 2,000 ng progressively increased perfusion pressore by 12.1 +/- 2.4, 62.0 +/- 7.9, and 74.3 +/- 13.5 mm Hg, respectively, and increased PGE2 by 28 +/- 7, 80 +/- 3, and 129 +/- 57 ng/50 ml effluent, respectively. Bradykinin and angiotensin II induced a similar dose response on PGE2 release. However, dD'AVP in doses up to 20,000 ng minimally enhanced PGE2 release (20 +/- 16 ng/50 ml) and did not alter perfusion pressure. Simultaneous administration of AVP (200 ng) with the specific AVP pressor antagonist, d-cyclo-O-methyl-tyrosine-AVP, in a 1:10 (agonist to antagonist) weight ratio blunted the increase in perfusion pressure by 59 +/- 9% and blunted the increase in PGE2 release by 59 +/- 10% (P < 0.05). In a 1:100 weight ratio, the pressure antagonist reduced the AVP pressure response by 86 +/- 6% and reduced PGE2 by 84 +/- 7% (P < 0.01). These data suggest that the AVP stimulation of renal PGE2 synthesis is related primarily to its pressor and not to its antidiuretic activity in this in vitro kidney model. (Endocrinology 108: 495, 1981)     

Helicobacter species ribosomal DNA in the pancreas, stomach and duodenum of pancreatic cancer patients

AIM: To determine whether gastric and enteric Helicobacter species are associated with pancreatic cancer. METHODS: Patients with exocrine pancreatic cancer (n = 40), neuroendocrine cancer (n=14), multiple endocrine neoplasia type 1 {n = 8), and chronic pancreatitis (n = 5) were studied. Other benign pancreatic diseases (n = 10) and specimens of normal pancreas (n=7) were included as controls. Pancreatic tissue specimens were analyzed by He/icobacter-specific PCR-assay and products were characterized by denaturing gradient electrophoresis and DNA-sequencing. From a subset of the pancreatic cancer patients, gastric and/or duodenal tissue as well as gallbladder and ductus choledochus tissue were analyzed. Gallbladder and choledochus samples were included as controls. Stomach and duodenum samples were investigated to analyze whether a gastric helicobacter might disseminate to the pancreas in pancreatic cancer patients. Pancreatic specimens were analyzed by Bacteroides-specific PCR for detecting the translocation of indigenous gut microbes to the diseased pancreas. RESULTS: Helicobacter DNA was detected in pancreas (tumor and/or surrounding tissue) of 75% of patients with exocrine cancer, 57% of patients with neuroendocrine cancer, 38% of patients with multiple endocrine neoplasia, and 60% of patients with chronic pancreatitis. All samples from other benign pancreatic diseases and normal pancreas were negative. Thirty-three percent of the patients were helicobacter-positive in gastroduodenal specimens. Surprisingly, H. bilis was identified in 60% of the positive gastro-duodenal samples. All gallbladder and ductus cho-ledochus specimens were negative for helicobacter. Bacteroides PCR-assay was negative for all pancreatic samples. CONCLUSION: Helicobacter DNA commonly detected in pancreatic cancer suggests a possible role of the emerging pathogens in the development of chronic pancreatitis and pancreatic cancer.     

The secretory activity of the stomach, duodenum and pancreas in patients with chronic opisthorchiasis

Serum IgE, gastrin, and insulin levels were measured by radioimmunoassay and gastric secretion was studied by the method of submaximal histamine stimulation in 59 inhabitants of Sverdlovsk and 51 former inhabitants of Tyumen Province, who had chronic opisthorchiasis. In the hypoendemic focus, increased IgE content was observed mostly in young people, and in the hyperendemic focus it was in middle-aged and old people, this parameter correlating with decreased levels of gastrin and insulin in the serum. Gastric basal acid secretion was decreased in more than 70% patients from the both groups. However, hyperimmunoglobulinemia tends to show elevated hydrochloric acid debit.     

Toxicity of NSAIDs in the stomach and duodenum.

