Increase In Gastric Acid Secretion Research Articles

Gastric acid secretion after blockade of angiotensin AT 1 receptors in the Na +-depleted rat

This study tested the hypothesis that angiotensin II acting through the angiotensin AT 1 receptor plays an important role in the control of gastric acid secretion. Basal gastric acid secretion and gastric blood flow were lower in Na +-depleted animals, in which the renin-angiotensin system was activated, than in animals maintained on a normal Na + diet. Intravenous infusion of pentagastrin at 0.6 μg/kg/min increased gastric acid secretion to a greater extent in normal Na + than in Na +-depleted animals. In addition to stimulating gastric acid secretion, pentagastrin increased gastric blood flow by proportionally the same amount in both normal and low Na + animals. However, because basal gastric blood flow was considerably reduced in Na +-depleted animals, the increase produced by pentagastrin extended only to the levels observed in non-pentagastrin-treated normal Na + animals. Lower gastric blood flow in response to pentagastrin may explain the smaller increase in gastric acid secretion observed in Na +-depleted animals. In Na +-depleted animals, the selective angiotensin AT 1 receptor antagonist losartan did not affect basal gastric acid secretion or gastric blood flow, suggesting the involvement of mechanisms other than angiotensin II. Following blockade of angiotensin AT 1 receptors, pentagastrin significantly increased gastric blood flow in Na +-depleted animals to levels observed with infusion of the pentapeptide in normal Na + animals. The results suggest that the decrease in pentagastrin-stimulated acid secretion in Na +-depleted animals is mediated by angiotensin II acting through the angiotensin AT 1 receptor, most probably through vascular mechanisms.

Gastric inhibitory polypeptide and gastric acid secretion in pregnant rats

The effects of pregnancy on the basal and pentagastrin-stimulated gastric acid secretion and the level of plasma gastric inhibitory polypeptide (GIP) in rats were studied on pentobarbital-anaesthetized non pregnant rats and rats in the 1st, 2nd, or 3rd week of gestation. Acid output was determined by titration of the gastric perfusate. Basal secretion was collected for 45 min before a 30 min infusion of pentagastrin (8 μg/ml/300g body weight). Concentration of plasma GIP was measured by a radioimmunoassay (RIA). The immunoreactivity of GIP-like substance in the extract of the rat placenta collected from the rat at day 21 of gestation was examined by RIA. The biological activity of GIP-like substance in the rat placenta extract was tested by the reduction of pentagastrin-stimulated gastric acid secretion in male rats. The basal level ofgastric secretion was higher in late pregnancy as compared with the non pregnant rats. Pentagastrin induced a greater increase of gastric acid secretion in early but not late pregnant rats as compared with the non-pregnant animals. The basal and postpentagastrin level of plasma GIP was higher in rats in late pregnancy. Both immunoreactivity and biological activity of GIP exist in the rat placenta extract. These results suggest that the normalization of gastric acid secretion in late pregnant rats is at least in part due to the production of GIP-like substance from placenta.

Gastric adaptation to stress: role of sensory nerves, salivary glands, and adrenal glands.

Single exposure to water immersion and restraint stress (WRS) in rats produces acute gastric mucosal damage, but repetitive WRS insults lead to gastric adaptation to stress ulcerogenesis. This study was designed to assess the mechanism of this adaptation, particularly the role of sensory nerves, salivary glands, adrenal glands, and gastric acid secretion. WRS was applied for a standard period of 3.5 h, either once or repeated every other day for up to 8 days in intact rats and in animals with capsaicin-induced deactivation of sensory nerves, vagotomy, salivectomy, adrenalectomy, and inhibition of gastric acid secretion by H2-blocker. WRS applied once produced multiple gastric erosions accompanied by a significant increase in gastric acid secretion and a decrease in gastric blood flow (GBF) and DNA synthesis. Repeated WRS insults resulted in a significant decrease in the number of gastric lesions, reaching a maximum after four consecutive exposures to WRS. This adaptation to stress ulcerogenesis was accompanied by a decrease in gastric acid secretion and an increase in GBF and mucosal generation of DNA synthesis. Salivectomy, which decreased the luminal content of epidermal growth factor (EGF) (by about 80%), markedly attenuated this adaptation, and this was reversed by the addition of exogenous EGF. Capsaicin-induced ablation of sensory nerves eliminated gastric adaptation to WRS, and this was accompanied by a significant decrease in the GBF, but pretreatment with calcitonin gene-related peptide restored gastric adaptation to stress in capsaicin-denervated rats. Selective vagotomy and adrenalectomy failed to affect gastric adaptation to WRS, whereas gastric acid inhibition by ranitidine enhanced this adaptation. The stomach is able to adapt to repeated stress insults by enhancing GBF and DNA synthesis, and this adaptation is mediated, at least in part, by sensory nerves and EGF.

