Site-specific formation of gastric ulcers by the electric stimulation of the left or right gastric branch of the vagus nerve in the rat

The present study was conducted to investigate the role of the parasympathetic nervous system innervating the stomach in gastric ulcer formation, with special reference to its neuroanatomic characteristics in rats. First, the effects of electric vagal stimulation on the gastric mucosa were examined. The electric stimulation of the left or right gastric branch of the vagus nerve caused gastric mucosal lesions to develop. Interestingly, however, gastric lesions were found on the anterior wall in the rats that had received electric stimulation to the left gastric branch of the vagus nerve and on the posterior wall in the rats that had received stimulation to the right gastric branch. Next, the cells of origin projecting to the left or right gastric branch of the vagus nerve were identified by means of a horseradish peroxidase retrograde tracer method. The left and right gastric branches were found to be innervated by the left and right dorsal motor nuclei of the vagus nerve in the medulla oblongata, respectively. It has been reported that the left and right dorsal motor nuclei of the vagus nerve separately innervate the anterior or posterior gastric wall. The present results, therefore, suggest that the long-lasting excitation of neurons in the dorsal motor nucleus facilitates the site-specific formation of gastric ulcers through the left or right gastric branch of the vagus nerve.     

Intracisternal thyrotropin-releasing hormone-induced vagally mediated gastric protection against ethanol lesions: Central and peripheral mechanisms

Abstract The vagus is involved in mediating gastric cytoprotection and adaptive cytoprotection. However, the central and peripheral mechanisms through which the vagus expresses its action are still poorly known. Medullary thyrotropin-releasing hormone (TRH) plays an important role in the vagal regulation of gastric function. The stable TRH analogue, RX 77368, micro-injected into the cisterna magna or the dorsal motor nucleus (DMN) of the vagus at a dose that did not influence gastric acid secretion prevented gastric injury induced by intragastric administration of 60% ethanol in conscious or urethane-anaesthetized rats. The cytoprotective action of TRH is mediated through vagal cholinergic release of prostaglandin E₂ (PGE₂). Prostaglandin E₂ action is unrelated to changes in gastric mucosal blood flow (GMBF). In addition, other peripheral mechanisms involve calcitonin gene-related peptide (CGRP) contained in capsaicin sensitive afferent fibres and nitric oxide, both of which mediate the associated increase in GMBF induced by intracisternal injection of RX 77368. These data indicate that medullary TRH induces vagally mediated gastric protection against ethanol lesions. Its action is expressed through the muscarinic dependent release of PGE₂ and nitric oxide, and efferent function of capsaicin-sensitive afferent fibres releasing CGRP.     

Central thyrotropin-releasing factor analog prevents ethanol-induced gastric damage through prostaglandins in rats.

The effects of intracisternal injection of the stable thyrotropin-releasing factor (TRH) analog RX 77368 on gastric lesions induced by 60% ethanol and gastric prostaglandin E2 (PGE2) release were studied in rats. RX 77368 (1.0 and 1.5 ng) injected intracisternally inhibited (by 58% and 78%, respectively) macroscopic gastric damage induced by ethanol. Higher doses (3 and 300 ng) inhibited ethanol-induced gastric injury only in rats pretreated with omeprazole (20 mg/kg SC). Gastric acid output measured in conscious rats 2 hours after pylorus ligation was not modified by intracisternal injection of RX 77368 at 1.5 ng but was significantly increased by 54% at the 3-ng dose. The protective effect of TRH analog (1.5 ng) was completely abolished by indomethacin (5 mg/kg IP) and atropine (2 mg/kg SC) pretreatment. In pylorus-ligated rats, intracisternal RX 77368 (1.5 ng) inhibited ethanol-induced gastric lesions by 64%. Intracisternal injection of RX 77368 (1.5 ng) increased PGE2 levels measured in the effluent of dialysis fibers implanted into the corpus submucosa of urethane-anesthetized rats. Peripheral administration of omeprazole, atropine, indomethacin, or RX 77368 (1.5 ng IV) did not influence gastric damage induced by ethanol. These data show that the stable TRH analog, RX 77368, injected intracisternally at low non-secretory doses acts in the brain to protect against ethanol lesions through prostaglandin and cholinergic pathways. These findings suggest that central vagal activation induced by TRH may play a role in the control of mucosal integrity against ethanol through cholinergic prostaglandin release.     

