Role of mucosal microcirculation in gastric lesions induced by lateral hypothalamic lesions in rats

To evaluate the pathophysiology underlying gastric mucosal lesions induced by lateral hypothalamic (LH) lesions, we investigated the changes in acid secretion, gastric mucosal blood flow, gastric mucus and mucosal integrity in the corpus during the 4 h period and 48 h after the production of bilateral electrolytic LH lesions in male Sprague-Dawley rats. Gastric mucosal lesions were macroscopically produced 24 h (63%) and 48 h (83%) after LH lesions, although there were no visible lesions at 7 h. Gastric acid secretion was significantly increased 48 h after LH lesions, compared with that in the control group. Gastric mucosal blood flow and transmucosal potential difference (PD) in the LH lesion group immediately decreased after LH lesions and did not recover during 4 h and at 48 h. On the contrary, in the control group, gastric mucosal blood flow decreased after the brain surgery but soon recovered, and there was no significant change in PD. LH lesions resulted in the reduction of intramucosal mucus to 50% 3 h after LH lesions. Moreover, we exposed the stomach to 10 mmol/L taurocholic acid (TCA) 3 h after LH lesions to examine the disruption in gastric mucosal defensive function in rats with LH lesions. The recovery of the reduced PD by TCA was slow and gastric mucosal lesions were easily formed in the LH lesion group. These results suggest that gastric mucosal ischaemia after lesioning of LH immediately results in the disruption of mucosal defensive function before the formation of visible gastric lesions, and predisposes to the formation of gastric mucosal lesions by a delayed increase in acid secretion.     

Gastric secretion in rats with chronic gastric fistulae and in stomach-perfused, anesthetized rats

A method of establishing chronic gastric fistulae in rats is described. In rats with chronic gastric fistulae, the basal acid output was 48.8 +/- 2.9 microEq/100 g/hr and the basal pepsin output was 543 +/- 28 micrograms tyrosine/100 g/hr. The effects of urethane-induced anesthesia, pyloric ligation, and acute laparotomy on gastric secretion in rats were examined. Both urethane-induced anesthesia and acute laparotomy depressed gastric secretions. In Ghosh-Schild rats, the basal acid output was 3.2 +/- 0.4 microEq/100 g/hr and the basal pepsin output was 70 +/- 13 micrograms tyrosine/100 g/hr. The persistent and very low level of of gastric secretion in these animals appears to result from the combination of both urethane anesthesia and invasive surgery. Because the rats with chronic gastric fistulae do not require anesthesia, invasive surgery, or pyloric ligation, which may play very important roles in the regulation of gastric functions, this kind of preparation is a suitable method for studying the physiology and pharmacology of gastric secretions in the rat.     

Prostaglandin-stimulated gastric mucus secretion in man.

In 6 healthy volunteers, following intragastric instillation of a prostaglandin analogue pentagastrinstimulated gastric secretion of acid, pepsin, and glycoprotein N-acetylneuraminic acid (NANA) was assessed. There was only a slight and statistically insignificant inhibition of acid output while pepsin secretion remained entirely unaffected. On the other hand, gastric mucus (NANA) secretion was significantly increased dependent on the prostaglandin dose administered. It is concluded that prostaglandins in addition to their well-known gastric acid inhibitory action may exert mucus stimulating properties and thus may have a direct protective effect on the gastric mucosa.     

胃痛灵对大鼠胃粘膜血流量及脾虚大鼠模型的影响

为深入探讨胃癌灵保护胃粘膜的作用机制，研究了胃痛灵（WTL）对无水乙醇损伤大鼠胃粘膜血流量（GMBF）、脾虚大鼠D-木糖吸收率、胃壁结合粘液量以及胃酸分泌和胃蛋白酶活性的影响。结果显示WTL能够明显增加大鼠GMBF（P＜0．05）、胃壁结合粘液量（P＜0．05），提高脾虚大鼠D-木糖吸收率（P＜0．05），增强胃粘膜防御机能，但对脾虚大鼠胃酸的分泌和胃蛋白酶活性均无明显影响。在体外也无中和胃酸的能力。     

Gastric secretion of platelet activating factor and precursors in healthy humans: effect of pentagastrin.