Pancreatic polypeptide in dorsal vagal complex stimulates gastric acid secretion and motility in rats

High concentrations of receptors for pancreatic polypeptide (PP), a pancreatic hormone, were recently discovered in the dorsomedial region of the dorsal vagal complex (DVC). We hypothesized that gastric acid secretion and motility, digestive functions strongly influenced by vagovagal reflexes organized within the DVC, would be affected by PP applied directly to this vagal sensorimotor integration area. After urethan-anesthetized rats were prepared for antral motility recording or titrometric analysis of gastric acid output, phosphate-buffered saline or various doses of PP in phosphate-buffered saline were micropressure injected into the medial DVC. Injections of PP into the DVC produced significant, long-lasting, and dose-dependent increases in gastric acid secretion and antral motility. These gastric responses were blocked by bilateral cervical vagotomy and by atropine, suggesting that intramedullary PP stimulates vagal cholinergic pathways, resulting in enhanced gastric functions. Because PP is not synthesized within the central nervous system, these results point to a new mechanism whereby the digestive tract may modulate its own autonomic control: direct humoral action on vagovagal reflex circuits within the brain stem.

Somatostatin inhibits gastrin-induced histamine secretion and synthesis in the rat

Somatostatin is a potent inhibitor of gastric acid secretion. However, the effect of somatostatin on gastric histamine secretion and synthesis has not been well understood, despite the fact that histamine plays a key role in the regulation of gastric acid secretion. This study was designed to determine the effect of somatostatin on gastric histamine mobilization and acid secretion in conscious rats. In conscious rats with a gastric fistula, a 4 h intravenous infusion of gastrin-17 I (1 nmol/kg/h) evoked a marked increase in fundic histidine decarboxylase activity (the sole histamine-forming enzyme) and reduced fundic histamine content with a concomitant increase in gastric acid secretion. Somatostatin-14 (10 nmol/kg/h) significantly inhibited gastrin-induced gastric acid secretion and fundic histidine decarboxylase activity and prevented a gastrin-induced decrease in fundic histamine content. In conscious rats with a vesical fistula, somatostatin-14 (10 nmol/kg/h) significantly inhibited the urinary histamine excretion induced by a gastrin-17 I (1 nmol/kg/h) infusion. These findings suggest that the inhibitory action of somatostatin on gastrin-induced acid secretion is mediated by the inhibition of histamine mobilization.

Effects of GABA and l-glutamate on the gastric acid secretion and gastric defensive mechanisms in rat lateral hypothalamus

The effects of administration of an inhibitory GABAergic or excitatory glutaminergic neurotransmitter into the lateral hypothalamic area (LHA) on gastric acids, an aggressive mechanism, and transepithelial potential difference (PD) and mucosal blood flow (MBF), defensive mechanisms, were examined in anesthetized rats, since lesions of LHA in these animals cause gastric mucosal damage and electrical stimulation stimulates gastric acids and antral contractions. Microinfusion of the inhibitory neurotransmitter, muscimol (GABA agonist) resulted in an increase in gastric acid secretion and in PD and MBF. The GABA antagonists picrotoxin and bicuculline methiodide, in contrast, decreased these three factors. The excitatory neurotransmitter l-glutamate induced only an increase of MBF. Thus, the GABAergic system in LHA stimulates the gastric functions, both defensive and aggressive mechanisms, while the glutaminergic system increases only a portion of the defensive system. The results suggest that there is a significant interaction between LHA and stomach functions.

Cholecystokinin in the regulation of gastric acid and endocrine pancreatic secretion in humans.

