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PubMed1984

Comparative study of the cytoprotective effects of anticholinergic agents on the gastric mucosal lesions produced by intragastric administration of 0.6 M HCl in rats.

CFY strain rats (both sexes, 180-210 g) were fasted for 24 hr. Several anticholinergic agents atropine, oxyphencyclimine, propantheline, trantheline, hexocyclium) were administered (i.p.) in equimolar doses (28.78 nM X kg-1), and to compared to the cyto-protective effect of atropine sulfate (0.01 mg X kg-1). Their effects were studied in (1) one hour pylorus-ligated rats, being given when the surgical procedure had just finished: volume and acid output were measured; (2) the gastric mucosal lesions induced by 0.6 M HCl. Drugs were applied 30 min before the administration of HCl (1 ml, i.g.). Rats were killed 1 hr later and the number and severity of lesions were calculated. We found that (1) atropine, oxyphencyclimine, and propantheline did not significantly decrease acid secretion, while trantheline and hexocyclium inhibited acid output; (2) all drugs provided significant protection against the gastric damage induced by HCl; (3) no significant difference was found in the extent of protection produced by the different drugs in the HCl-model. We conclude that atropine, oxyphencyclimine, and propantheline are gastric cytoprotective agents.

Animals↗
PubMed1984

Interrelationships between the gastric cytoprotective effects of vitamin A and beta-carotene and the gastric mucosal superoxide dismutase activity in rats.

Gastric mucosal damage was produced in rats by the intragastric administration of 96% ethanol or 0.6 M HCl, according to the method of Robert et al. Vitamin A or beta-carotene, in doses of 10 mg/kg, given intragastrically 30 min before the administration of the necrotizing agents. The animals were killed 1 hr after the administration of the necrotizing agents. The following experimental parameters were studied, without and with application of vitamin A and beta-carotene; number of gastric lesions (ulcers); severity of gastric mucosal lesions (ulcers); gastric mucosal superoxide dismutase (SOD) activity. It was found that; vitamin A and beta-carotene, in doses of 10 mg/kg, are able to prevent significantly both the number and severity of gastric mucosal lesions (ulcers) produced by the application of 96% ethanol or 0.6 M HCl; the significant increase of ethanol-induced gastric mucosal SOD activity can be inhibited by the application of vitamin A and beta-carotene; vitamin A and beta-carotene are capable of preventing the development of gastric mucosal lesions (ulcers) produced by the intragastric administration of 0.6 M HCl, while these agents fail to compensate for the HCl-induced decrease of gastric mucosal SOD activity. It has been suggested that; vitamin A and beta-carotene are gastric cytoprotective agents; the ulcer preventive effects of vitamin A and beta-carotene are partly dependent on their scavanger behaviour.

Animals↗
PubMed1984

Determination of vitamin A, vitamin A precursors and cytoprotective carotenoids in animal and human blood.

In the past few years, considerable progress has been made in the investigation of the function of retinoids and carotenoids in higher animals and human including their role in cytoprotection. This has resulted in a considerable development in the analytical methods in the field of carotenoids and retinoids in biological materials. We have developed a method for the qualitative and quantitative determination of retinol and carotenoids in animal and human blood, using straight-phase liquid chromatography. Details of this work are presented jointly with a brief review of other analytical methods of these compounds.

Animals↗
PubMed1984

Gastric cytoprotection by pirenzepine is not mediated by catecholamines.

The effects of pirenzepine (in a dose of 25.0 mg X kg-1) and atropine (2.5 mg X kg-1) were studied on the development of gastric ulceration produced by pylorus ligation, polymyxin B and absolute ethanol, as well as on the gastric secretory responses and plasma level of noradrenaline. It was found that: (1) pirenzepine significantly decreased the development of ulcer formation produced by pylorus ligation, polymyxin B and absolute ethanol without any antisecretory response; (2) atropine inhibited gastric acid secretion, but no effect was obtained on ulcus produced by pylorus ligation, polymyxin B and absolute ethanol; (3) the plasma level of noradrenaline could be decreased by atropine and pirenzepine, although the difference did not reach statistical significance. It has been concluded that catecholamines are not involved in the gastric cytoprotective mechanism of pirenzepine.

