L. Nagy

Stimulation of capsaicin-sensitive sensory peripheral nerves with topically applied resiniferatoxin decreases salicylate-induced gastric H+ back-diffusion in the rat

Capsaicin-sensitive sensory nerves (CSSN) exert local protective functions in the stomach and have been proposed to regulate gastric H+ back-diffusion. The present study aimed to evaluate the possible influence of stimulation of CSSN with the intragastrically (ig) applied capsaicin analogue, resiniferatoxin (RTX), on gastric H+ back-diffusion and mucosal injury caused by ig application of HCl (2 ml 0.15 mol/L) or acidified salicylate (200 mg/kg in 2 ml 0.15 mol/L HCl) after 1 or 2 h in the pylorus-ligated rat. Stimulation of CSSN with a low concentration (0.04 µg/ml) of RTX markedly decreased H+ back-diffusion caused by acidified salicylate. After acute bilateral truncal vagotomy or treatment with atropine sulphate, RTX did not inhibit gastric acid back-diffusion. Surgical vagotomy alone increased, while RTX or atropine markedly diminished, the development of gastric mucosal injury in these models. In saline-treated rats, RTX significantly reduced gastric secretory volume and acid output. The inhibitory effect lasted for 1 h. These data suggest an essential role for CSSN in regulation of gastric acid secretion and in maintaining the integrity of the gastric mucosa that appear to depend on intact vagal nerves.

Interrelationships between membrane-bound ATP-dependent energy systems,gastric mucosal damage produced by NaOH,hypertonic NaCl, HC1, and alcohol, and prostacyclin-induced gastric cytoprotection in rats

Rat gastric mucosal lesions (ulcers) were produced by topical application of 0.2 M NaOH, 25% NaCl, 0.6 M HCl and 96% ethanol. The animals were sacrificed 1 hr after administration of the different necrotizing agents. The number of gastric lesions (ulcers) was noted and their severities scored. Different doses (5 and 50 micrograms.kg-1) of prostacyclin (PGI2) were given intraperitoneally at 30 minutes before administration of necrotizing agents, and their effects were studied on the number and severity of gastric lesions (ulcers). At the time of killing of animals, the rat gastric fundic mucosa was removed for biochemical examinations. Tissue levels of adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP) and lactate were determined enzymatically, while the tissue content of cyclic adenosine monophosphate (cAMP) was measured by radioimmunoassay. The values of the adenylate pool (ATP + ADP + AMP), the ratio of ATP X ADP-1 and the energy charge (ATP + 0.5 ADP X ATP + ADP + AMP-1) were calculated. All biochemical results were calculated in relation to one mg mucosal protein. It was found that:1. the tissue levels of ATP, cAMP, AMP decreased significantly, while the tissue level of ADP increased (without statistical significance) in all models, during the development of gastric mucosal damage; 2. the tissue level of lactate increased only in the model produced by 0.6 M HCl, while its level was unchanged in the other models during the development of gastric mucosal damage; 3. PGI2 decreased dose-dependently the number and severity of gastric lesions (ulcers); 4. the tissue level of ATP, ratio of ATP X ADP-1 and energy charge were decreased significantly, while the tissue level of ADP was increased significantly by PGI2 in all models; 5. the tissue level of lactate and the adenylate pool remained unchanged during the PGI2 effects. It was concluded that: 1. the development of gastric mucosal damage, produced by topical application of 0.2 M NaOH, 25% NaCl, 0.6 M HCl and 96% ethanol, is associated with an active metabolic adaptation of the gastric fundic mucosa; 2. the metabolic adaptation of the rat gastric fundic mucosa is further increased by PGI2, without resulting in hypoxaemic damage of the gastric mucosa; 3. the feed-back mechanism system - between the membrane-bound ATP-dependent energy systems - is broken during the development of gastric mucosal damage produced by different necrotizing agents, which is modified further by PGI2 at the time of gastric cytoprotection.(ABSTRACT TRUNCATED AT 400 WORDS)

Direct cellular effects of some mediators, hormones and growth factor-like agents on denervated (isolated) rat gastric mucosal cells