NSAIDs are widely used for analgesic, anti-inflammatory and anti-thrombotic indications. Such use carries the risk of gastrointestinal complications (1% over 6 months) which NSAIDs may promote from both ulcerous and nonulcerous lesions. Symptoms are poor predictors of serious lesions and complications, which may occur without previous symptoms. NSAIDs also delay healing of peptic ulcers, even to the extent of intractability, and may cause recurrence after gastric surgery. Prophylactic therapy is indicated in high-risk patients (age > 60 years, previous ulcer history, high dose, concomitant use of corticosteroids or anticoagulants). Misoprostol, omeprazole and high-dose famotidine have been shown to reduce the occurrence of both gastric and duodenal ulcers in NSAID users. At present, the role of Helicobacter pylori in NSAID-induced gastroduodenal lesions is controversial and there is no agreement in considering the organism as a risk factor and indicating its eradication in NSAID users.     

Intramural distribution of regulatory peptides in the human stomach and duodenum

The distribution of regulatory peptides was studied by radioimmunoassay in the separated mucosa, submucosa and muscularis externa of the human oxyntic stomach, antrum and duodenum. Immunoreactive gastrin, secretin, gastric inhibitory polypeptide and motilin were virtually confined to the mucosa and duodenal submucosa, where endocrine cells are present. Only minor amounts of motilin and gastrin (3.2 +/- 0.5% and 4.3 +/- 0.8% of their total content, means + SEM, respectively) were found in the separated duodenal muscle. Somatostatin-, vasoactive intestinal polypeptide-, substance P-, and mammalian bombesin-like peptides showed distinct differential distributions in all layers. Substance P was low in the stomach and markedly increased in the duodenum, especially in the mucosa (fundus 0.8 +/- 0.2 pmol/g, duodenum 66 +/- 12). Vasoactive intestinal polypeptide and somatostatin, although well represented in the stomach, also increased in the duodenum in all layers of the wall (whole fundus 281 +/- 33 and 334 +/- 46 pmol/g, antrum 124 +/- 18 and 426 +/- 59, duodenum 507 +/- 99 and 1816 +/- 149, respectively). Mammalian bombesin immunoreactivity was comparatively abundant in the oxyntic stomach (mucosa 34 +/- 4.5 pmol/g, muscularis externa 29 +/- 4.8), less so in the antrum (6.3 +/- 1.5 and 11 +/- 3.2 pmol/g, respectively). Low concentrations of this peptide were measured in the duodenum, practically confined to the muscle (this layer 5.1 +/- 1.5 pmol/g, or 83 +/- 5.6% of the total content).     

Somatostatin inhibits gastric acid secretion after gastric mucosal prostaglandin synthesis inhibition by indomethacin in man.

The inhibitory effect of indomethacin, 200 + 200 mg administered per os over 24 hours, on the prostaglandin E2 generative capacity of gastric mucosal tissue was determined in healthy male volunteers. The effect of prostaglandin synthesis inhibition on somatostatin induced suppression of food-stimulated acid secretion was tested. Peptone meal stimulated acid secretion was quantified in five healthy volunteers by intragastric titration with and without indomethacin pretreatment. Somatostatin doses of 200, 400, and 800 pmol/kg/h each significantly inhibited the peptone stimulated acid output. Indomethacin treatment, resulting in 90% inhibition of prostaglandin E2 synthesis, did not affect glucose- or peptone-stimulated acid output or modify the inhibitory action of somatostatin. Clinically, acid inhibition by somatostatin has been used to treat bleeding peptic ulcers. Ulcer haemorrhage may be preceded by an excessive use of drugs that inhibit prostaglandin synthesis such as aspirin or other non-steroidal anti-inflammatory agents. Recent observations in the rat indicate that prostaglandins mediate the inhibitory action of somatostatin on gastric acid secretion. The present results suggest that prostaglandins are not required for inhibition of gastric acid secretion by somatostatin in man.     

Stimulation of human purine synthesis de novo by fructose infusion.