Central and peripheral vagal mechanisms involved in gastric protection against ethanol injury

Abstract Activation of medullary thyrotropin-releasing hormone (TRH), at a dose subthreshold to increase gastric acid secretion, protects the gastric mucosa against ethanol injury through vagal cholinergic pathways in urethane-anaesthetized rats. Peripheral mediators involve the efferent function of capsaicin-sensitive splanchnic afferents leading to calcitonin gene-related peptide (CGRP)- and nitric oxide (NO)-dependent gastric vasodilatory mechanisms. In addition, gastric prostaglandins participate in gastric protection through mechanisms independent of the stimulation of gastric mucosal blood flow and mucus secretion. Medullary TRH has physiological relevance in the vagal-dependent adaptive gastric protection induced by mild (acid or ethanol), followed by strong, irritants. Additional neuropeptides, namely peptide YY (PYY), somatostatin analogues, CGRP and adrenomedullin, also act in the brainstem to induce a vagal-dependent gastric protection against ethanol through interactions with their specific receptors in the medulla. Central PYY and adrenomedullin act through vagal cholinergic prostaglandins and NO pathways, while somatostatin analogue acts through vagal non-adrenergic, non-cholinergic vasoactive intestinal peptide and NO mechanisms. Although their biological relevance is still to be established, these peptides provide additional tools to investigate the multiple vagal-dependent mechanisms which increase the resistance of the gastric mucosa to injury.     

Role of thyrotropin-releasing hormone in stress ulcer formation in the rat

The role of the hypothalamic peptide thyrotropin-releasing hormone in stress ulcer formation was investigated. In experiment 1, TRH was peripherally administered (10 g/kg) to rats subjected to cold-restraint stress and compared to an inactive peptide; in experiment 2,TRH was administered intracerebroventricularly (0.02, 0.1, and 0.5 g/kg) to rats with no adjunctive experimental stress; in experiment 3, TRH antiserum was given intracerebroventricularly to rats subjected to stress and compared to normal rabbit serum. When TRH was administered subcutaneously in rats subjected to stress, it significantly aggravated ulcer formation, and this effect was inhibited by atropine and vagotomy. When administered intracerebroventricularly, TRH alone induced, in a dose-dependent fashion, the formation of gastric ulcers. TRH antiserum infused intrace-rebroventricularly inhibited ulcer formation induced by cold-restraint stress. In conclusion, TRH seems to play a role in stress ulcer formation, possibly by a cholinergic mediated mechanism.This work was supported in part by grants from the National Research Council and the Ministry of Public Instruction.     

Cold-restraint- and TRH-induced ulcer models demonstrate different biochemical and morphological manifestations in gastric and hepatic tissues in rats

In the present study, two ulcer models—central thyrotropin-releasing hormone (TRH) injection and cold-restraint stress (CRS) application—were compared. Animals were treated either with salmon calcitonin (sCT) or saline intracerebroventricularly (ICV) before CRS exposure or ICV TRH injection. In both models, besides ultrastructural properties, ulcer indexes and lipid peroxidation (LP) and glutathione (GSH) levels of liver and stomach were determined. While TRH treatment did not affect GSH and LP levels of the stomach and led to a slight decrease in hepatic GSH levels. CRS induced a marked reduction in gastric and hepatic GSH and an increase in LP levels of both tissues. sCT pretreatment prevented the reduction of gastric and hepatic GSH levels and morphological damage of both tissues in the CRS group. However, the same treatment did not prevent the TRH-induced reduction of hepatic GSH levels and, interestingly, it worsened the ultrastructural disturbances in the liver. Although sCT prevented macroscopic ulcer formation in both models, it did not totally reverse the microscopic effects of TRH.     