The release of platelet activating factor (PAF-ACETHER or PAF) and its precursors in the gastric lumen was assessed in 13 normal subjects in basal condition and after stimulation by gastrin. Acid, pepsin, and sialic acid outputs were determined under the same conditions. Gastric juice was collected using a nasogastric tube after overnight fast in basal condition for 60 minutes, then under pentagastrin infusion (6 micrograms/kg/hr for 60 minutes). Platelet activating factor was detected at low concentration in 4/13 subjects under basal condition (mean (SEM) 1.2 (0.6) pg/hr) while high concentrations of lyso platelet activating factor (6.1 (1.8) microgram/hr) and of alkyl-acyl-glycerophosphocholine (AAGPC) (11.5 (3) micrograms/hr) were found in 13 and 11 subjects, respectively. Platelet activating factor was not detected during pentagastrin infusion, while lyso platelet activating factor and alkyl-acyl-glycerophosphocholine were detected in 13 and in 12 subjects, respectively. Compared with the basal condition these platelet activating factor precursors increased significantly (p < 0.001) going up to fivefold baseline (31.8 (6.8) micrograms/hr and 53 (9.3) micrograms/hr respectively) in response to pentagastrin. There was a positive correlation between platelet activating factor precursors and acid or pepsin output but not between platelet activating factor precursors and sialic acid. As sialic acid may be considered an index of mucus glycoprotein degradation, it seems that gastrin stimulation of gastric epithelial cells results in a concomittant secretion of platelet activating factor precursors, acid, and pepsin irrespective of mucus glycoprotein degradation.     

Experimental deficiency of gastric “mucus barrier”

Adult male rats with permanent gastric fistulas, in some of whom the cardia and pylorus had been ligated, were infused intravenously for 24 hr with histamine dihydrochloride. The output of HCl, pepsin, and hexosamine in 24-hr secretion was studied. Prior to infusion, rats' stomachs were washed with either normal saline or 2M NaCl; hypertonic NaCl is known to induce reduction of gastric mucus. In animals with reduced gastric mucus, glandular peptic ulcers were found at the end of histamine infusion. No gastric lesions were detected in stomachs washed with normal saline. The occurrence of peptic ulcers in rats correlated satisfactorily with the alteration of the gastric mucus barrier but was not dependent upon the acidity or pepsin content of gastric juice.The technical assistance of Mrs. T. Hoogen, Mrs. M. McCubbin, and Mr. K. Lazenby is gratefully acknowledged.     

Effect of somatostatin on meal-induced gastric secretion in duodenal ulcer patients

The effect of somatostatin, a growth hormone release-inhibiting hormone (GH-RIH), on basal and meal-, pentagastrin-, or histamine-stimulated gastric acid and pepsin secretion was studied in six duodenal ulcer patients. Intravenous GH-RIH infused in graded doses ranging from 0.62 to 5.0 μg/kg/hr produced a dose-related inhibition of pentagastrin-induced acid secretion reaching about 15% of control level at the dose of 5.0 μg/kg/hr. Acid inhibition was paralleled by a decrease in the pepsin output and accompanied by a dosedependent reduction in serum growth hormone and insulin levels measured by radio-immunoassay. GH-RIH used in a single dose of 2.5 μg/kg/hr produced about 85% inhibition of acid secretion induced by a meal (measured by intragastric titration) accompanied by a significant decrease in serum gastrin and insulin levels. The effect of GH-RIH on histamine-stimulated secretion was very modest and observed only after stopping the GH-RIH infusion. Thus GH-RIH suppressed acid and pepsin secretion induced by pentagastrin and a meal, and this effect was accompanied by a suppression of serum growth hormone and gastrin levels which may contribute to the inhibition of gastric secretion observed.     