In this study, a selective antagonist of cholecystokinin (CCK)-A receptors, loxiglumide, was used to evaluate the role of CCK in the control of the release of gastrin and pancreatic hormones (insulin, glucagon, pancreatic polypeptide (PP), and somatostatin) after stimulation with exogenous CCK and ingestion of a standard liquid mixed meal in healthy humans. Exogenous CCK-8, which induced a small but significant increase in gastric acid secretion, resulted in dose-dependent increments in plasma PP levels without significant changes in plasma levels of insulin, glucagon, or somatostatin. Pretreatment with loxiglumide resulted in a marked increase in CCK-induced gastric acid secretion and abolished the increments in plasma PP without alteration of plasma insulin, glucagon, or somatostatin levels. Ingestion of the liquid meal resulted in an immediate rise in intragastric pH from basal values of about 2 to pH6 lasting 90-120 min, and this was accompanied by significant increments in plasma gastrin, insulin, glucagon, PP, and somatostatin. Administration of loxiglumide (1200 mg orally) caused a reduction in the postprandial intragastric pH and the two- to three-fold increase in plasma gastrin. Plasma insulin and glucagon levels in tests with loxiglumide tended to increase, probably owing to accelerated gastric emptying, whereas plasma PP and somatostatin were significantly reduced. This study provides evidence that CCK exerts an inhibitory effect on gastric acid secretion and plasma gastrin release as well as a stimulatory influence on the release of PP and somatostatin via CCK-A receptors but does not influence directly insulin or glucagon secretion in man.

Development of new lipophilic derivatives of tetragastrin: physicochemical characteristics and intestinal absorption of acyl-tetragastrin derivatives in rats.

In order to improve the intestinal absorption of tetragastrin (TG), we synthesized lipophilic derivatives of TG by acylation of its N-terminal amino group with acetic acid, caproic acid, and lauric acid. The purified TG derivatives, acetyl-tetragastrin (Ac-TG), caproyl-tetragastrin (Cap-TG), and lauroyl-tetragastrin (Lau-TG), were confirmed to be more lipophilic than the parent TG by high-performance liquid chromatography (HPLC). The pharmacological activities and the intestinal absorption of TG and its derivatives were examined by measuring gastric acid secretion. Stimulation of gastric acid secretion by these derivatives after intravenous administration was stronger than with native TG. When the acetyl- and caproyl-derivatives were administered into the large intestinal loops, a marked increase in gastric acid secretion was observed in comparison with TG, while no significant effect occurred following administration of the TG derivatives into the small intestines. These results indicated that chemical modification of TG with fatty acids improves the absorption of TG from the large intestines.

Effect of aging on gastric and duodenal mucosal prostaglandin concentrations in humans

The effect of aging on gastric and duodenal mucosal prostaglandins has not been reported. Gastric and duodenal mucosal prostaglandin concentrations were measured in 46 healthy adults, 35 of whom were relatively young (21-40 years old) and 11 of whom were considerably more elderly (aged 52-72 years). Mucosal biopsy specimens were obtained endoscopically from the fundus, antrum, duodenal bulb, and postbulbar duodenum, and extracts were assayed for prostaglandin F2 alpha and E2 concentrations by radioimmunoassay. Older age was associated with significantly lower fundic, antral, and post-bulbar duodenal prostaglandin concentrations. A second experiment was performed in 20 additional subjects (9 younger, 11 older) to determine whether lower mucosal concentrations in older subjects were reproducible and, if so, whether reduced gastric mucosal prostaglandins would have a physiological counterpart, namely increased gastric acid secretion. As in the original experiment, fundic, antral, and postbulbar mucosal prostaglandin levels were significantly lower in older subjects than in younger subjects. Mean basal acid output was significantly higher in older than younger subjects (9.8 +/- 2.5 vs. 4.8 +/- 1.6 mmol/h). It is concluded that gastric and duodenal prostaglandin concentrations decline with aging in humans and that the decline in fundic mucosal prostaglandins is associated with an increase in gastric acid secretion. (Gastroenterology 1992 Apr;102(4 Pt 1):1118-23)

Effect of aging on gastric and duodenal mucosal prostaglandin concentrations in humans