In order to clarify the mechanism of hyperuricemia and hyperuricosuria resulting from rapid infusion of fructose in man, the effects of an intravenous infusion of 125-200 g of fructose given over 3-4 hr on the rate of purine synthesis de novo was measured in one individual with osteoarthritis and four patients with gout. The incorporation of 1-minus 14C glycine into urinary uric acid was measured, and the pool size and turnover of urate were assessed by renal excretion of simultaneously administered 15-N urate. Fructose caused an expansion of body urate pool in all subjects, while urate turnover was increased in four. The rate of incorporation of 14-C glycine into urinary uric acid corrected for extrarenal disposal was increased in all cases (21%-430%). In two patients, rates of incorporation of 14-C glycine into urinary creatinine were increased by 10% and 11%, while rates of incorporation into uric acid were increased 84% and 159%, respectively, as a result of fructose infusion. Specific enhancement of the rate of purine synthesis de novo was suggested by these findings. The rate of infusion appeared more important than total dose in determining the magnitude of this effect. Whether the increased rate of purine synthesis was a result of direct stimulation by a fructose metabolite or was secondary to fructose-induced purine nucleotide depletion is uncertain, since the kinetics of glycine incorporation were consistent with either mechanism. Erythrocyte PP-ribose-P concentrations, however, were diminished during infusion rather than increased as might be expected if fructose infusion stimulated purine synthesis by increasing availability of this regulatory substrate.     

Serotonergic systems of the biliary tract, stomach and duodenum in the norm and at the experimental stomach ulcer]

Stimulation of the sympathetic trunk against the background of the vagus nerve irritation was shown to cause the enhancement of the electromotor activity of the gallbladder, Oddi's sphincter, stomach and duodenum blocked by ganglionary and peripheral serotonin blockers. A lateral-medial gradient of the serotonergic innervation of the biliary tract was revealed. The gastro- and duodenoprotective action of the 5-HT 1,2-serotonin blocker was established at the experimental stomach ulcer.     

Stimulation of glycogen synthesis by insulin in human erythroleukemia cells requires the synthesis of glycosyl-phosphatidylinositol.

Although the insulin-dependent hydrolysis of glycosyl-phosphatidylinositol (GPI) may play an important role in insulin action, an absolute requirement for this glycolipid has not been demonstrated. Human K562 cells were mutated to produce a cell line (IA) incapable of the earliest step in PI glycosylation, the formation of PI-GlcNAc. Another cell line (IVD) was deficient in the deacetylation of PI-GlcNAc to form PI-GlcN and subsequent mannosylated species. Each line was transfected with wild-type human insulin receptors. Similar insulin-stimulated receptor autophosphorylation was observed in all three lines, along with a nearly identical increase in the association of phosphorylated insulin receptor substrate 1 with endogenous PI 3-kinase. Both normal and GPI-defective lines also displayed a similar 2- to 3-fold increase in phosphorylation of the Shc protein and its association with growth factor receptor-bound protein 2 in response to insulin. In contrast to these results, striking differences were noted in insulin-stimulated glycogen synthesis. In normal cells, glycogen synthesis was significantly increased by insulin, whereas no insulin stimulation was observed in GPI-deficient IA cells, and only a trace of stimulation was detected in IVD cells. These results indicate that tyrosine phosphorylation produced by insulin is not dependent on GPI synthesis, and this effect is not sufficient to elicit at least some of the metabolic effects of the hormone. In contrast, GPI synthesis is required for the stimulation of glycogen synthesis by insulin in these cells. These findings support the existence of divergent pathways in the action of insulin.     

Stimulation of rabbit synoviocyte prostaglandin E2 synthesis by lipopolysaccharides and their subunit structures

Lipopolysaccharides (LPS) induce synoviocyte activation and may lead to destruction of synovial joint tissues. We assessed the production of prostaglandin E2 (PGE2) as a measure of synoviocyte activation by LPS and their subunit structures. Diphosphoryl lipid A was the smallest portion of lipid A tested that stimulated PGE2 production. The polysaccharide fraction of LPS, containing the O antigen, was also active. Intraarticular injections of the polysaccharide resulted in a synovitis very similar to that found in association with the intact LPS molecule. These observations suggest that both parts of LPS might be involved in gram-negative, organism-associated synovitis.     

Visual analogue scales for endoscopic evaluation of nonsteroidal anti-inflammatory drug-induced mucosal damage in the stomach and duodenum

The use of visual analogue scales in the evaluation of mucosal lesions may reduce sample size requirements in clinical trials, but they may be complex to use, and adding guide points may reduce their informative value. We found that two investigators with differing levels of endoscopic experience reached comparable conclusions in 4 clinical trials (738 scores), and their scores were highly correlated, with similar dispersion characteristics. With guide texts along the scales, thus avoiding points on the actual scales, no tendency towards accumulation was seen in 1449 scores. These results encourage the use of visual analogue scales in endoscopic studies.