Evidence that gastric antisecretory action of lipopolysaccharide is not due to a toxic effect on gastric parietal cells

We have recently found that bacterial lipopolysaccharide (LPS) or endotoxin at minute doses inhibits the secretion of gastric acid and pepsin in rats. The present study was performed to determine whether this antisecretory action of LPS was a reversible biological response or a result of the destruction of gastric parietal cells by endotoxin. The intraperitoneal injection of LPS into pylorus-ligated rats resulted in a dose-related (40-4000 ng/kg) decrease in gastric acid secretion, with maximal inhibition being observed at a dose of 4000 ng/kg. The stomach then was examined both macroscopically and microscopically for the presence or absence of mucosal lesions or damaged gastric parietal cells. No morphological changes in the gastric mucosal structure including parietal cells were observed even in the rats injected with 4000 ng/kg of LPS. Next, basal gastric acid output was compared in the rats that had received LPS (4000 ng/kg, intraperitoneal) or saline alone 24 hr before. There was no significant difference in gastric acid secretion between the saline- and LPS-pretreated groups, indicating that the secretory capacity of gastric parietal cells returned to the control level at 24 hr after the injection of a maximal antisecretory dose of LPS. These results clearly suggest that the LPS-induced inhibition of gastric secretion results not from its toxic or destructive effect on the gastric secretory mechanism but from its reversible biological effect on gastric physiology.     

Secretion of gastric mucus following maximal pentagastrin stimulation

The aim of the thesis was the observation of the gastric mucus secretion on the basis of carbohydrate components and protein secretion into the gastric lumen. 15 healthy volunteers were investigated: 7 males and 8 females aged 20-37 (average rate 27). In this group gastric juice was aspirated after administration of single 6 micrograms/kg BW stimulus of pentagastrin. Concentration and output of hydrochloric acid, pepsin, protein and carbohydrate components of gastric juice fucose, sialic acid, hexosamines and hexoses were measured. Carbohydrate components and proteins included informations concerning gastric mucus secretion into gastric lumen. It was shown that the highest gastric mucus secretion occurred before maximal gastric acid secretion. This is of importance for keeping balance between so called aggressive and protective mechanisms. It is of great importance in pathophysiology of stomach.     

Acid, pepsin, and mucus secretion in patients with gastric and duodenal ulcer before and after colloidal bismuth subcitrate (De-Nol).

Basal and pentagastrin stimulated gastric secretion was measured in seven patients with duodenal, and six with gastric ulcers before and after four weeks' treatment with colloidal bismuth subcitrate (as De-Nol), one tablet four times a day. Each duodenal and all but one of the gastric ulcers healed. After De-Nol there were no significant changes in basal, or pentagastrin stimulated volume, acid output, or primary parietal component. There were marked decreases in basal (duodenal ulcer -25%; gastric ulcer -16%) and pentagastrin stimulated total pepsin outputs, (duodenal ulcer -42%, gastric ulcer -36%). There were insignificant decreases in basal output of mucus, but postpentagastrin stimulated mucus output was significantly inhibited (p less than 0.05) in patients with duodenal (-16%) and with gastric ulcer (-27%). The drop in gastric proteolysis after De-Nol is unlikely to be because of the healing of the ulcers and is more likely to be because of the drug. The ulcer healing efficacy of De-Nol may be related to this decline in the proteolytic action of gastric juice, but is unlikely to be because of a quantitative change in mucus, or in acid secretion.     

Famotidine,a new H2-receptor antagonist

We studied pentagastrin-stimulated acid and pepsin secretion with three doses (5, 10, and 20 mg) of a new H₂-receptor antagonist (famotidine) administered orally to normal male volunteers. A dose response was identified: 2 hr after oral dosing, 5 mg famotidine suppressed stimulated acid secretion to 60% of control and was comparable to 300 mg cimetidine (55% suppression). Higher doses of famotidine yielded significantly more suppression of acid secretion (10 mg yielding 70% and 20 mg, 90%). Pentagastrinstimulated acid secretion remained decreased (50% of control) 12 hr after oral dosing with 20 mg famotidine. The reduction in pepsin output paralleled the reduction in acid secretion and was primarily due to a reduction in the volume of secretion and not to a change in pepsin concentration. We calculated the components of gastric secretion (acid from parietal cells) and bicarbonate secretion (from nonparietal cells) and found that the primary effect of the H₂-receptor antagonists was a dramatic reduction in parietal cell output without a significant decrease in nonparietal secretion. Famotidine proved to be a potent inhibitor of both the parietal component of gastric acid and pepsin output. Famotidine was significantly more potent than cimetidine; 5 mg of famotidine was comparable to 300 mg of cimetidine.This study was supported by the Veterans Administration and by a grant from Merck Sharp and Dohme Research Laboratories, West Point, Pennsylvania.     