The brain-gut axis has an important role in the mechanism of gastric cytoprotection in vivo. The aim of this study was to evaluate the in vitro effect of protective agents without any central and peripheral innervation. A mixed population of rat gastric mucosal cells was isolated by the method of Nagy et al (Gastroenterology (1994) 77, 433-443). Cells were incubated for 60 min with cytoprotective drugs such as prostacyclin, histamine, pentagastrin and PL-10 substances (synthesized parts of BPC). At the end of this incubation cells were treated by 15% ethanol for 5 min. Cell viability was tested by trypan blue exclusion test and succinic dehydrogenase activity. The following results were obtained: 1) prostacyclin, histamine and pentagastrin had no direct cytoprotective effect on isolated cells; and 2) PL-10 substances significantly protected the cells against ethanol-induced cellular damage. This led to the following conclusions: 1) in the phenomenon of gastric cytoprotection only the growth factor-like agents have a direct cellular effect; and 2) the intact peripheral innervation is basically necessary for the development of mediators and hormone-induced gastric cytoprotection.

H+ secretion and Na+ -K+-dependent ATPase system in the human gastric mucosa

Es wurde bei Untersuchungen an 45 Patienten eine positive und mathematisch signifikante Korrelation zwischen der H+ Sekretion under Aktivitätsgrösse der ATPase von Membrane der Fundusschleimhaut gefunden.

GASTRIC AND SMALL INTESTINAL ENERGY METABOLISM IN MUCOSAL DAMAGE

Publisher Summary This chapter discusses gastric and small intestinal energy metabolism in mucosal damage. The results of the biochemical examinations carried out in the control and in the damaged mucosa specimens give a cross-section biochemically of the tissue metabolism. Accepting these arguments, a good selection of the biochemical methods must be done, which are suitable ones to approach the main lines of tissue metabolism. The well-controlled equilibrium, between the energy systems, is broken by different noxious agents in pathological circumstances. The extreme increase of ATP breakdown into ADP by membrane ATPase represents an aggressive situation to produce mucosal damages in the models. In the gastric mucosal damages, by immobilization and by swimming, the extent of ATP transformation to cAMP increases significantly. These changes of energy systems are valid in relation to development of acute gastric mucosal damages.

Interrelationships between the Gastric Secretory Responses, Prostaglandin E2 Inhibition and Serum Level of Immunoreactive Gastrin in Pylorus-Ligated and Antrectomized Rats

The effects of prostaglandin E2 (PGE2) have been studied on the gastric secretion and the serum level of immunoreactive gastrin in pylorus-ligated and antrectomized rats. It has been observed that: (1) a significant inhibition of gastric secretion (volume and acid output) was caused by PGE2, applied in doses of 75, 150 and 300 microgram/kg body weight, subcutaneously, in both pylorus-occluded and antrectomized rats: PGE2 inhibition of gastric secretion was more pronounced in rats with antrectomy; (2) no significant changes were found in the serum gastrin levels of both pylorus-ligated and antrectomized rats, and (3) no significant changes in serum levels of immunoreactive gastrin were produced by different doses of PGE2, in comparison with their marked inhibitory effects on gastric H+ secretion. It was concluded that there is no essential role of the immunoreactive gastrin, originated from the antral part of the stomach, neither in development of gastric hypersecretion nor in PGE2-produced inhibition on gastric secretion of the pylorus-occluded rats.

Role of the Vagal Nerve in the Development of Gastric Mucosal Injury and its Prevention by Atropine, Cimetidine, β-Carotene and Prostacyclin in Rats

Peptic ulceration including acute erosions is a multifactorial disease involving well-known factors such as trauma, stress, sepsis, hemorrhagic shock, burns, pulmonary and liver diseases1–9 and drugs such as reserpine10, epinephrine11–13, nonsteroidal antiinflammatory drugs7, steroids and other chemicals14.

