Development Of Gastric Lesions Research Articles

新しいＨｉｓｔａｍｉｎｅ Ｈ２‐受容体きっ抗薬，Ｎｉｚａｔｉｄｉｎｅ，のラットの胃液分泌および実験胃・十二指腸損傷に対する効果

We examined the antisecretory and antilesion activities of nizatidine in rats. Male SD or Donryu rats (200-260 g) were used under fasted or fed conditions. Nizatidine, given orally or parenterally (intraperitoneally, subcutaneously or intraduodenally) at 0.3-150 mg/kg, inhibited both basal (pylorus-ligation preparations) and histamine-stimulated gastric acid secretion (acute fistula preparations) in a dose-dependent manner. The potency of nizatidine was 2 to 8 times greater than cimetidine when the ED50 values (mg/kg or mu mole/kg) of each agent were compared. The antisecretory activity of nizatidine, given orally, persisted for more than 3.5 hr, but disappeared 6 hr later. Nizatidine, given orally or subcutaneously at 0.3-150 mg/kg, prevented development of gastric lesions induced by water immersion, pylorus ligation (Shay), histamine, aspirin, or indomethacin in a dose-dependent manner. Duodenal ulcers induced by mepirizole were also markedly prevented with nizatidine. The potency of nizatidine on stress lesions or duodenal ulcers was about 20 or 14 times greater than that of cimetidine, respectively. Nizatidine, given orally 3 times a day for 4 weeks, significantly (P less than 0.05) accelerated the healing of acetic acid-induced gastric ulcers which were delayed by prolonged treatment with indomethacin. These results suggest that nizatidine is a useful drug for the treatment of peptic ulcers in man.

Intrahypothalamic microinjection of calcitonin prevents stress-induced gastric lesions in rats

Injection of salmon calcitonin into the lateral ventricle or the cisterna magna was reported to potently inhibit gastric lesions induced by cold restraint stress. The forebrain sites of action were investigated using unilateral microinjection of salmon calcitonin prior to exposing conscious pylorus-ligated rats to cold restraint stress for 2 hr. Calcitonin (100 ng), microinjected in 100 nl volume by pressure ejection from glass micropipette positioned into the lateral or ventromedial hypothalamus or the paraventricular nucleus, prevented the development of gastric lesions whereas microinjections into the caudate putamen, the cerebral cortex or the hippocampus were ineffective. The antiulcerogenic effect of lateral hypothalamic injection was dose dependent and specific since calcitonin gene-related peptide, tested under the same conditions, had no effect. Microinjection of calcitonin at 100 ng dose into the ventromedial hypothalamus did not modify gastric secretion whereas microinjection into the lateral hypothalamus or the paraventricular nucleus induced 75–82% inhibition of gastric acid output in pylorus-ligated rats exposed to restraint stress. These results demonstrate that the hypothalamus including the lateral, ventromedial and paraventricular nuclei are responsive sites of action for calcitonin-induced inhibition of cold restraint stress ulcers. The antiulcerogenic effect may be related to suppression of gastric acid secretion along with other mechanisms that remain to be elucidated.

Influence of thyroid states on stress gastric ulcer formation

Thyroid hormones exert a critical developmental and regulatory role on the morphology and biochemistry of gastrointestinal mucosal cells. However, the relationship between thyroid function and stress gastric lesion formation remains undetermined. This study was designed to test the hypothesis that thyroid states may affect the acute development of gastric lesions induced by cold-restraint stress. Normal (euthyroid), hyperthyroid (200 μg of T 4 i.p. × 7 days) and hypothyroid (thyroidectomized) rats were used. Gastric lesion incidence and severity was significantly (p < 0.05) increased in hypothyroid rats, whereas in contrast hyperthyroid rats developed significantly less gastric lesions. As anticipated, plasma levels of thyroxin (T 4) were significantly (p < 0.01) elevated in hyperthyroid rats, and undetectable in hypothyroid rats. Acute pretreatment with i.p. cimetidine (100 mg/Kg), but not T 4 (200 μg/Kg) 1 h prior to stress completely prevented gastric lesions formation in hypothyroid rats. Finally, binding of H-dihydroalprenolol to β-adrenergic receptors on brain membranes prepared from frontal cortex was reduced by 20% in hypothyroid rats after 3 h of stress. These and other data contained herein suggest that thyroid hormones contribute to modulate the responsiveness of the gastric mucosa to stress. The increased rate of ulcerogenesis observed in hypothyroid rats appears to be mediated by gastric acid secretion. The central mechanism of this response may involve decreased brain nonadrenergic receptor function.