Effect of duodenal acidification on gastric mucus and acid secretion in conscious cats.

In cats with gastric fistulae and Heidenhein pouches, the effect of acid entering the duodenum on secretion of acid, pepsin, and mucus from the Heidenhain pouch during maximal acid stimulation with pentagastrin or histamine, was studied. Duodenal acidification produced stimulation of pepsin and mucus secretion comparable to that induced by exogenous hormones (secretin and the combination of secretin with cholecystokinin). In addition, duodenal acidification caused an increase in acid secretion, thus suggesting that, in addition to secretin and cholecystokinin, a factor that stimulates acid secretion was also released by acid.     

Hydrochloric acid, pepsin and mucus secretion in the stomach of healthy probands following a single insulin administration with simultaneous pentagastrin infusion

A single dose 0.2 U/kg b.w. of insulin was administrated after an hour of infusion of pentagastrin 2 micrograms/kg b.w. for 6 healthy volunteers aged about 27 (22-30); the investigation was carried out for 1.5 h. The control group consisted of 6 health volunteers aged about 27 (21-36) which were administrated infusion of pentagastrin. While applicating stimuli the gastric juice was aspirated for analysis. In 15-minutes fraction of gastric juice the volume, concentration and output of hydrochloric acid, pepsin, protein and carbohydrates components of gastric mucus: hexoses, hexosamine, fucose and sialic acid were measured. It was stated that insulin decreases gastric secretion stimulated by pentagastrin in two first 15-minutes fractions after administration of insulin dependently on decrease of gastric juice volume. Insulin-hypoglycemia is a stimulus decreasing gastric mucus secretion, stimulated by pentagastrin. On this ground the conclusion can be arrived, that pentagastrin evokes the mechanism decreasing gastric mucus secretion, probably adrenergic. Insulin does not change hydrochloric acid secretion, but it appears to be en extremely strong stimulus for pepsin secretion which proves hypothesis, that secretion of this enzyme is regulated mainly by vagus.     

Gastric secretion during aging in pyloric-ligated rats and effects of pentagastrin

Changes in basal- and pentagastrin-stimulated gastric acid, pepsin secretion as well as gastric mucosal histidine decarboxylase activity were examined in 4- to 21-month-old pyloric ligated Fischer-344 rats. In addition, serum gastrin levels, gastric mucosal DNA, and RNA content were determined in these rats. The results revealed that whereas acid secretion decreased progressively with age, pepsin output increased between 4 and 14 months of age and then decreased sharply. Serum gastrin levels decreased progressively with age, and 3 h of pyloric obstruction produced no apparent change in serum gastrin levels in any of the age groups. Gastric mucosal weight, DNA, and RNA content in 4-month-old rats were not significantly different from those of 14-month-old animals. However, in 21-month-old rats, each of these values were found to be significantly lower than in their 4- or 14-month-old counterparts. A single injection of pentagastrin (250 μg/kg) significantly stimulated acid and pepsin secretion (45–52%) in 4-month-old rats, but not in 14- and 21-month-old animals, when compared with the corresponding saline-injected controls. Gastric mucosal histidine decarboxylase activity increased steadily between 4 and 21 months of age. Pentagastrin caused a significant 78% stimulation in histidine decarboxylase activity in 4-month-old rats, but had no effect on the enzyme activity in 14-month-old animals, when compared with the corresponding saline-injected controls. However, in 21-month-old rats, pentagastrin inhibited histidine decarboxylase activity by 55% when compared with the saline-injected controls. It is concluded that a) aging decreases capacity of the gastric mucosa to secrete acid and pepsin, b) in aged rats, decreased acid and pepsin output could in part be attributed to mucosal atrophy; c) responsiveness of the gastric mucosa to pentagastrin decreases with age; and d) in aged animals, gastric acid secretion is not regulated by histamine.     

