Stress-induced Gastric Ulcers In Rats Research Articles

Paracetamol potentiates stress-induced gastric ulceration in rats

The effect of paracetamol on gastric ulcers produced by restraint at 4 degrees C for 2 h (stress) was studied in rats. Paracetamol treatment s.c. or p.o., with a dose as high as 250 mg kg-1, did not produce any haemorrhagic lesions in the glandular mucosa. Oral administration with 250 mg kg-1, however, significantly reduced the mast cell count in the gastric glandular mucosa and potentiated haemorrhagic ulceration but not mast cell degranulation caused by stress. The potentiating action was maximum when paracetamol was given between 15 and 30 min before stress. Ranitidine, astemizole, dimethylsulphoxide, sucralfate and verapamil did not protect against the adverse action of paracetamol on stress-evoked lesions. This study suggests that paracetamol worsens stress-induced stomach ulceration by an action which appears not to be due to histamine release, free radical production or intracellular calcium disturbance in the gastric mucosa.

The protective mechanism of FPL55712 against stress-induced gastric ulceration in rats.

Cold-restraint stress produced stomach ulceration which was accompanied by a decreased glandular mucosal mast cell count and blood flow. Pretreatment with FPL55712, a leukotriene antagonist, dose-dependently prevented ulcer formation and mast cell depletion; however, it did not affect the reduced mucosal blood flow, nor did it significantly influence acid secretion and pepsin output. The role of the leukotrienes in stress ulceration is discussed in the light of the findings with FPL55712 on gastric glandular mucosal mast cell degranulation.

Pathogenesis of water-immersion stress-induced gastric ulcers in rats with renal failure.

Rats with or without renal failure, produced by uranyl acetate, were subjected to water-immersion stress for 6 h. The severity of stress-induced gastric ulcers in the renal failure group was significantly higher than that in the control group. The intragastric pH did not significantly differ between the two groups. Transmucosal electrical potential difference, gastric mucosal blood flow, and gastric mucosal hexosamine content in the renal failure group were significantly lower than in the control group. These results suggest that decreases in defensive factors, rather than an increase in an aggressive factor, may be more closely involved in the development of acute gastric ulcers in rats with renal failure.

Zinc deficiency: Its role in gastric secretion and stress-induced gastric ulceration in rats

The effects of zinc deficiency on gastric secretion and on cold-restraint stress-induced ulceration in rat stomachs have been studied. Administration of graded zinc deficient diets for 5 weeks significantly depressed the serum zinc concentration and decreased body weight gain in the rats. These diets significantly increased the gastric secretory volume, acid and pepsin. Zinc deficiency produced or aggravated the formation of glandular ulceration in the absence or presence of stress, respectively; it also decreased the mast cell count in the gastric glandular mucosa. It is concluded that zinc deficiency adversely affects the rats by reducing the body weight gain and producing ulceration which is probably mast cell-mediated. On the other hand, it increases gastric secretory functions.

L-Deprenyl attenuates stress ulcer formation in rats

Both intraperitoneal and intracerebroventricular (i.c.v.) administration of the monoamine oxidase-B inhibitor l-deprenyl markedly attenuated restraint stress-induced gastric ulcers in rats. l-Deprenyl given i.c.v. attenuated stress ulcers in microgram doses and virtually abolished ulcer formation at a dose of 2.0 μg. These data suggest that intact or augmented central dopaminergic function may be an essential component of gastric mucosal protection.

The effects of sulindac and its metabolites on acute stress-induced gastric ulcers in rats

Rats were given a single intragastric administration of the prodrug sulindac (4.0 mg/kg) or its sulfide (1.0, 2.0, 4.0, or 8.0 mg/kg) or sulfone (1.0, 2.0, 4.0, or 8.0 mg/kg) metabolites and were then subjected to acute stress in the form of immobilization for 3 hr in a cold environment. Control rats received an equal volume of propylene glycol vehicle or nothing po. Other rats received 200 mg/kg acetylsalicylic acid (ASA) with or without stress, to compare the gastrointestinal effects of sulindac metabolites with those of a known non-steroidal anti-inflammatory agent. The sulfide metabolite exacerbated stress-induced gastric glandular ulcer incidence and severity in a dose-related manner relative to all groups except the ASA-stress group, which exhibited the greatest amount of gastric damage. The sulfone metabolite did not potentiate ulcer incidence or severity beyond control (stress only) levels at lower doses. However, at 4.0 and 8.0 mg/kg, the observed ulceration was greater than that seen in stressed but otherwise untreated animals. Sulindac, vehicle, and otherwise untreated rats exhibited a similar degree of stress-induced gastric damage. It appears that the prodrug does not significantly enhance stress-related gut disease, but that the active sulfide metabolite does. Although the clinical literature suggests that the sulfone metabolite is inactive, the present results suggest otherwise. While this metabolite did not, by itself, induce gastric damage at higher doses, sulfone did exacerbate stress ulcer formation. This is the only report of which we are aware, indicating a possible toxic effect of the sulfone metabolite.