Importance of pepsin and stomach distension in morphological alterations of stress-induced gastric lesions in pylorus-ligated rats.

Pylorus ligation changed the morphology and location of gastric lesions induced by water-immersion stress (WI stress) in rats; linear lesions in the corpus mucosa disappeared, and punctate lesions appeared in both the corpus and antrum, in association with the loss of H+ and the gain of Na+ in the gastric contents. Oral administration of antipeptic drugs such as amylopectin sulfate and sulfated glyptide or porcine pepsin significantly prevented or aggravated the lesions, respectively, although another type of elongated lesion appeared in response to high doses of antipeptic drugs. These antipeptic drugs or exogenous pepsin significantly reduced or increased pepsin activity, respectively, without effect on the acid output. Similar punctate lesions were produced in the atropinized rats (10 mg/kg) by instillation of acid solution (100 mM HCl plus 54 mM NaCl) with pepsin into the pylorus-ligated stomach and subjecting to WI stress. On the other hand, when the gastric contents were drained through a fistula to prevent accumulation of gastric juice in the pylorus-ligated stomach, WI stress again induced linear lesions only in the corpus mucosa. Acid hypersecretion in these rats induced by intravenous infusion of histamine, tetragastrin, or carbachol significantly aggravated the severity of lesions but did not change their morphology. These results suggest that pepsin in the presence of acid is prerequisite for development of gastric lesions in pylorus-ligated rats induced by WI stress. The morphological alterations may be accounted for by the distensions of the stomach due to accumulation of gastric juice in the lumen caused by pylorus ligation, but not due to acid hypersecretion.

Nabumetone, a new nonsteroidal anti-inflammatory drug: Criteria for therapeutic selection: Selective summary and conclusions

T he papers presented have summarized the development of nabumetone from preclinical through clinical studies with emphasis on its possible use in rheumatoid and osteoarthritis. Basic consideration of the mechanisms of action of anti-inflammatory agents has been provided in the overview by Dr. Kantor, and the subsequent authors have evaluated the performance of nabumetone in animal models and human studies with special emphasis on gastrointestinal toxicity..Mangan, Flack, and Jackson have shown that in animal models nabumetone may diverge from the usual consistent correlation between the development of gastric lesions and the anti-inflammatory efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs). Increased gastric tolerance is further suggested in human studies measuring gastrointestinal blood loss or endoscopically observed gastric lesions. In a study using radioactive chromium-labeled cells, Lussier and LeBel demonstrated that nabumetone produces no more blood loss than placebo under conditions in which aspirin causes considerable bleeding. Using endoscopic examination, Roth found substantially less gastropathy with nabumetone than with naproxen. This difference from naproxen is corroborated by a second endoscopy study reported by Greb and associates. Subsequent presentations by Willkens and Altman outlined the basic considerations necessary for evaluating agents used in the treatment of rheumatoid arthritis and osteoarthritis, respectively. Dr. Michael Weisman has provided an excellent keynote discussion on the difficult problem of determining the proper use of x-rays in evaluating the efficacy of therapeutic agents for rheumatoid arthritis. In the double-blind efficacy trials reported in this issue, nabumetone was again compared with naproxen in patients with rheumatoid arthritis or osteoarthritis. In these studies, no differences in gastropathy were demonstrated. Since no ulcers were observed for either drug in the six months of double-blind comparison, it is apparent that longer treatment periods may be required in order for the differences in endoscopically observed lesions to manifest themselves clinically. Many of the patients from the double-blind studies were continued on or switched to nabumetone, with open treatment in increasing dosages continuing for extended periods. As discussed by Jackson, nearly 2,000 patients have been treated with nabumetone in the United States for a period of six months or longer. Almost 1,000 have been treated for more than a year, and significant numbers for two and even three years. These evaluations have included dosages up to 2,000 mg per day, with little increase in toxicity. During these studies, a total of Ii ulcers were detected. One of these was in a patient with viral encephalopathy, whereas another was in a patient who had had a single dose of nabumetone following six months of naproxen therapy. Deleting this last event, IO ulcers among approximately 2,000 patients yields an incidence of 0.5 percent, not substantially different from what might be expected in the general population. Since there is an asynchrony between symptoms and endoscopic findings with NSAID-associated gastropathy, more careful examination may have detected a somewhat higher incidence of gastric lesions in those patients treated with nabumetone. Nevertheless, these findings suggest that this agent might provide a reasonable improvement in gastrointestinal tolerance at no expense in decreased efficacy. In addition to the trend toward gastrointestinal safety, other interesting points have been raised by several of the authors. It is interesting that in patients with varying degrees of renal impairment who received single doses of nabumetone in the study reported by Boelaert et al, there

