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Serotonin (5-HT) is released from enterochromaffin cells in the gastrointestinal tract. Serotonin, via the activation of 5-HT2and 5-HT3receptors on vagal fibers, mediates pancreatic secretion through the mechanism independent from cholecystokinin. Melatonin (5-HT derivative) or L-tryptophan (melatonin or 5-HT precursor) given systemically or intraduodenally to the rats stimulate amylase secretion, but the mechanism is not clear. The aims of this study was to investigate the involvement of 5-HT in the pancreatostimulatory effect of melatonin or L-tryptophan, administered intraduodenally.

AbstractBackground:Helicobacter pylori(Hp)infection is involved in various gastroduodenal pathologies. Also, the potential role of Hpinfection has been proposed in several extragastroduodenal disorders, such as cardiovascular, skin or immunological diseases. The role of Hpinfection in acute pancreatitis has not been tested. The aim of this study was to determine the influence of Hpinfection on the course of acute ischemia/reperfusion-induced pancreatitis in rats. Methods:Inoculation with CagA- and VacA-positive Hpor administration of vehicle were performed after visceral ischemia. Visceral ischemia was evoked by clamping of the celiac artery for 30 min. Four weeks later, after full recovery from primary ischemia-induced damage, acute pancreatitis was evoked by limitation of pancreatic blood flow (PBF) in the splenic artery for 30 min using microvascular clips. Rats were sacrificed 1 h or 1, 3, 5, 10, and 21 days after removal of the vascular clips. Hpinfection was assessed by the urease test and gastric histology. Results:In Hp-negative rats ischemia followed by reperfusion caused acute pancreatitis as manifested by a reduction in PBF and pancreatic DNA synthesis, as well as by increases in plasma amylase, lipase, interleukin-1β (IL-1β) and interleukin-10 (IL-10). The morphological features of pancreatic tissue showed necrosis, strongly pronounced edema, hemorrhages and leukocyte infiltration. The maximal intensity of pancreatic damage was observed between the 1st and 3rd day of reperfusion, then pancreatic tissue underwent regeneration. Hpinfection resulted in a significant reduction in PBF and an aggravation of pancreatic ischemia 1 h and 3 and 5 days after reperfusion. Plasma amylase in Hp-infected rats was significantly higher than in Hp-negative animals 1 h and 1 and 3 days after ischemia, whereas in lipase this significant difference was observed between the 1st and 3rd day. DNA synthesis in Hp-positive rats was additionally reduced 1 h and 3 and 5 days after ischemia. Also ischemia evoked an increase in serum IL-1β and IL-10, and morphological manifestations of pancreatitis were additionally enhanced by Hpinfection. Conclusions:(1) Hp infection increases the severity of ischemia-induced pancreatitis; (2) Hpinfection increases production of pro-inflammatory IL-1β, and (3) Hpinfection aggravates disturbances in pancreatic microcirculation in acute pancreatitis.Copyright © 2002 S. Karger AG, Basel and IAP

AbstractBackground:Recent identification of specific leptin receptors in the pancreas suggests that this peptide may also play some role in this gland. Aim:To examine the effect of intraperitoneal (i.p.) or intracerebroventricular (i.c.v.) administration of leptin in rats on caerulein-induced pancreatitis (CIP), pancreatic gene expression of leptin and inflammatory cytokine production. Methods:caerulein (25 μg/kg) was infused subcutaneously into conscious rats over 5 h to produce CIP. Leptin (1, 5, or 10 μg/kg) was injected i.p. or i.c.v. 30 min prior to the CIP induction. The plasma level of TNFα and IL-4 was determined by ELISA, while plasma leptin was measured by RIA and leptin gene expression in pancreas by RT-PCR. Results:CIP was characterized by the usual pancreatic edema, reduction in pancreatic blood flow (PBF) and an increase in serum levels of amylase, TNFα and IL-4. Pretreatment with i.p. or i.c.v. leptin of the CIP rats partially reversed the harmful effects of CIP on the pancreas, and reduced pancreatic inflammation and the fall in PBF. This was accompanied by a dose-dependent reduction in serum levels of amylase and TNFα, while serum IL-4 in the CIP rats pretreated with leptin rose dose-dependently as compared to control rats with CIP alone. Pretreatment with leptin resulted in the dose-dependent rise in plasma leptin level over that observed in vehicle-treated controls. Leptin mRNA expression in the pancreas was dose-dependently increased after infusion of caerulein. Leptin content in isolated pancreatic acini was also increased dose-dependently by caerulein added to the incubation medium bathing these acini. Conclusions:(1) Exogenous leptin protects the pancreas against damage by CIP; (2) endogenous leptin seems to limit the extend of pancreatic damage, and (3) these protective effects of leptin could be attributed to the reduction in TNFα and to the increase in IL-4 production.Copyright © 2002 S. Karger AG, Basel and IAP