The role of thyrotropin-releasing hormone (TRH) in the pathogenesis of water-immersion stress in rats—inhibition of TRH release from the stomach by atropine,ranitidine or omeprazole—

The role of thyrotropin-releasing hormone (TRH) in the development of gastric erosions and ulcers induced by water-immersion stress was studied. Intraperitoneally administered bethanechol induced a decrease in the gastric wall immunoreactive TRH (ir-TRH) concentrations and an increase in gastric juice ir-TRH concentrations in a dose-related manner, while atropine induced an increase in gastric wall ir-TRH concentrations and a decrease in gastric juice ir-TRH concentrations under non-stress condition. Intraperitoneally administered omeprazole did not influence gastric wall ir-TRH concentrations but elevated gastric pH. Water-immersion stress induced a decrease in gastric wall ir-TRH concentrations and an increase in gastric juice ir-TRH concentrations with a decrease in gastric pH prior to ulcer formation. Pretreatment with atropine or ranitidine inhibited the development of stress ulcers, reduced changes in ir-TRH concentrations in the gastric wall and gastric juice, and induced an increase in gastric pH. Omeprazole inhibited stress ulcer formation and changes in gastric wall and gastric juice ir-TRH concentrations. These results suggest that TRH release from the stomach wall into gastric juice is of importance in the pathogenesis of stress ulcer and that its release is mediated by both muscarinergic and histaminergic (H₂) systems. Furthermore, omeprazole has an inhibitory effect on TRH release under stress ulcer.     

Locations of peptic ulcers in children

The locations of peptic ulcers in children were studied in a total of 55 cases; 19 with gastric ulcers, 31 with duodenal ulcers and 5 with a combination of both. The male children were predominantly affected with these three types. The mean age of the children with gastric ulcers was significantly lower than those with duodenal ulcers (P<0.005). Gastric ulcer was markedly predominant in the antrum, and commonly present in the anterior and posterior walls of the stomach, and infrequently on the greater curvature. Ten of 24 cases (42%) had ulcerations on the anterior wall of the antrum. In seven cases, ulcerations were located on the posterior wall. Duodenal ulcers mostly occurred in the bulb. The anterior and/or posterior walls of the bulb were commonly associated with ulcerations. The present observations concerning gastric and duodenal ulcer location are essentially in agreement with results from adult studies. Perforations were demonstrated in the anterior wall or lesser curvature in both gastric and duodenal ulcers. In five of seven replapse cases, ulcerations had recurred in the same area.     

Vagal hyperactivity in stress induced gastric ulceration in rats

Indirect evidence suggests that stress ulceration is provoked by vagal hyperactivity. However, direct evidence of hypervagal activity during stress conditions is lacking. Experiments were designed to directly measure vagal activity under different stress conditions in rats. Starvation stress for 48 h did not change the mean amplitude of action potentials, but their frequency was significantly decreased. Restraint stress at 22°C increased vagal activity, both amplitude and frequency, in the first 60 min; these responses were markedly enhanced by cold (4°C) and persisted for at least 2 h. Starvation for 48 h did not induce any gastric mucosal lesions. Restraint alone produced petechiae in the gastric mucosa, but cold restraint induced severe haemorrhagic ulcers. It is concluded that cold restraint stress provokes a prolonged vagal hyperactivity, which is one of the causative factors for gastric ulceration.     

Locations of peptic ulcers in children

The locations of peptic ulcers in children were studied in a total of 55 cases; 19 with gastric ulcers, 31 with duodenal ulcers and 5 with a combination of both. The male children were predominantly affected with these three types. The mean age of the children with gastric ulcers was significantly lower than those with duodenal ulcers (P less than 0.005). Gastric ulcer was markedly predominant in the antrum, and commonly present in the anterior and posterior walls of the stomach, and infrequently on the greater curvature. Ten of 24 cases (42%) had ulcerations on the anterior wall of the antrum. In seven cases, ulcerations were located on the posterior wall. Duodenal ulcers mostly occurred in the bulb. The anterior and/or posterior walls of the bulb were commonly associated with ulcerations. The present observations concerning gastric and duodenal ulcer location are essentially in agreement with results from adult studies. Perforations were demonstrated in the anterior wall or lesser curvature in both gastric and duodenal ulcers. In five of seven relapse cases, ulcerations had recurred in the same area.     