Effect of corticotropin on gastric acid,pepsin, and mucus secretion in dogs with fistulas

The aim of the present investigation was to study the effect of prolonged daily intramuscular injection of 40 units of corticotropin gel on gastric acid, pepsin, and mucous secretion in 6 dogs with gastric fistulas. Another 4 dogs received daily saline injections and were used as controls. A significant increase in the rate of secretion and acid output was observed after ACTH administration. The secretion of pepsin was not affected. Changes in the composition of mucus also were observed. Significant decrease in the output of fucose and significant decreases in the stoichiometric molar ratios of fucose to hexosamine and of fucose to sialic acid were observed during ACTH administration. The demonstration of alteration in both the neutral and acidic mucopolysaccharides of the gastric mucous secretion during ACTH administration leads us to suspect that the gastric mucosal barrier might be impaired.Supported in part by Grants AM 07245 and 09790 from the National Institute of Arthritis and Metabolic Diseases, U. S. Public Health Service.     

Pulsatile luteinizing hormone release, and the inhibitory effect of estradiol-17 beta in gonadectomized male and female rats: effects of neonatal androgen or exposure to constant light

The characteristics of pulsatile LH release and the acute inhibition of LH release by estradiol-17 beta (E2) were studied in long term (21 days) gonadectomized female and male Wistar rats. Three groups of female rats were examined; animals exposed either to summer lighting (14-h on; 10-h off; LD) or continuous illumination (LL) and animals treated neonatally with testosterone propionate (TP) and exposed to LD. The mean plasma LH concentrations and interpulse intervals were similar in both male and LD female rats. However, treatment of female rats with TP or exposure to LL reduced the mean plasma LH concentration in female rats and increased the interpulse interval when compared with LD female or male rats. The amplitude of the LH pulses was significantly greater in the LD female rats compared with those in the male rats; since pituitary responsiveness to a single iv injection of 50 ng LHRH/100 g BW was similar in the two groups, this suggests that the amount of LHRH released per pulse of LH is greater in the female than in the male. The greater amplitude but similar frequency of LH pulses in the LD female compared with the LD male suggest that the MCR of LH may be greater in the female. The pulse amplitude in the TP-treated rats was similar to that in the rats exposed to LL and since pituitary responsiveness to LHRH was significantly greater in the TP rats, there was probably more LHRH released per pulse of LH in the LL-treated rats. Pituitary responsiveness to LHRH was significantly lower in the LL- and TP-treated rats compared with males and LD females. The timing of the inhibition of LH secretion by E2 was similar in all four groups of animals, and in LD females was not affected by a 92% depletion of serotonin, 100% depletion of 5-hydroxyindoleacetic acid, or a 33% depletion of dopamine in the hypothalamus produced by the administration of parachlorophenylalanine.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effect of Acetylsalicylic Acid on the Constituents of the Gastric Mucosal Barrier

The effect of luminal application of acetylsalicylic acid (ASA) on the liberation of gastric mucosal barrier constituents at pH 5.0 and 2.0 was investigated. The Lucite chamber stomach-flap preparation was used in 18 dogs whose basal H secretion was inhibited by Cimetidine. An ASA dose of 10 mmol at pH5.0 caused a moderate increase in content of proteins, glycoproteins, and glycolipids in the instillates. This was accompanied by an increase in transmucosal potential difference (PD) without concomitant changes in the appearance of the gastric mucosa. However, the content of mannose used as an indicator of plasma leakage remained unchanged. A 20 mmol ASA dose at pH5.0 produced further enrichment of the instillates in mucus constituents, and an increase in mannose content was observed, but PD still remained elevated. In contrast, the same dose of ASA at pH 2.0 severely depleted the gastric mucosal barrier of its mucus constituents and caused a marked increase in leakage of plasma elements. These changes were accompanied by a substantial drop of PD and gastric mucosal damage. These data indicate that the topical application of ASA causes the liberation of mucus constituents, which results in weakening of the gastric mucosal barrier and thus facilitates the pepsin and acid penetration of gastric mucosa. The extent of mucosal damage caused by aspirin strongly depends on the pH of luminal exposure.     