The effect of aging on gastric and duodenal mucosal prostaglandins has not been reported. Gastric and duodenal mucosal prostaglandin concentrations were measured in 46 healthy adults, 35 of whom were relatively young (21–40 years old) and 11 of whom were considerably more elderly (aged 52–72 years). Mucosal biopsy specimens were obtained endoscopically from the fundus, antrum, duodenal bulb, and postbulbar duodenum, and extracts were assayed for prostaglandin F2α and E2 concentrations by radioimmunoassay. Older age was associated with significantly lower fundic, antral, and postbulbar duodenal prostaglandin concentrations. A second experiment was performed in 20 additional subjects (9 younger, 11 older) to determine whether lower mucosal concentrations in older subjects were reproducible and, if so, whether reduced gastric mucosal prostaglandins would have a physiological counterpart, namely increased gastric acid secretion. As in the original experiment, fundic, antral, and postbulbar mucosal prostaglandin levels were significantly lower in older subjects than in younger subjects. Mean basal acid output was significantly higher in older than younger subjects (9.8 ± 2.5 vs. 4.8 ± 1.6 mmol/h). It is concluded that gastric and duodenal prostaglandin concentrations decline with aging in humans and that the decline in fundic mucosal prostaglandins is associated with an increase in gastric acid secretion.

カプロン酸を用いた化学修飾によるテトラガストリンの消化管吸収の改善

Tetragastrin (TG) has a potent pharmacological activity as gastrin. However, the oral bioavailability of TG is extremely low(about 3%) because of its high hydrophilicity and extensive hydrolysis in the gastrointestinal mucosa. in order to improve intestinal absorption of TG, we synthesized a new lipophilic derivative of TG by chemical modification of the peptide with caproic acid, and caproyl-TG (Cap-TG) was obtained. Cap-TG was confirmed to be more lipophilic than TG by high performance liquid chromatography. Intravenous injection of Cap-TG showed 1.7 fold higher activity than TG. The gastric acid secretion activities of these compounds were measured in rats after intestinal administration. When Cap-TG was administered into large intestinal loop, a marked increase in gastric acid secretion was observed in comparison with TG, while we found no significant effect following the small intestinal administration of Cap-TG. These results indicated that chemical modification of TG with caproic acid might be a useful approach for improving the large intestinal absorption of TG.

Disparate effects of intracisternal RX 77368 and ODT8-SS on gastric acid and serotonin release: role of adrenal catecholamines

Intracisternal injection of the thyrotropin releasing hormone (TRH) analogue RX 77368 (100 ng) or the somatostatin analogue ODT8-SS (1 μg) produced an 82% and 101% increase in gastric acid secretion in 2 h pylorus-ligated rats. In contrast, dissimilar effects were produced by intracisternal injection of these peptides on the secretion of serotonin into the gastric lumen. Intracisternal RX 77368 (100 ng) produced a 496% increase in intraluminal serotonin release, while in contrast, intracisternal ODT8-SS (1 μg) produced a 78% inhibition in intraluminal serotonin release. Bilateral adrenalectomy reversed the stimulatory effect of intracisternal RX 77368 (100 ng) on serotonin, but not acid release. The data reveal a difference in the ability of the two peptides, which act as gastric secretagogues, to produce intraluminal acid and serotonin release, and suggest that combined activation of the vagus and the adrenal gland are important in mediating basal and RX 77368-stimulated serotonin release into the gastric lumen. In particular, differential effects on adrenal catecholamine release are implicated in the divergent effects of the two peptides.

Effect of age on gastric acid secretion and serum gastrin concentrations in healthy men and women

The effects of age on basal, meal-stimulated, and human gastrin-17-stimulated gastric acid secretion rates and serum pepsinogen concentrations were evaluated in 41 healthy men and women. Older subjects (ages 44–71 years; mean, 57 years) had higher mean basal, meal-stimulated, and gastrin-17-stimulated acid secretory rates and basal serum pepsinogen I and II concentrations than younger subjects (ages 23–42 years; mean, 33 years). Age-related differences in acid secretion were especially prominent in men, and age-related differences in serum pepsinogen I and II concentrations were more prominent in women. Higher gastric acid secretion rates in older subjects could not be explained by body size (height, weight, body surface area, or fat-free body mass) or by the higher incidence of infection with Helicobacter pylori. Using a multivariate linear regression model, age had an independent positive effect on acid secretion, and H. pylori infection had an independent negative effect. It was concluded that aging is associated with an increase in gastric acid secretion in humans, especially in men, while infection with H. pylori is associated with lower acid secretion rates.