Gastric ulcer formation induced by kainic acid injection into the dorsal motor nucleus of the vagus nerve (DMN) and identification of the neuronal input to the DMN in rats

Parasympathetic preganglionic cells innervating the stomach are located in the dorsal motor nucleus of the vagus nerve (DMN) in the medulla. The present experiments were carried out to elucidate that the long-lasting excitation of DMN neurons by kainic acid, a long-acting neuronal excitant, induced gastric ulcers and to identify the input neuronal systems projecting to the DMN by means of horseradish peroxidase (HRP) method in rats. Twenty four hours after kainic acid injection into the DMN, gastric ulcerative lesions were induced in 12 out of 14 rats. The ulcer index in experimental group, 10.2 +/- 6.5 mm, was significantly higher than that in the control group, 0.5 +/- 1.0. Mucus content in gastric mucosa was significantly lower than that of the control group. Fourty four hours after HRP injection into the DMN, HRP labeled cells were distributed from medulla to cortex, especially in medullary reticular formation, interpositis cerebellar nucleus, several hypothalamic nuclei, central amygdala nucleus and insular cortex. These results suggest that long-lasting excitation of DMN neurons facilitate gastric ulcer formation and that a decrease in mucus content in gastric mucosa plays an important role in the process of gastric ulcer formation by kainic acid injection into the DMN. Since the cortex, amygdala and hypothalamus has been shown to be closely associated with emotion and stress, it could be speculated that emotional changes and stress might induce the changes of excitability of DMN neurons via higher order neuronal systems.     

Effects of free radical scavengers on indomethacin-induced aggravation of gastric ulcer in rats

Effects of treatment with free radical scavengers in the healing process of acetic acid-induced gastric ulcer on the ulcer aggravation induced by indomethacin were investigated. Gastric ulcers were produced on the anterior wall of the stomach of male Sprague-Dawley rats by submucosal injection of 20% acetic acid. To investigate the role of oxygen radicals, rats with gastric ulcer were treated with scavengers for six weeks and then treated with indomethacin (1 mg/kg/day). While superoxide dismutase (10,000 units/kg/day) did not affect the ulcer area after indomethacin treatment, allopurinol (50 mg/kg/day) slightly inhibited the increase in ulcer area. Dimethyl sulfoxide (1% solution,ad libitum) produced a significant decrease in size of the ulcer after indomethacin treatment. Increased lipid peroxides in the gastric mucosa after indomethacin treatment decreased significantly in the rats of the dimethyl sulfoxide and allopurinol groups. These results indicate that lipid peroxidation mediated by oxygen radicals plays an important role in the mechanism of ulcer aggravation induced by indomethacin.     

Thyrotropin-releasing hormone in the dorsal vagal complex stimulates hepatic blood flow in rats

Central administration of thyrotropin-releasing hormone (TRH) enhances hepatic blood flow in animal models. TRH nerve fibers and receptors are localized in the dorsal vagal complex (DVC), and retrograde tracing techniques have shown that hepatic vagal nerves arise mainly from the left DVC. However, nothing is known about the central sites of action for TRH to elicit the stimulation of hepatic blood flow. The effect of microinjection of a TRH analogue into the DVC on hepatic blood flow was investigated in urethane-anesthetized rats. After measuring basal flow, a stable TRH analogue (RX-77368) was microinjected into the DVC and hepatic blood flow response was observed for 120 minutes by laser Doppler flowmetry. Either left or right cervical vagotomy or hepatic branch vagotomy was performed 2 hours before the peptide. Microinjection of RX-77368 (0.5-5 ng) into the left DVC dose-dependently increased hepatic blood flow. The stimulation of hepatic blood flow by RX-77368 microinjection into the left DVC was eliminated by left cervical and hepatic branch vagotomy but not by right cervical vagotomy. By contrast, microinjection of RX-77368 into the right DVC did not significantly alter hepatic blood flow. These results suggest that TRH acts in the left DVC to stimulate hepatic blood flow through the left cervical and hepatic vagus, indicating that neuropeptides may act in the specific brain nuclei to regulate hepatic function.     