Animals↗
PubMed1984

Effect of PGF2 alpha administered in cytoprotective and antisecretory doses on the ethanol- and HCl-induced gastric mucosal damage and gastric mucosal superoxide dismutase activity in rats.

Gastric mucosal damage was provoked by the topical application of 96% ethanol (1 ml) or 0.6 M HCl, (1 ml) by the method of Robert et al. [11]. Different doses of PGF2 alpha 100, 200 and 400 micrograms/kg) were given ip 30 min before the administration of the necrotizing agents. The animals were killed 1 hr after the application of the necrotizing agents. The number and severity of gastric lesions (ulcers) were recorded. Gastric mucosal superoxide dismutase (SOD) activity was measured by the method of Misra and Fridovich [8]. It was found that: PGF2 alpha dose-dependently decreased the number and severity of gastric lesions produced by 96% ethanol or 0.6 M HCl: gastric mucosal superoxide dismutase activity could be increased significantly by PGF2 alpha in the HCl-model: gastric mucosal superoxide dismutase activity could be significantly decreased by PGF2 alpha administration in the ethanol-model: no significant difference was obtained between the ulcer preventive effect of PGF2 alpha and the changes in the gastric mucosal SOD activity. It was concluded that: the ulcer preventive effect of PGF2 alpha partly depends on the scavanger mechanism (in the ethanol-model): the cytoprotective (100 micrograms/kg) and by antisecretory (400 micrograms/kg) doses of PGF2 alpha; exert similar effects on the changes of gastric mucosal SOD activity.

Animals↗
PubMed1984

Distinction between antiulcer effect and cytoprotection.

Gastric ulcerations were produced in rats by oral administration of aspirin (ASA) suspended in a vehicle consisting of either water or increasing concentrations of HCl (0.005 M to 0.35 M). The lesions were prevented by antisecretory doses of a histamine H2 blocker (cimetidine) and by an anticholinergic agent (pro-banthine), but only when the acidity of the vehicle was low (0.05 M to 0.15 M), not at higher (0.35 M). On the other hand, 16,16-dimethyl PGE2 prevented ulcer formation even when ASA was suspended in all HCl concentrations, including 0.35 M HCl. In other studies, gastric mucosal necrosis was produced by oral administration of absolute ethanol. These lesions were not affected by cimetidine or two anticholinergic agents, pro-banthine and methscopolamine bromide, nor by alkalinization of the gastric lumen with NaHCO3 or pH 7 buffer; however, these ethanol-induced lesions were completely prevented by 16,16-dimethyl PGE2. We conclude that antisecretory agents, by blocking endogenous formation of acid, are antiulcer as long as no acid or only small amounts of acid (1 ml of 0.15 M or less) are given together with ASA. When higher concentrations are used (e.g. 0.35 M HCl), the antisecretory effect of the inhibitors is overcome by the exogenous acid, and ulcers still form. Under these conditions, only "true" cytoprotective agents, such as 16,16-dimethyl PGE2, prevent ASA-induced ulcers, even in the presence of high acidity. Although cimetidine and pro-banthine were shown earlier to reduce ASA-induced ulcers at nonantisecretory doses, these agents may still decrease acid formation within the gastric glands.(ABSTRACT TRUNCATED AT 250 WORDS)

16,16-Dimethylprostaglandin E2↗
PubMed1984

Role of submandibular saliva and epidermal growth factor in gastric cytoprotection.