Role of mucosal blood flow in duodenal ulcer formation induced by dulcerozine

To clarify the role of mucosal blood flow in the pathogenesis of ulcer formation, the authors investigated dulcerozine-induced duodenal ulcers in rats. Administration of dulcerozine, 500 mg/kg by intragastric route or 250 mg/kg given intraperitoneally, induced acute ulcers in the duodenum, but not the stomach, in all rats. Using the pyloric ligation method, it was determined that although dulcerozine significantly increased gastric acid secretion, no duodenal ulcers were observed in these animals. The administration of 1 ml of 0.1 N HCl every hour for 6 hours did not induce duodenal ulceration. The mucus glycoprotein content of the corpus, antrum and proximal duodenum did not differ following dulcerozine administration. Duodenal mucosal blood flow, which was measured by an electrolytically generated hydrogen gas clearance technique, decreased significantly following dulcerozine administration even in pylorus-ligated rats. In contrast, there was an increase in the gastric mucosal blood flow following administration of the drug. Therefore, not only an increase in gastric acid secretion but also a decrease in duodenal mucosal blood flow are suggested to be responsible for dulcerozine-induced duodenal ulceration.

Gastric mucosal damage induced by lateral hypothalamic lesions in female rats: Influence of age and ovariectomy

Male rats given lateral hypothalamic (LH) lesions exhibit an acute increase in gastric acid secretion and develop erosions of the glandular portion of the stomach within 24 h. Since this process has been examined predominantly in male rats, the present experiments were devised to study the effects of LH lesions on the gastric mucosa of female rats. In Experiment 1, 1-year-old Sprague-Dawley female rats given LH lesions exhibited erosions in the rumenal portion of the stomach, a pattern unlike that found in both young and old male rats. Although the glandular mucosa lacked evidence of gross defects, the mucosa appeared blanched and covered with a mucus-like secretion. Experiment 2 demonstrated that, like male rats, LH lesions produced gastric hypersecretion in 1-year-old females. The results of the first two experiments indicate that the dissimilar patterns of gastric mucosal injury between males and older females cannot be accounted for on the basis of differences in gastric acid secretion. Experiment 3 demonstrated that, unlike older females but like males, 4-month-old female rats given LH lesions developed gastric erosions in the glandular mucosa only. Additionally, ovariectomy had no significant effect in altering the extent of gastric pathology. Taken together, these results suggests that (1) age and gender are important variables in neurogenic gastric mucosal injury, (2) differences in the type of gastric ulceration cannot be accounted for by differences in acid secretion, (3) ovarian hormones do not appear to play a significant role in gastric ulceration following brain damage.

Role of salivary glands and epidermal growth factor (EGF) in gastric secretion and mucosal integrity in rats exposed to stress

EGF, produced mainly by salivary glands, inhibits gastric acid secretion, stimulates the proliferation of gastric mucosal cells and protects the mucosa against various ulcerogens, but its role in the pathogenesis of stress ulcerations is unknown. In this study, rats with intact or resected salivary glands were exposed to water immersion and restraint stress (WRS) without and with pretreatment with exogenous EGF or dimethyl PGE2 (dmPGE2) at doses which were shown previously to protect the mucosa against topical irritants. During 1.5–12 h of WRS, the formation of gastric ulcerations increased progressively with the duration of stress reaching peak after 6 h of stress and being significantly higher in rats with removed salivary glands than in intact animals. Gastric acid secretion and DNA synthesis in oxyntic mucosa declined with the duration of WRS, but after sialoadenectomy a significant increase in gastric acid secretion and a further decline in DNA synthesis were observed after WRS. EGF contents in the gastric lumen and the gastric mucosa were several times higher in rats subjected to stress than in control unstressed animals, indicating that stress causes an extensive release of EGF. Both exogenous EGF (17 nmol/kg/h) and dmPGE2 (143 nmol/kg) prevented, in part, the formation of gastric lesions, while inhibiting gastric acid secretion both in rats with intact or resected salivary glands. We conclude that water immersion and restraint stress is accompanied by an excessive release of EGF, which appears to attenuate gastric secretion, enhances the DNA synthesis and may limit the formation of stress-induced gastric ulcerations.