Gastric antisecretory and antiulcer effects of simvastatin in rats

BACKGROUND AND AIM: Recently, statins have appeared to have additional benefits beyond their lipid lowering effects, which has led to the interest in the use of this class of drugs outside the realm of cardiovascular disease. Simvastatin (SIM) is a commonly prescribed statin with anti-inflammatory and antioxidant properties. Excessive generation of oxygen-derived free radicals (ODFR) and proinflammatory mediators has been implicated in the pathogenesis of gastric ulcers. This investigation aimed to study the effect of SIM on experimentally induced gastric acid secretion and ulcer formation. METHODS: Adult Wistar rats were divided into experimental groups containing six animals. Acid secretion studies were undertaken using pylorus-ligated rats pretreated with SIM (20, 40, and 60 mg/kg). The effect of orally administered SIM was also studied on indomethacin- and ethanol-induced gastric ulcers. The levels of myeloperoxidase (MPO), non-protein sulfhydryls (NP-SH), nitric oxide (NO), antioxidant enzymes, and gastric wall mucus were measured in the glandular stomach of rats following ethanol-induced gastric lesions. RESULTS: Administration of SIM significantly and dose-dependently inhibited the volume of gastric secretion and the acidity. Pretreatment with SIM significantly reduced the formation of indomethacin- and ethanol-induced gastric lesions. The antiulcer activity of SIM was associated with significant attenuation of adverse effects of ethanol on gastric wall mucus, NP-SH and MPO. SIM modified the gastric NO levels and reversed the ethanol-induced decrease in glutathione-S-transferase and increase in superoxide dismutase and catalase. CONCLUSIONS: These findings clearly suggest the involvement of proinflammatory agents and ODFR in the pathogenesis of gastric lesions. The gastroprotective effects of SIM are mediated by inhibition of neutrophils activity, reduction of oxidative stress, and maintenance of vascular integrity. This study was conducted in rats; its relevance to human gastric ulcers is not known and warrants further study.     

Intraluminal thyrotropin-releasing hormone affects gastric somatostatin and acid secretion through its specific receptor in rats

BACKGROUND: Although thyrotropin-releasing hormone (TRH) is present in the gastric mucosa and juice, the pathophysiologic significance of TRH is poorly understood at the peripheral level of the stomach. In the present study we analyzed the TRH-induced secretion profiles of somatostatin, histamine, and acid in the rat stomach. METHODS: The effects of intraluminal perfusion of TRH on somatostatin, histamine, and acid and the influence of the specific anti-TRH receptor antibody were investigated by using the rat gastric intraluminal perfusion model. RESULTS: Intraluminal TRH caused an immediate decrease in somatostatin secretion in a dose-dependent manner, and this change occurred preceding an increase in acid secretion. In contrast, this treatment did not yield any significant changes in histamine contents in the effluent. Pretreatment of the gastric lumen with the anti-TRH receptor antibody caused a complete inhibition of TRH-induced changes in somatostatin and acid secretion. CONCLUSIONS: These findings suggest that intraluminal TRH affects somatostatin and acid secretion in a paracrine manner via its specific receptor in the rat stomach.     

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 increases 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.     

Medullary sites of action of the TRH analogue, RX 77368, for stimulation of gastric acid secretion in the rat