The role of submandibular epidermal growth factor in protection of the gastric mucosa was investigated in rats. Removal of the submandibular glands and thereby submandibular epidermal growth factor (EGF) caused rats to develop gastric lesions (ulcerations and ulcers) after administration of the duodenal ulcerogen cysteamine. The median output of EGF in gastric juice was reduced from 45.6 pmol/12 h (total range 17.5-65.0) in unoperated controls to less than 0.06 pmol/12 h (total range less than 0.06-1.82) in rats given cysteamine after extirpation of the submandibular glands. The contents of EGF in the submandibular glands was unchanged during cysteamine treatment. Furthermore, the effects of intragastric instillation of exogenous EGF, infusion of saliva without EGF, and infusion of saliva with a high concentration of EGF on the development of cysteamine-induced gastric lesions were investigated in rats without submandibular glands. Exogenous EGF and saliva with a high but still physiological concentration of EGF significantly reduced the median area in the stomach displaying ulcers and ulcerations, whereas saliva without EGF had no effect. Although EGF is a known inhibitor of gastric acid secretion, the dose used in the present study had no effect on gastric acid secretion in chronic gastric fistula rats; removal of the submandibular glands also did not have any such effect. We conclude that exocrine secretion of submandibular EGF has a cytoprotective function in the stomach, an effect that may be physiological.

Animals↗
PubMed1982

Modification of the cytoprotective effect of prostacyclin on gastric epithelial cells of rats by colchicine.

The effect of prostacyclin (PGI2) and colchicine on fundic gastric mucosa of sexually mature female Wistar rats was investigated histochemically after restraint stress. Under PGI2 treatment the ulcer index decreased significantly; this effect was moderately inhibited by colchicine. The mucus content of epithelial cells was decreased during restraint and was increased by PGI2 treatment. This protective action was also inhibited by colchicine. The nuclear volume of fundic epithelial cells increased significantly in restraint and decreased following colchicine application. These phenomena were not influenced by PGI2. According to our results the cytoprotective effect of PGI2 is not accompanied by nuclear volume changes.

Animals↗
PubMed1983

Role of bacteria in gastric ulceration produced by indomethacin in the rat: cytoprotective action of antibiotics.

Indomethacin produces mucosal lesions in both the gastric antrum and small intestine in rats refed for 1 h after a 24-h fast. This study was designed to determine the role of bacteria in the formation of the antral lesions. A mixture of antibiotics (bacitracin, neomycin, and polymyxin B) prevented the antral lesions as well as intestinal lesions. The antibiotics also decreased the gastric corpus lesions induced by indomethacin in the fasted rat. Under a germ-free condition, indomethacin did not produce severe lesions in the small intestine of the refed rat but provoked many lesions in the antrum of the refed rat and in the corpus of the fasted rat. Corpus lesions induced by indomethacin in the fasted rat were decreased markedly by neomycin and slightly by polymyxin B, but not by bacitracin. Corpus lesions produced by an absolute ethanol, however, were prevented by each of the antibiotics. The inhibitory effect of neomycin on the corpus lesions was not blocked by pretreatment with indomethacin. In pylorus-ligated rats, neomycin did not decrease gastric acid secretion. The concentration of nonprotein sulfhydryls in the gastric mucosa was not altered by the treatment with neomycin. The antibiotic solutions were hypotonic. It is concluded that (a) bacteria are not important in the formation of antral and corpus lesions induced by indomethacin, and (b) antibiotics prevent gastric ulceration not by its antibacterial action, but by a "cytoprotective" action. The mechanism is unknown, but it may be different from that of antisecretory drugs, prostaglandins, mild irritants, hypertonic solutions, and sulfhydryl compounds.

Animals↗
PubMed1983

Prostaglandin cytoprotection and lysosomal stability in acute canine gastric erosions.

Prostaglandin cytoprotection may be related to lysosomal stability. In six mongrel dogs, bacterial peritonitis was created by the intraperitoneal instillation of Bacteroides fragilis, Pseudomonas aeruginosa, Streptococcus faecalis and Klebsiella pneumoniae in addition to canine gallbladder bile. In three dogs, gallbladder bile alone was instilled. Three of the six dogs with bacterial peritonitis also received 16,16-dimethyl prostaglandin E2 (PGE2) (0.2 micrograms/kg intramuscularly q6h) 24 hours before and for 3 days after the induction of peritonitis. In the dogs with bacterial peritonitis not receiving PGE2, gastroscopic examination demonstrated acute fundic erosions. None of the other dogs developed acute gastric erosions. In the dogs with bacterial peritonitis not receiving PGE2, fundic mucosal biopsy specimens demonstrated decreased lysosomal stability. In the dogs receiving PGE2, lysosomal stability was similar to that in the animals with bile peritonitis. These experiments demonstrate that PGE2 prevents the development of acute gastric erosions by stabilizing lysosomal membranes.