Gastric effects of thyrotropin-releasing hormone microinjected into the dorsal motor vagal nucleus in cats

We investigated the gastric acid secretory and motility responses to microinjection of thyrotropin-releasing hormone (TRH) into the dorsal motor nucleus of the vagus (DMV) in anesthetized cats. Gastric acid output was collected every 15 min through a gastric cannula after saline flush and titrated to pH 7.0. Antral and corpus contractions were continuously recorded by extraluminal force transducers. TRH dissolved in 200 nl of saline and microinjected unilaterally into the DMV induced a dose-dependent (50–200 ng) increase in gastric acid secretion. The acid secretory response began in the first 15 min collection and lasted 45 min. TRH frequently increased the force of contractions of the antrum and corpus within one minute of microinjection. The minimal effective dose for eliciting increased motility was lower than for inducing acid secretion. These results demonstrate that TRH acts in the DMV of cats to stimulate gastric acid secretion and contractions.

Neurogenic stress ulceration caused by laparatomy under anesthesia plus restraint. The device of a new rat model

We report herein, a new method devised of producing neurogenic stress ulceration in rats. An experimental subarachnoid hemorrhage (SAH) was produced in rats by injecting 0.2 ml of arterial blood from other rats into the cisterna magna. Three days later, the rats were laparotomized for 1 hour under ether anesthesia, followed by restraint for 3 hours in wakefulness. The SAH rats were found to develop stress ulcers (UL-I) in the glandular stomach, which were significantly (p less than 0.001) more marked than those in non-SAH rats. Measurements were performed on gastric acid secretion, an important aggressive factor. It was found that the SAH rats undergoing the laparotomy-restraint stress showed a more marked increase in gastric acid secretion and a more marked reduction in MBF, than the non-SAH rats. The effects of bilateral vagotomy, upper abdominal sympathectomy and bilateral adrenalectomy were examined, and it was revealed that the SAH rats were under the condition of hyperreactivity both in the sympathetic and parasympathetic systems and, on this basis, the laparotomy-restraint stress caused the stress gastric ulceration. In this rat model, the laparotomy stress was applied under anesthesia and any exposure to low temperatures which may have interfered with blood circulation was avoided.

Cysteamine-induced duodenal ulcer and the hepatoduodenal branch of the vagus nerve

We investigated the role of the autonomic nervous system in gastric acid secretion, somatostatin concentration and PAS-positive mucus production in Brunner's glands in cysteamine-induced duodenal ulcer. Vagotomized rats were used. No ulcers occurred in the groups with vagotomies of the hepatoduodenal, truncal or gastric branches after cysteamine administration. However, in the hepatoduodenal branch vagotomized group, there was an increase in gastric acid secretion after cysteamine administration. A similar increase was observed in the control group, but the decreases in somatostatin concentration and PAS-positive mucus seen in the control group were not found in the hepatoduodenal vagotomized group. These results suggest that the hepatoduodenal branch of the vagus nerve might play an important role in the ulcerogenic process of cysteamine-induced duodenal ulcer.

Stimulatory Effect of Some Therapeutic Drugs Used for Improving Cerebral Insufficiency on Gastric Acid Secretion in Rats

Baclofen, gamma-amino-beta-hydroxybutyric acid (GABOB), calcium hopantenate (HOPA) and citicoline, which are clinically used for improving cerebral insufficiency, were tested for their effects on gastric acid secretion in the perfused stomach of urethane-anesthetized rats. These drugs were administered intravenously or subcutaneously. They produced a significant increase in gastric acid secretion, although the extents in increase were different. The duration of action was 1-2 h. The potency order was baclofen greater than GABOB greater than or equal to citicoline greater than or equal to HOPA. The stimulatory response to each drug was completely inhibited by atropine. In contrast, the peripheral secretory activity of each drug was not demonstrated in the isolated lumen-perfused stomach of mice. These results indicate that all the tested drugs produce an increase in gastric acid secretion probably via central cholinergic activation and that gastric acid stimulation by compounds improving the cerebral insufficiency might be included in side effects in their clinical use.