The effects of 5-lipoxygenase inhibitors and leukotriene antagonists on the development of gastric lesions induced by nonsteroidal antiinflammatory drugs in mice.

The findings presented in this report show that: (1) 5-lipoxygenase inhibitors and some leukotriene antagonists protect the gastric mucosa against lesions induced by oral or parenteral administration of most NSAIDs, with the possibility of some variation in effects with aspirin.

Sex differences in stress-induced gastric ulceration: Effects of castration and ovariectomy

The present study investigated sex differences in susceptibility to stress-induced ulcers. Gastric mucosal lesions were produced in mice and rats through the use of a paradigm in which some animals were shocked and others were exposed to stimuli arising from the shocked animals. Under these conditions, shocked and nonshocked animals showed an approximately equal incidence of gastric lesions. There were significant differences between the sexes in the incidence of gastric lesions following stress, with males of both species showing a higher incidence of ulceration. Castration reduced the severity of ulceration in males, but ovariectomy had no effect on ulceration in females. The data suggest that male sex hormones play an important role in the development of gastric lesions in both mice and rats under the experimental conditions employed.

Effect of hypophysectomy, adrenalectomy, pituitary hormone secretion and gastric acid secretion on neurotensin induced gastric protection against stress gastric lesions

In previous studies we have established that intracisternal (i.c.) but not peripheral 〈intravenous〉 administration of neurotens in (NT), a brain and gastrointestinal tridecapeptide, totally prevents the development of gastric lesions produced by cold-restraint stress (CRS) with food-deprived rats. In this investigation, removal of the pituitary and adrenal gland, anterior pituitary hormone secretion and gastric acid secretion were evaluated independently as potential intermediates for NT's protective effect.

Evaluation of tiquizium bromide (HSR-902) as an antiulcer agent

The effects of HSR-902, an antimuscarinic agent, on development of various gastric and duodenal lesions, gastric secretion, pupil size and salivation in rats were compared with those of pirenzepine.2HC1 (pirenzepine, antiulcer agent) and timepidium bromide (timepidium, antispasmodic). 1) HSR-902 (10-100 mg/kg), given orally, dose-dependently inhibited the developments of gastric lesions induced by water-immersion stress, aspirin, indomethacin, serotonin and reserpine and duodenal lesions induced by cysteamine and mepirizole. The activities of HSR-902 were almost equal or somewhat more potent than those of pirenzepine, and they were more potent than those of timepidium. 2) HSR-902 (30 and 100 mg/kg, p.o.), when examined using pylorus-ligated preparations, dose-dependently inhibited the gastric acid output, pepsin output, and gastric acid and pepsin concentrations, but did not inhibit the gastric volume (HSR-902, in a higher dose, slightly increased the gastric volume.). Pirenzepine (100 mg/kg, p.o.), like atropine sulfate, inhibited the gastric volume, acid output and pepsin output, but did not inhibit the gastric acid and pepsin concentrations. Timepidium (100 mg/kg, p.o.), however, hardly influenced these parameters except for increasing the gastric volume. 3) HSR-902 (100 mg/kg, p.o.) induced the mydoriasis and inhibited the pilocarpine-induced salivation, and its activities were less potent than those of pirenzepine. These results suggest that HSR-902 is a promising agent for the treatment of peptic ulcer.