Brain and spinal sites of action of the stable thyrotropin-releasing hormone (TRH) analogue, RX 77368 [pGlu-His-(3,3'-dimethyl)-Pro-NH2], for stimulation of gastric acid secretion have been investigated in urethane-anesthetized rats with gastric fistula. RX 77368 microinjected at a 7.7-pmol dose into the dorsal vagal complex or nucleus ambiguus stimulated gastric acid secretion to 62.2 +/- 15.9 and 45.3 +/- 14.3 mumol/h, respectively, whereas in the vehicle-treated group acid secretion was 0.5 +/- 1.0 mumol/h. A 10-fold higher dose of RX 77368 was inefficient when microinjected into the medial septum, central amygdala, or lateral hypothalamus. The gastric secretory response to microinjection of RX 77368 into the nucleus ambiguus was dose related (0.7-77 pmol), long-lasting (greater than 90 min), and blocked by vagotomy. TRH (144 pmol) injected into the nucleus ambiguus also stimulated gastric acid secretion but was less potent than the stable TRH analogue, whereas the unrelated peptide, oxytocin, was inactive. Intrathecal injection of RX 77368 at doses up to 2500 pmol did not modify gastric acid secretion. These results demonstrate that the dorsal vagal complex and nucleus ambiguus are TRH sites of action for stimulation of gastric acid secretion through vagal dependent pathways. These findings, added to the high concentrations of TRH-like immunoreactivity and receptors present in these nuclei, suggest a possible role of medullary TRH in the vagal regulation of gastric acid secretion.     

Influence of the site of a duodenal ulcer on its subsequent course

The aim of this study was to determine if the site of a duodenal ulcer influences its subsequent course. Three hundred and eighteen duodenal ulcer patients diagnosed by endoscopy in Sydney were studied. The ulcer was situated on the anterior wall of the bulb in 49% and the posterior wall of the bulb in 23%. These patients were followed up until symptoms recurred or for 1–2 years. The risk of symptom recurrence was unaffected by the site of the index ulcer, occurring in 129 of 157 patients with anterior wall ulcer (82%), 56 of 72 patients with posterior wall ulcers (78%), and 27 of 32 patients with anterior and posterior wall ulcers (84%). Sixty-four patients were endoscoped within 1 month of recurrence of ulcer-like symptoms and active ulcer craters were demonstrated in 49 (77%).     

Carcinogenic Action of 2,7-Diacetylaminofluorene on the Stomach of Rats with Experimental Gastric Ulcer

Penetrating ulcers of gastric glandular mucosa were produced in male Buffalo rats by thermocautery. These rats, and uninjured control animals, were fed with a diet containing a known carcinogen, 2,7 diacetylaminofluorene (2,7-DAAF). The purpose of this study was to find whether the presence of gastric ulcer will enhance the incidence of gastric carcinoma. In 14% of rats in which gastric ulcers were associated with the exposure to oral carcinogen, gastric adenocarcinomas were found. No gastric tumors were diagnosed in rats having uninjured gastric mucosas prior to the ingestion of carcinogen. It is concluded that the contact of chemical carcinogen 2,7-DAAF with injured, healing gastric mucosa, enhanced the malignant transformation of gastric cellular elements. Under the conditions of this experiment, the presence of gastric ulcer contributed to the appearance of gastric adenocarcinoma.     

Central nervous system action of thyrotropin-releasing hormone to increase gastric mucosal blood flow in the rat

The central nervous system effects of thyrotropin-releasing hormone (TRH) on gastric acid secretion and mucosal blood flow were studied in rats. Corpus mucosal blood flow was measured by the hydrogen gas clearance technique and acid output by a continuous gastric perfusion method in fasted, urethane-anesthetized rats. Thyrotropin-releasing hormone (1 or 5 micrograms) injected into the cerebral lateral ventricle induced concomitant increases in gastric acid secretion and mucosal blood flow. Intravenous infusion of step doses of TRH (60 and 180 micrograms/kg.h) had no effect on these parameters. Bilateral vagotomy and atropine (0.15 mg/kg) completely blocked the effects of intracerebroventricular injection of TRH (5 micrograms) on gastric acid secretion and mucosal blood flow. In contrast, intravenous omeprazole (20 mumol/kg) completely inhibited the increase in gastric acid secretion but not the increase in mucosal blood flow elicited by intracerebroventricular administration of TRH (5 micrograms). These results demonstrate that TRH acts in the brain to stimulate gastric acid secretion and mucosal blood flow through vagal dependent pathways and peripheral muscarinic receptors. Part of the effect of central TRH on gastric mucosal blood flow is not secondary to the stimulation of acid secretion and appears to represent a direct cholinergic vasodilatory response.