Exogenous and endogenous acid and pepsins in the pathogenesis of duodenal ulcers in the rat

A continuous subcutaneous infusion for 24 hr of the gastric secretagogues, pentagastrin (4 g/kg/min) together with carbachol (0.8 g/kg/min) produced a 100% incidence of duodenal ulcers (DU) in male albino Wistar rats. The mean acid output producing these duodenal ulcers was 2.3 mmol/24 hr, with a gastric secretory volume of 25 (±1) ml/24 hr at an acid concentration of 91 (±2) mmol/liter. The pepsin activity in the gastric juice was 185 g/ml. To simulate this acid-pepsin hypersecretion, acid and/or pepsin was infused intragastrically for 24 hr. The intragastric infusion of hydrochloric acid (0.1 M, 0.2 M, 0.5 M) alone and hog purified pepsin (2.5, 5, 10 mg/24 hr) at a constant rate of 1 ml/hr for 24 hr failed to produce duodenal ulcers in rats although gastric lesions in the body of the stomach were produced. The infusion of 0.2 M HCl with 5 mg pepsin over 24 hr produced DU in two of 10 rats. However, pooled secretagogue-stimulated gastric juice, infused intragastrically, produced DUs in 11 of 12 rats. Acid alone does not produce DU expermentally in rats at the rate of infusion used in these experiments. Acid and exogenous porcine pepsin (similar to human pepsin 3 on agar gel electrophoresis) rarely produced duodenal ulcers. However, acid and endogenous rat pepsin are needed together for the duodenal ulcerogenesis. This pepsin may be an obligatory ulcerogenic factor in the rat.     

Role of Mucus Reduction and Luminal Acid Elevation in Increased Susceptibility of Stomach to Nonsteroidal Antiinflammatory Drug-Induced Injury in Arthritic Rats

We investigated the role of gastric mucus and acid secretion in the increase of nonsteroidal antiinflammatory drug-induced gastric lesions in adjuvant-induced arthritic rats. Both aspirin- and indomethacin-induced gastric injury were remarkably worsened in the arthritic rats. In the arthritic rats, the amounts of mucus glycoprotein in both the mucosa and adherent gel layer were respectively decreased to 70% and 34% of those in normal rats, while gastric acid secretion was augmented to 1.5-fold. The gastroprotective antiulcer agent ecabet sodium, which increased the mucus content in the gel layer but did not affect the luminal acid contents, prevented the increase of both lesions induced by aspirin and indomethacin. Cimetidine also inhibited the formation of aspirin- and indomethacin-induced damage as well as the acid secretion in the arthritic rats. In conclusion, an imbalance between gastric defensive and aggressive systems due to the loss of adherent mucus glycoprotein and the elevation of the luminal acid contents seems to account for the increased susceptibility of the lesion-inducing properties of nonsteroidal antiinflammatory drugs in arthritic rats.     

胃溃灵对胃粘膜损伤大鼠胃粘膜分泌的影响

目的 :研究胃溃灵对乙酸引起胃粘膜损伤大鼠胃粘膜分泌的影响。方法 :将 5 0只 SD大鼠制成乙酸胃粘膜损伤模型 ,并随机将大鼠等分为 5组 ,次日起给每组大鼠分别灌服等量生理盐水、大、中、小剂量 ( 12 g/ kg、6g/kg、3 g/ kg)胃溃灵、雷尼替丁 ,10 d后处死大鼠 ,观察大鼠胃粘膜损伤程度。采用阿尔新蓝与胃液中糖蛋白结合的方法 ,分别测定大鼠胃内游离粘液量、胃壁粘液量。结果 :胃溃灵能明显提高大鼠胃内游离粘液、胃壁粘液的分泌量 ,能明显抑制乙酸对大鼠胃粘膜的损伤。结论 :胃粘液分泌量增加可加强对粘膜的屏障作用 ,这是胃溃灵保护胃粘膜损伤的机制之一。