Animals↗
PubMed1982

Cytoprotection by PGE2, atropine, pirenzepine and vagotomy in rats.

Gastric cytoprotective effects of vagotomy, PGE2 and antimuscarinic compounds (pirenzepine, atropine) were studied in the rat. Both pharmacological and surgical treatment prevented the gastric damage induced by intragastric administration of acetylsalicylic acid plus hydrochloric acid. The mechanisms of action are discussed.

Animals↗
PubMed1982

On the cytoprotective action of sulfhydryl-containing substances.

Sulfhydryl substances (cysteine, glutathione, cysteamine and BAL) provide protection against experimental gastric ulcer induced by indomethacin while being ulcerogenous in stress-ulcer. Experimental data indicate the necessity to distinguish between "real" and "occasional" cytoprotective drugs.

Animals↗
PubMed1980

Cytoprotective effect of 16, 16' dimethyl prostaglandin E2 and some drugs on an acute galactosamine induced liver damage in rat.

Present experiment was aimed to study whether 16, 16' dimethylprostaglandin E2 (dmPGE2), Hepatofalk (HF), or Orotofalk (OF) may prevent an acute liver damage induced in rats with D-galactosamine (GalN). Fifty male rats were divided into 5 groups: 1. controls, 2. rats receiving GalN 750 mg/kg b. w. intraperitoneally, 3. animals pretreated with 5 microgram/kg dmPGE2 given subcutaneously 24 hours prior to, 30 min prior to and 6 hours after GalN. Rats of group 4 received HF 0,8 ml/kg intramuscularly and group 5 OF 0,3 caps/kg intragastrically 24 hours prior to, 30 min prior to and 6 hours after GalN. Animals were sacrificed 24 hours after GalN injection. Histological, histochemical and ultrastructural studies of the liver were performed. In rats receiving GalN alone (group 2) typical severe liver damage consisting of acidophilic necrosis of hepatocytes, periportal and intralobular inflammatory infiltration, hypertrophy and hyperplasia of Browicz-Kupffer cells has been observed. Histochemical investigations showed in this group fatty degeneration and a decrease in glycogen content in hepatocytes, irregular distribution of lysosomes, numerous cytolysosomes and uneven decrease in lysosomal enzymes activity (acid phosphatase and beta-glucuronidase). Ultrastructural studies revealed depletion in glycogen, fat droplets, hypertrophy of smooth endoplasmic reticulum and numerous autophagic vacuoles. Some of these vacuoles or residual bodies were dropping out into intercellular space. Focal accumulation of lamellar cytomembranes as well as condensation of heterochromatin in nuclei were also observed. Pretreatment of animals with dmPGE2 (group 3), HF (group 4) or OF (group 5) prior to GalN prevented liver cell necrosis. Histological, histochemical and ultrastructural picture of the liver was in these groups close to normal. Only very slight hypertrophy and hyperplasia of Browicz-Kupffer cells, was seen as well as depletion of glycogen and hypertrophy of smooth endoplasmic reticulum in hepatocytes. We conclude dmPGE2, HF and OF offered impressive cytoprotection against GalN induced liver damage in rat.

16,16-Dimethylprostaglandin E2↗
PubMed1994

Clinical status of the new cytoprotective agent, amifostine.