Antipyretic activity of new compounds 4-(3-oxo-1,2-benzisothiazolin-2-yl) phenylalkanoic acids, their esters, amides and 1,1-dioxide derivatives

Antipyretic activity of new compounds, 4-(3-oxo-1,2-benzisothiazolin-2-yl)phenylalkanoic acids, their esters, amides and 1,1-dioxide derivatives has been studied. The acid compound of the benzoic series (I:a), tested at graded doses, exerted a noticeable antipyretic action; it had two times the “potency” of benzisothiazolone but an almost equal “efficacy”. Its “potency” however was not proportional to the development of gastric lesions and to the acute toxicity. A decreased pharmacological activity has been observed in phenylalkanoic acids in the following order: R = COOH > CH 2COOH > CH(CH 3)COOH > CH(C 2H 5)COOH, probably due to their increasing lipophilic character. By contrast among 1,1-dioxide derivatives the most effective in preventing pyrogen-induced fever was the ethyl ester (V:c) of benzoic series which appeared to be as active as paracetamol. The interest arising from these observations is here after discussed.

Mechanisms of irritative activity of compound 48/80 on rat gastric mucosa.

A single intraperitoneal injection of compound 48/80 (48/80) (0.5-3 mg/kg) into anesthetized rats caused a dose-dependent reduction of the transmucosal potential difference (PD) and intraluminal pH (pH), and induced gastric lesions within 2 h. These same changes were seen with an intraperitoneal injection of histamine, but not with serotonin. There was a significant correlation between the lesion index and the PD reduction, although the integrity of the resting gastric mucosal barrier remained unaltered. The PD reduction caused by 48/80 was dose-dependently inhibited by tripelennamine (H1-antagonist) and FPL-52694 (mast cell stabilizer) and partially suppressed by methysergide (serotonin antagonist), but the changes in pH were prevented by FPL-52694 and cimetidine (H2-antagonist). The reduction of PD and pH induced by histamine was inhibited by tripelennamine or cimetidine, respectively, but these responses were not inhibited by FPL-52694 or methysergide. Gastric lesions induced by 48/80 were potently inhibited by tripelennamine and FPL-52694, and partially by cimetidine, whereas those induced by histamine were significantly prevented by tripelennamine and cimetidine, but not by FPL-52694. Methysergide had no effect on the development of gastric lesions in response to 48/80 or histamine. These results suggest that a single injection of 48/80 reduced the PD and stimulated acid secretion, thereby producing gastric lesions. These effects of 48/80 may be due to activation of H1- and H2-receptors by acutely released endogenous histamine.

Vinegar is a Dietary Mild Irritant to the Rat Gastric Mucosa

Exposure of the rat stomach to acetic acid (0.3—3%) caused a concentration-dependent reduction of transmucosal potential difference (PD) and increase of luminal pH (gastric alkaline response). These concentrations of acetic acid, when given topically to the stomach, significantly prevented development of gastric lesions induced by subsequent exposure to absolute ethanol, the inhibition being 42.3%, 95.8% and 70.4% at concentrations of 0.3%, 1% and 3%, respectively. Gastric alkaline response and protection of ethanol-induced gastric lesions caused by 1% acetic acid were significantly attenuated by pretreatment of the animals with indomethacin (5 mg/kg, s.c.). Although other related carboxylic acids at 1% concentration such as citric acid (52 mM), maleic acid (86 mM) and formic acid (217 mM) affected both PD and luminal pH In varying degrees, these agents, except for 1% maleic acid, failed to prevent gastric lesions in response to absolute ethanol. Similar to 1% acetic acid (167 mM), gastric alkaline response and adaptive cyto-protection induced by 1% maleic acid were significantly antagonized by pretreatment with indomethacin. Formic acid also induced a significant gastric alkaline response, but this effect was not affected by indomethacin. These results suggest that dilute acetic acid such as vinegar (approximately 3% acetic acid) acts as a mild irritant to the stomach, and induces alkaline response and adaptive cytoprotection, mediated by endogenous prostaglandins. Other related carboxylic acids may have similar effects, but those depend upon the concentrations used.