Role of Vagal Nerve in Defence Mechanisms against NSAID-Induced Gastrointestinal Mucosal Damage

Many papers suggested only an aggressive role of the vagus nerve on the gastrointestinal (GI) mucosa; however, the essential role of the vagus nerve was proven in GI mucosal defence against different chemicals, e.g., ethanol, HCl, non-steroidal anti-inflammatory drugs (NSAIDs). In order to evaluate the role of the vagus nerve in the development of GI mucosal damage evoked in the rat by the administration of NSAIDs, the present studies were designed to: (1) compare the changes in the NSAID-induced GI mucosal damage after acute surgical and chemical (atropine treatment) vagotomy; (2) investigate the effect of sensory nerve stimulation and chemical deafferentation on the NSAID-induced gastric mucosal damage; (3) evaluate the cytoprotective action of prostacyclin under the above experimental conditions; (4) study the effect of surgical vagotomy on the gastroprotection induced by different drugs.Gastric mucosal damage was produced by intragastrically (acidified salicylates) or systemically (indomethacin) applied NSAIDs, while the small intestinal and large bowel mucosal injury was produced by systemic indomethacin application.Results(1) acute surgical vagotomy aggravated, whereas, chemical vagotomy prevented the GI mucosal damage produced by topically and systemically applied NSAIDs; (2) indomethacin produced significantly more damage in the small intestine than in the large bowel and stomach (order is small intestine > stomach > proximal colon) which is aggravated by acute surgical vagotomy in all these areas of the GI tract; (3) stimulation of capsaicin-sensitive sensory nerves with the capsaicin analogue resiniferatoxin protected against gastric mucosal damage by acidified salicylates and indomethacin; (4) chemical deafferentation enhanced the aspirin-induced gastric mucosal injury, while it did not interfere with the prostacyclin-induced gastric cytoprotection; (5) the mucosal protective effects of PGI2, atropine, cimetidine, sucralfate and scavengers (β-carotene) disappeared after acute surgical vagotomy.

FEED-BACK MECHANISM SYSTEMS BETWEEN THE ATP–ADENYLATE CYCLASE–cAMP AND ATP–Na+–K+-DEPENDENT ATP-ASE–ADP IN THE RAT AND HUMAN GASTRIC FUNDIC MUCOSA IN RELATION TO GASTRIC ACID SECRETION

Publisher Summary This chapter examines the feedback mechanism systems between the ATP-adenylate cyclase-cAMP and ATP–Na+–K+-dependent ATP–ASE–ADP in the rat and human gastric fundic mucosa in relation to gastric acid secretion. In a study described in the chapter, the observations were carried out in the gastric fundic mucosa of rats and humans who underwent gastric resection because of peptic ulceration. The gastric hypersecretion is developed by pyloric ligation of rats. This method is widely used by gastroenterologists and pharmacologists to study the developmental mechanisms of gastric hypersecretion and of gastric ulceration. The pyloric ligation was carried out on rats, and the gastric secretory responses were studied simultaneously with the changes of biochemical constituents of gastric fundic mucosa. The tissue levels of adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP), and cyclic adenosine monophosphate (cAMP) were determined. The Mg2+-dependent and Na+–K+-dependent ATPases were separated from the gastric mucosa by treatment of NaI and by separating centrifugation. The results showed that the gastric H+ secretion increases in the first 7 h, which remains at the same level after that time. The mucosal level of ATP significantly decreases at 4 h after pyloric ligation, while it increases gradually to 7 h, thereafter decreasing gradually.

ROLE OF THE FUNCTIONAL STATE OF THE GASTRIC MUCOSA IN RELATION TO DEVELOPMENT OF EPINEPHRINE EFFECTS ON RAT STOMACH

Publisher Summary The pathogenesis of peptic ulcer is a controversial subject. It is controversial partly because its causes are unknown, its etiology is only poorly understood, and the accumulated evidence suggests a complex, multifactorial pathogenesis. In the last few years, many papers dealt with the role of the sympathetic nervous system and catecholamines on gastric secretion, gastric mucosal circulation, and ulcer formation. This chapter discusses the role of the functional state of the gastric mucosa in relation to development of epinephrine effects on rat stomach. Acute gastric mucosal lesions and hemorrhages frequently occur in patients and experimental animals under various stress situations and after administration of ulcerogenic drugs. It is known that the activity of the membrane ATPase, prepared from gastric mucosa is significantly decreased by epinephrine.