The effect of 15(S)-15-methyl PGE2, methyl ester (15-ME-PGE2), used intravenously in a standard dose of 0.5 µg/kg-hr on gastric secretion and serum gastrin level was studied in 6 duodenal ulcer patients. 15-Me-PGE2 caused an immediate and almost complete inhibition of basal gastric acid and pepsin secretion. Acid secretion induced by a peptone meal and determined by intragastric titration technique was almost as high as the maximal response to histamine and accompanied by a significant rise in serum concentration of immunoassayable gastrin. 15-Me-PGE2 caused a sudden and complete inhibition of gastric acid response to a peptone meal. 15-Me-PGE2 did not significantly affect serum gastrin levels both under basal conditions and in response to a peptone meal. Gastric acid and pepsin outputs induced by maximal stimulation with pentagastrin (4 µg/kg-hr) was inhibited by 15-Me-PGE2 by about 70% and that induced by histamine by about 45%. After the with-drawal of 15-Me-PGE2 infusion, gastric secretion remained reduced for the remainder of the test. We concluded that 15-Me-PGE2 is a very strong inhibitor of gastric acid and pepsin secretion induced by various secretory stimuli, particularly under basal conditions and in response to a meal. In view of prolonged inhibitory activity, 15-Me-PGE2 may have clinical potential in the treatment of peptic ulcer disease.

In conscious cats provided with chronic gastric fistulas, metiamide, an H2-receptor antagonist, when given intravenously in a dose of 12 µmol/kg-hr, strongly inhibited gastric acid output stimulated maximally with histamine, pentagastrin, caerulein, insulin, urecholine, and peptone meal. Atropine sulfate administered in a dose of 0.288 µmol/kg-hr also inhibited gastric response to all these stimulants except histamine. These results can be explained by the hypothesis of interaction of various receptors of parietal cells, might be regarded as evidence for histamine mediation in the physiological stimulation of parietal cells, or may suggest the nonselectivity of the action of metiamide on parietal cell receptors.

Antacids show gastroprotective action against various irritants in experimental animals and enhance the healing of chronic gastroduodenal ulcers in humans but the mechanisms of these effects are unknown. The present study was designed to determine whether prostaglandin (PG) and epidermal growth factor (EGF), which also have protective and antiulcer properties, contribute to the action of antacids on rat's stomach. It was found that Maalox 70 and its active component, Al(OH)3, enhance significantly the healing of chronic gastric and duodenal ulcers observed during 7 and 14 days after their induction. Pretreatment with indomethacin caused a significant prolongation of ulcer healing, and this was accompanied by a significant reduction in PG and EGF formation, suggesting that both factors may be involved in ulcer healing. Maalox and Al(OH)3 failed to prevent the suppression of PG by indomethacin but were equally effective in ulcer healing in rats without and with indomethacin administration, suggesting that endogenous PG may not play any important role in the healing process by these drugs. Removal of salivary glands, the major source of EGF, also prolonged ulcer healing but, again, Maalox was as effective in ulcer healing as in rats with intact salivary glands. Our findings that Maalox at pH above 3.0 binds significant amounts of EGF, enhances the binding of EGF to the ulcer area, and stimulates mucosal growth, suggest that EGF may be involved in ulcer healing; however, because antacids are also effective after sialoadenectomy, EGF does not seem to be the major factor in ulcer healing by these drugs.