The effects of centrally administered neuropeptides on the development of gastric lesions in the rat

Centrally administered neuropeptides were investigated for their effects on the development of gastric lesions in rats. Thyrotropin releasing hormone (TRH), vasoactive intestinal peptide (VIP) and gonadotropin releasing hormone (LHRH) produced gastric lesions acutely, with TRH demonstrating the most pronounced effect in terms of incidence and severity. Ten-fold higher doses of the same peptides administered intravenously produced none or very few gastric lesions. Moreover, pretreatment with atropine partially inhibited their production. Corticotropin releasing factor (CRF) exhibited only mild ulcerogenic effets, and the gastric lesions induced with this peptide developed more slowly than with TRH, VIP and LHRH. Although ulcerogenic in their own right, none of these four neuropeptides significantly potentiated the potent ulcerogenic effects of cold-restraint stress. Since other neuropeptides, including somatostatin, human pancreatic growth hormone releasing factor (hpGRF), substance P, bombesin, and neurotensin, had no demonstrable effects on gastric mucosa, we can conclude that the lesions were not a general effect of intracisternal administration of neuropeptides. The results suggest that within the central nervous system, there are several neuropeptides that play a significant role in the development of gastric lesions via, at least in part, vagal-dependent mechanisms.

Gastric lesions produced by conditioned emotional stimuli in the form of affective communication and effects of benzodiazepines

Formation of gastric lesions in response to conditioned emotional stimulus (CES) and effects of benzodiazepines were studied in mice. The CES was introduced in the form of affective communication through a communication box. The “senders” were exposed to electric foot shock and the “responders” were able to receive affective cues such as visual, auditory and olfactory from “senders”. The “senders” and “responders” exhibited significantly greater gastric lesions than the controls. Diazepam at doses of 2 × 1 − 2 mg/kg (p.o.) and oxazolam at a dose of 2 × 2 mg/kg (p.o.), reduced the formation of gastric lesions of the “responders” induced non-physically by CES. The present results indicate that “responders” showed bodily changes under CES treatment, particularly in the development of gastric lesions, and that gastric lesions produced by CES were protected by diazepam and oxazolam.

The stomach after cholecystectomy

Removal of the gallbladder results in an accelerated enterohepatic circulation of bile salts. It has been suggested that reflux of bile into the stomach after cholecystectomy may predispose a patient to the development of gastric lesions. To examine this hypothesis, 349 patients with endoscopically proved gastric ulcers or mucosal lesions were age and sex matched with 349 patients with upper gastrointestinal symptoms who had normal endoscopic findings. The frequency of cholecystectomy was determined to be 4.3 percent in the gastric ulcer group (control 3.7 percent) and 3.8 percent in the mucosal lesions group (control 4.2 percent). There was no statistical difference between patients with gastric ulcer and the control subjects, mucosal lesions and controls in the frequency of cholecystectomy using individually matched case-control comparison. The relative risk for gastric ulcer-matched control comparison was 1.3 (95 percent confidence limit 0.3 to 6.3). The relative risk for mucosal lesion-matched control comparison was 0.85 (95 percent confidence limit 0.2 to 2.9). The data did not support the hypothesis that cholecystectomy increases the propensity to develop gastric lesions.

Serotonergic changes in specific areas of rat brain associated with activity--stress gastric lesions.

To study serotonergic involvement in the development of gastric lesions following activity wheel stress, three groups of rats (gastric lesions, no gastric lesions, and home--cage controls) were killed following exposure to the experimental procedures. The brains were dissected into eight specific areas and subjected to analyses for serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) using high performance liquid chromatography with EC detection. Lower levels of 5-HT were found in the midbrain, cortex, and hippocampus of rats with gastric lesions compared to either the no lesion group, subjected to shorter periods of activity--stress, or the home--cage control group. Levels of 5-HT and 5-HIAA were elevated in the pons/medulla oblongata of both the lesion and the no lesion groups compared to the home--cage controls. Corticosterone levels in blood were also significantly elevated in the lesion group. These data on serotonin changes in the CNS suggest a possible role for this neurotransmitter in stress-induced gastric pathology.