Interactions amongst factors which influence severity of gastric ulceration in rats

A number of factors have previously been demonstrated to influence the severity of stress-induced gastric ulceration in rats, including prior exposure to pre-shock and allowing animals a post-stress rest or recovery period. The primary purpose of this experiment was to investigate how one of these factors might modulate the expression of the other. Animals were pre-exposed to either signalled or unsignalled shock (using “learned helplessness” parameters), or no shock. They were later subjected to 2 hours restraint-in-water (immersion) stress, or appropriate handling control procedures. Half of the animals were sacrificed immediately on removal from the water-restraint, and half were sacrificed after a 2 hour recovery period in their home cages. Analysis of the severity and number of glandular stomach lesions indicated that animals subjected to the pre-shock exhibited greater ulceration than unshocked animals, as long as no post-stress rest period was allowed. Additionally, the effect of post-stress rest was masked by experience with pre-shock. This reciprocal modulation of treatment influences may offer suggestions for understanding discrepancies in the literature on the effects of these two modulating variables.

Role of brain neurotransmitters on neurotensin-induced gastric cytoprotection

We have reported previously that intracisternal (IC) administration of neurotensin (NT) prevents stress-induced gastric ulcers in rats. This effect of NT appears to be mediated by the central nervous system because peripheral (IV) NT is totally ineffective. The present study sought to clarify the central mechanism of the cytoprotective effect of NT by utilizing pharmacological treatments which alter the function of brain neurotransmitter systems. Pretreatment with intracerebroventricular (ICV) administration of agonists and antagonists of acetylcholine (ACh), γ-aminobutyric acid (GABA), and serotonin (5-HT) receptors or with an anti-opiate (naloxone) agent did not significantly alter NT-induced cytoprotection. However, pre-treatment with ICV haloperidol, a dopamine (DA) receptor antagonist, totally blocked NT's cytoprotective effect. In addition, pretreatment with methylphenidate, a DA receptor agonist, produced cytoprotection similar to IC NT. These data indicate that NT-induced cytoprotection is not mediated by 5-HT, GABA, ACh (muscarinic) receptors, or endogenous opiate systems, but suggest interactions between brain DA systems and NT.

Effect of elcatonin on experimental gastric and duodenal ulcers.

The antiulcer action of elcatonin, an analogue of natural eel calcitonin, was compared with that of cimetidine, secretin and solcoseryl. Elcatonin (3 to 10 mu/kg, s.c.) inhibited the development of gastric ulcers induced by pylorus ligation, water-immersion stress, aspirin and reserpine and duodenal ulcers induced by cysteamine in rats. Moreover, once daily injections of elcatonin (1 to 10 mu/kg/day, s.c.) promoted the healing of acetic acid-induced chronic gastric ulcers not only in rats but in dogs. The healing effect persisted after the cessation of administrations. Cimetidine (30 to 100 mg/kg, p.o.) inhibited the development of gastric ulcers induced by water-immersion stress, aspirin and reserpine and duodenal ulcers induced by cysteamine in rats. However, once daily administrations of cimetidine (30 to 100 mg/kg/day, p.o.) did not show significant effect on acetic acid-induced chronic gastric ulcers in rats. Secretin (30 to 100 mu/kg, s.c.) inhibited the development of gastric ulcers induced by pylorus ligation, water-immersion stress, aspirin and reserpine in rats, but was not effective on cysteamine-induced duodenal ulcers and acetic acid-induced chronic gastric ulcers in rats. Solcoseryl (2 ml/kg, s.c.) inhibited only the development of water-immersion stress-induced gastric ulcers in rats. These results suggest that elcatonin is different from these reference drugs in its properties of action on experimental ulcers. Mechanisms of the antiulcer action of elcatonin which has a superior effect on experimental ulcers are discussed.

Effect of Elcatonin on Experimental Gastric and Duodenal Ulcers

The antiulcer action of elcatonin, an analogue of natural eel calcitonin, was compared with that of cimetidine, secretin and solcoseryl. Elcatonin (3 to 10 u/kg, s.c.) inhibited the development of gastric ulcers induced by pylorus ligation, water-immersion stress, aspirin and reserpine and duodenal ulcers induced by cysteamine in rats. Moreover, once daily injections of elcatonin (1 to 10 u/kg/day, s.c.) promoted the healing of acetic acid-induced chronic gastric ulcers not only in rats but in dogs. The healing effect persisted after the cessation of administrations. Cimetidine (30 to 100 mg/kg, p.o.) inhibited the development of gastric ulcers induced by water-immersion stress, aspirin and reserpine and duodenal ulcers induced by cysteamine in rats. However, once daily administrations of cimetidine (30 to 100 mg/kg/day, p.o.) d>d not show significant effect on acetic acid-induced chronic gastric ulcers in rats. Secretin (30 to 100 u/kg, s.c.) inhibited the development of gastric ulcers induced by pylorus ligation, water-immersion stress, aspirin and reserpine in rats, but was not effective on cysteamine-induced duodenal ulcers and acetic acid-induced chronic gastric ulcers in rats. Solcoseryl (2 ml/kg, s.c.) inhibited only the development of water-immersion stress-induced gastric ulcers in rats. These results suggest that elcatonin is different from these reference drugs in its properties of action on experimental ulcers. Mechanisms of the antiulcer action of elcatonin which has a superior effect on experimental ulcers are discussed.