Current concepts of the regulation of gastric and pancreatic secretion suggest a striking degree of interdependence between the autonomic nerves and gastrointestinal hormones. These neurohormonal secretory mechanisms are of two types, the first originating centrally to mediate the cephalic phase, the second originating in the wall of the alimentary canal where both neural and hormonal mechanisms are activated during gastric and intestinal phases of secretory stimulation. Vagal activation by sham feeding or glucopenic agents results in the release of gastrin, direct stimulation of oxyntic glands, and sensitization of these glands to other endogenous stimulants. In man, vagal activation provokes a marked gastric secretory response that is only slightly affected by resection of the antrum and duodenal bulb, suggesting that vagal-gastrin release contributes to, but is not essential for, the gastric response to vagal stimulation. Furthermore, atropine and vagotomy enhance rather than inhibit the release of gastrin, which suggests both stimulatory and inhibitory components in the action of the vagus on gastrin release. Atropine and vagotomy are also known to suppress the pancreatic response to intestinal stimulants without affecting the action of exogenous hormones (cholecystokinin and secretin) on the pancreas. These effects have been attributed to the removal of vagal facilitation of release of intestinal hormones and/or the interruption of vago-vagal enteropancreatic reflexes involved in postprandial pancreatic stimulation. Recently, several hormonal peptides (VIP, somatostatin, gastrin, enkephalin) were found in the neurons of the gut (often referred to as purinergic nerves). These peptides may be delivered to the responding secretory cells not only by classical endocrine paths, but also by neurocrine and paracrine modes. The interplay with other neural and hormonal mechanisms and the physiologic roles of the peptides in the regulation of gastric and pancreatic secretion remain to be determined.

The effect of two methylated PGE2 analogs given orally on the pancreatic response to intravenous secretin has been studied in 8 healthy subjects. The secretion of bicarbonate was not changed by these PGE2 analogs. The secretion of enzymes during infusion of PGE2 analogs was significantly greater than in the control.

This study was designed to determine the role of mucosal generation of prostaglandins (PGs) in the ability of mild irritants (20% ethanol or 5% NaCl) to protect against the formation of mucosal lesions caused by necrotizing agents (100% ethanol or 25% NaCl) or acidified aspirin (ASA). Mild irritants protected against damage from necrotizing agents but not from ASA. This protection was accompanied by increased mucosal generation of PGE2 and PGI2-like substances. Exogenous PGE2 and PGI2 applied topically to the gastric mucosa in a nonantisecretory dose greatly inhibited the formation of lesions induced by either necrotizing agents or ASA. Pretreatment with indomethacin, which suppressed the generation of mucosal PGs augmented formation of lesions by necrotizing agents and partly counteracted the protective effect of mild irritants. We conclude that mild irritants, and exogenous PGs inhibit the formation of gastric lesions by necrotizing agents, at least in part, by mucosal generation of PGs.