EFFECT OF N-ACETYL-L-GLUTAMINE ALUMINUM COMPLEX (KW-110), AN ANTIULCER AGENT, ON THE NON-STEROIDAL ANTI-INFLAMMATORY DRUG-INDUCED EXACERBATION OF GASTRIC ULCER IN RATS

Gastric ulcer induced by the injection of acetic acid (0.025 mi of 20%) into the gastric wall of rats was healed considerably 5 days after the injection of acetic acid. Non-steroidal anti-inflammatory drugs (NSAID) such as aspirin, indomethacin, and phenylbutazone were given consecutively for 5 days, and they exacerbated the ulcer and enlarged the ulcer area. Aspirin caused exacerbation when it was given for the initial 5 days of the ulcer healing process. Phenylbutazone caused exacerbation by the administration for 5 days at the middle stage of the ulcer healing process. In contrast, indomethacin caused exacerbation not only when it was given for the initial 5 days but also when it was given for the middle 5 days. The effect of the antiulcer agent N-acetyl-L-glutamlne aluminum complex (KW-110) on the exacerbation was studied. KW-110 at an oral dose of 500 mg/kg inhibited remarkably the exacerbation induced by all of the NSAID used. The development of gastric lesions induced by these NSAID was also prevented by KW-110: Further study was carried outwith regard to the influences of KW-110 on the pharmacological properties of NSAID. The results showed no influences of KW-110 on the antiedematous and antipyretic actions of the NSAID.

Effect of N-acetyl-L-glutamine aluminum complex (KW-110), an antiulcer agent, on the non-steroidal anti-inflammatory drug-induced exacerbation of gastric ulcer in rats.

Gastric ulcer induced by the injection of acetic acid (0.025 ml of 20%) into the gastric wall of rats was healed considerably 5 days after the injection of acetic acid. Non-steroidal anti-inflammatory drugs (NSAID) such as aspirin, indomethacin, and phenylbutazone were given consecutively for 5 days, and they exacerbated the ulcer and enlarged the ulcer area. Aspirin caused exacerbation when it was given for the initial 5 days of the ulcer healing process. Phenylbutazone caused exacerbation by the administration for 5 days at the middle stage of the ulcer healing process. In contrast, indomethacin caused exacerbation not only when it was given for the initial 5 days but also when it was given for the middle 5 days. The effect of the antiulcer agent N-acetyl-L-glutamine aluminum complex (KW-110) on the exacerbation was studied. KW-110 at an oral dose of 500 mg/kg inhibited remarkably the exacerbation induced by all of the NSAID used. The development of gastric lesions induced by these NSAID was also prevented by KW-110. Further study was carried out with regard to the influences of KW-110 on the pharmacological properties of NSAID. The results showed no influences of KW-110 on the antiedematous and antipyretic actions of the NSAID.

Alpha adrenergic receptors and gastric function

AbstractAlpha‐2 agonists by an effect on alpha‐2 adrenoreceptors in the stomach (and probably in the brain also) suppress vagal nerve acetylcholine release thereby inhibiting gastric motility and secretion and inhibiting the development of gastric lesions in rats in the stress‐, reserpine‐, and cysteamine‐induced ulcer models. Since the effects of the alpha‐2 agonists are consistently inhibited by alpha‐2 blocking agents, their effects appear to be selectively mediated via the alpha‐2 receptor. It seems appropriate therefore that the role of the alpha‐2 receptors be recognized in studies of gastric function and ulcer development.

Effects of cholestyramine and synthetic hydrotalcite on acute gastric or intestinal lesion formation in rats and dogs.

Cholestyramine, a bile-binding agent, markedly inhibited the development of gastric lesions induced by water-immersion stress in rats and of gastric and intestinal lesions induced by indomethacin in rats and dogs with an intact pylorus. However, cholestyramine had no effect on gastric lesions induced by stress in pylorus-ligated rats and on aspirin-induced gastric lesions in rats and dogs with or without pylorus ligation. Hydrotalcite, a potent antacid, significantly inhibited the gastric lesions induced by stress and aspirin in rats and dogs with or without pylorus ligation. Hydrotalcite also inhibited the gastric lesions induced by a single administration of indomethacin in rats with an intact pylorus. In contrast, the agent had no effect on gastric and intestinal lesions induced by repeated administration of indomethacin to rats and dogs with an intact pylorus. These results suggest that while bile probably plays an important role in the pathogenesis of stress-induced gastric lesions and of indomethacin-induced gastric and intestinal lesions, bile does not appear to play a role in the pathogenesis of aspirin-induced gastric lesions.