Role of the autonomic nervous system in the cytoprotective effect of neurotensin against gastric stress ulcers in rats

Pharmacologic agents were used to study the role of the autonomic nervous system in the cytoprotection produced by intracisternal neurotensin against cold plus restraint stress-induced gastric ulcers in rats. Drugs which stimulated α- or β-adrenergic receptors or blocked muscarinic cholinergic receptors reduced the incidence of ulcers to a similar degree as intracisternal neurotensin; α-adrenergic or β-adrenergic blockade as well as cholinergic stimulation prevented neurotensin's beneficial effect. However, pretreatment with indomethacin blocked only the cytoprotective effect of neurotensin or β-adrenergic stimulation, but not that of muscarinic cholinergic blockade. In addition, pretreatment with reserpine or guanethidine also was effective in preventing cytoprotection by intracisternal neurotensin. These data indicate that the mechanism for cytoprotection by centrally administered neurotensin is mediated at least in part through activation of the sympathetic nervous system. This activation by neurotensin appears to produce cytoprotection by stimulation of gastric mucosal prostaglandin synthesis.

The role of the adrenal gland in cytoprotection against stress-induced gastric ulcers in rats.

Subcutaneous treatment with either prednisone or isoproterenol significantly prevented the development of cold plus restraint stress (CRS)-induced gastric ulcers in rats. The effect of each agent was dose-dependent. Bilateral adrenalectomy prevented isoproterenol, but not prednisone-induced gastric cytoprotection. However, prednisone (1 mg/kg X 5 days) restored the ability of isoproterenol to afford cytoprotection in adrenalectomized rats. Finally, inhibition of prostaglandin synthesis with indomethacin (5 mg/kg) totally abolished the cytoprotective response to both prednisone and isoproterenol in this CRS model. These results indicate that glucocorticoids modulate the cytoprotective effect of adrenal catecholamines, and that both adrenal glucocorticoids and catecholamines require an intact prostaglandin synthetic pathway for expression of their cytoprotective properties.

Cytoprotective effect of centrally administered neurotensin on stress-induced gastric ulcers.

Neurotensin, a peptide common to brain and gastrointestinal tissue, has been reported common to brain and gastrointestinal tissue, has been reported to inhibit both gastric acid secretion and gastric mucosal blood flow after central nervous system administration in rats. Therefore, the effect of intracisternal neurotensin on the development of gastric ulcers induced by cold-plus-restraint stress in the rat was studied. Following intracisternal injection, neurotensin (20-30 micrograms) significantly inhibited the development of gastric ulcers in this model. This effect was shown to be both dose related and route specific, inasmuch as neither lower doses of intracisternal neurotensin nor intravenous neurotensin were cytoprotective. In addition, potential actions of central neurotensin that may have mediated this beneficial effect were tested by administering somatostatin or oxotremorine intracisternally and cimetidine or haloperidol intraperitoneally. In contrast to intracisternal neurotensin, none of these substances reduced the incidence of gastric ulcers in this model. This was true despite the fact that cimetidine, but not neurotensin, significantly increased gastric pH. Finally, when cold-plus-restraint-stressed rats were pretreated with indomethacin, an inhibitor of prostaglandin synthesis, the cytoprotective effect of neurotensin was completely abolished. These results suggest that intracisternal neurotensin exerts a significant cytoprotective effect for stress-induced gastric ulcers in rats. This effect, which is mediated by the central nervous system, does not appear to be related to changes in body temperature, neuroleptic-like properties, or gastric acid secretion but requires an intact prostaglandin synthetic pathway.

Prevention of stress ulcer by cimetidine and somatostatin in rats.

In experiments on live animals we have examined to what extent prophylactic applications of cimetidine and somatostatin are able to prevent stress-induced ulcer in the rat. 130 male Wistar strain rats were exposed to a combined immobilisation-immersion stress, cimetidine was given subcutaneously and somatostatin as a continuous intraperitoneal infusion. Results show that cimetidine produces no change in the average ulceration index (U.I.), nor in the transmural potential (P.D.). However, somatostatin significantly lowers the incidence rate of stress-induced gastric ulcers in rats.

Prevention of chemically induced adrenal hemorrhage and lung injury by somatostatin in the rat

Cysteamine and propionitrile were the first members of a group of compounds shown to produce consistently acute and chronic duodenal ulcers and adrenocortical necrosis in rats. 1 The ulcer formation is associated with increased gastric acid output, elevated serum gastrin, delayed gastric emptying, 2 and can be prevented by somatostatin. 3,4 This effect of somatostatin has also been demonstrated in stress-induced gastric ulcers in rats. 5–7 Administration of cysteamine causes a high mortality, 1,3,4 which is not only affected by acute duodenal ulceration but also by a general toxic effect with adrenocortical necrosis and lung injury. Therefore, we investigated the possible effect of somatostatin on cysteamine-induced adrenal hemorrhage and lung injury in the rat.