Gastric ulcers were produced in conscious cats in 3 hr by simultaneous intravenous or intragastric administration of acetylsalicylic acid (ASA), plus intravenous infusion of histamine (80 µg/kg/hr), pentagastrin (8 µg/kg/hr), or intragastric instillation of HCl. The formation of these ulcers was accompanied by almost complete inhibition of prostaglandin (PG) biosynthesis, suggesting that the withdrawal of normal protection of gastric mucosa by PGs may be major factor in pathogenesis of ASA-induced gastric lesions. Prostacyclin (PGI2), infused at a dose producing about 50% inhibition of histamine or pentagastrin-induced acid secretion, significantly reduced the formation of gastric ulcers produced by ASA + histamine or pentagastrin. Inhibition of gastric acid secretion by about 50% using ranitidine, a new H2-receptor antagonist, also decreased the formation of gastric ulcers induced by ASA + gastric secretagogue, but the degree of this reduction was significantly smaller than after PGI2. In addition, PGI2 decreased significantly the severity of gastric ulcers produced by a combination of ASA plus gastric perfusion of HCl, the antiulcer effect being more pronounced when PGI2 infusion was started prior to, rather than during, ASA administration. This study confirms that the administration of ASA plus gastric secretagogue or gastric instillation of HCl is a reliable model of gastric ulcerations probably resulting from withdrawal of biosynthesis of mucosal PGs and shows that PGI2 is capable of preventing the formation of these ulcers by means other than its effect on gastric acid secretion.

The action of metiamide on histamine-, and pentagastrin-, insulin-, and meal-induced maximal gastric secretion was studied in six duodenal ulcer patients. Gastric acid secretion in tests with histamine, pentagastrin, or insulin stimulation was collected by a simple aspiration technique whereas that induced by a peptone meal was determined by the modified intragastric titration method of Fordtran and Walsh, in which acid output was measured by monitoring the rate at which 0.5 M sodium bicarbonate had to be added to keep the gastric content at the initial value of pH 5.0. Metiamide produced a dose-related inhibition of histamine-induced acid and pepsin outputs, and the dose required for 50% inhibition was about 1 mg/kg-hr. Metiamide given intravenously in a dose of 1 mg/kg-hr caused a strong and immediate inhibition of gastric acid and pepsin secretion induced by all stimuli used. Similar inhibition was observed after intragastric administration of metiamide in a single dose of 4 mg/kg. We conclude that metiamide is a very strong inhibitor of gastric acid and pepsin secretion induced by a variety of secretory stimuli and that it might deserve attention from clinicians as a side-effect-free depressant of acid secretion in the treatment of peptic ulcer disease.

Epidermal growth factor promotes the growth of and protects gastric mucosa against various ulcerogens, including stress, but little is known about its role in the pathogenesis of stress ulcerations. In this study, Wistar rats with intact and resected salivary glands were exposed to water-immersion and restraint stress. During 2–14 hours of water-immersion restraint stress, the formation of gastic ulcerations increased progressively and the duration of stress was accompanied by a decrease in DNA synthesis in the gastric mucosa. Following sialoadenectomy, a significant increase in the number of stress ulcerations and further reduction in DNA synthesis were observed. Exogenous epidermal growth factor and dimethyl prostaglandin E2significantly reduced the ulcerations in the stressed rats with intact salivary glands, but this reduction was significantly less pronounced after sialoadenectomy. Water-immersion restraint stress also resulted in about 50% reduction in mucosal prostaglandin E2generation, and the pretreatment with indomethacin, which suppressed prostaglandin E2by about 90%, almost doubled the number of stress ulcerations and abolished the gastroprotective effect of exogenous epidermal growth factor (but not dimethyl prostaglandin E2) against the stress lesions. An inhibition of ornithine decarboxylase activity by difluoromethyl ornithine also augmented stress-induced ulcerogenesis and abolished the protective action of epidermal growth factor while the administration of spermine almost completely prevented stress ulcerations in rats both without and with pretreatment with difluoromethylornithine. Water-immersion restraint stress also significantly reduced mucosal content of glutathione. Cysteamine increased tissue glutathione and reduced stress ulcerations but N-ethylmaleimide, an sulfhydryl blocker, decreased mucosal content of glutathione without affecting the stress ulcerations. This study indicates that the stress ulcers are accompanied by the reduction in mucosal synthesis of DNA, prostaglandin, and glutathione and that the presence of salivary glands attenuates the stress ulcerogenesis probably by releasing epidermal growth factor which acts, in part, by enhancing ornithine decarboxylase activity, mucosal growth, and prostaglandin and glutathione formation.