In summary, the data presented and reviewed at this symposium provide a strong rationale for the use of amifostine as a cytoprotective agent. Amifostine has been shown to reduce morbidity in cancer patients receiving radiation and chemotherapy without compromising the antineoplastic activity of the cancer therapies employed. Amifostine has been investigated extensively and appears particularly effective with cisplatin and cyclophosphamide, which operate via direct binding to the active species of these alkylating agents. It may also have a role in the protection of normal hematopoietic stem cells during bone marrow purging prior to bone marrow transplantation. Finally, amifostine may act synergistically with hematopoietic growth factors (ie, G-CSF) to protect and accelerate the recovery of hematopoietic stem cells exposed to high doses of radiation.

Agranulocytosis↗
PubMedDate not supplied

Gastric cytoprotective effect of morphine is probably not mediated by mu-receptors.

Morphine has a significant protective effect on ethanol-induced gastric lesions. This effect is antagonized by naloxone, suggesting that it is mediated by opioid receptors. In the rat, mu-receptors have been shown to be involved in other gastrointestinal actions of opioids. However, the potent partial agonist at mu-receptors, buprenorphine, not only failed to protect but actually aggravated ethanol-induced lesions at higher doses. The gut-selective mu-agonist, loperamide, also did not have a protective effect, while the mixed opioid, pentazocine, which has an antagonistic action at mu-receptors, by itself protected against ethanol-induced gastric lesions. Our results suggest that mu-receptors are probably not involved in the gastric cytoprotective action of opioids.

Administration, Oral↗
PubMed1994

Interleukin-1 beta-mediated metallothionein induction and cytoprotection against cadmium and cis-diamminedichloroplatinum.

Metallothioneins (MTs) are major intracellular protein thiols that have been associated with resistance to the cytotoxicity of heavy metals and some cytotoxic anticancer drugs. The accumulation and subcellular location of MT and its functionality were examined in a human hormone-independent prostatic tumor cell line (DU-145) exposed to cytokines that participate in autocrine growth and the acute phase response. Incubation of DU-145 cells with interleukin-1 beta (IL-1 beta) caused a concentration-dependent increase in MT protein reaching a 2- to 3-fold maximum increase 24 to 48 hr after treatment with 10 U of IL-1 beta/ml; smaller increases were seen with human recombinant IL-1 alpha and tumor necrosis factor alpha. DU-145 cells constitutively expressed only MT-IIa and MT-Ie mRNA and the IL-1 beta-mediated increase in MT protein was preceded by a marked elevation solely in MT-IIa mRNA. Basal MT was immunolocalized by confocal microscopy primarily to the nucleus of DU-145 cells with some granular deposits near the cell surface. IL-1 beta treatment increased nuclear MT. DU-145 cells pretreated with IL-1 beta were 2- to 3-fold resistant to the toxicity of CdCl2 and cis-diamminedichloroplatinum(II) (cisplatin). Both MT induction and cytoprotection against CdCl2 and cisplatin were blocked by concomitant incubation with a recombinant human IL-1 receptor antagonist protein. These results suggest the responsiveness of human prostatic tumor cells to cytotoxic electrophilic anticancer drugs can be diminished by direct exposure to the cytokine IL-1 beta, possibly by a mechanism involving MT.

Cadmium↗
PubMed1994

Cytoprotective effect of prostaglandin I2 analogues on superoxide-induced hepatocyte injury.

BACKGROUND: Prostaglandin I2 (PGI2) analogues have been suggested to protect the liver from ischemia-reperfusion injury, but the exact mechanism remains to be proved. METHODS: Primary cultured rat hepatocytes were exposed to superoxide generated by mixing hypoxanthine and xanthine oxidase, and changes in cell viability, cytosolic free calcium concentration ([Ca2+]i), and adenosine 3',5'-cyclic monophosphate (cAMP) concentration were assessed. The PGI2 analogue (OP2507 or OP41483) at 1 to 100 ng/ml was given as treatment. RESULTS: PGI2 analogues suppressed hepatocyte death in a dose-dependent manner (p < 0.01; OP2507 at 10 and 100 ng/ml, OP41483 at 100 ng/ml). At the end of 1-hour preincubation with OP2507, a significant rise in cAMP concentration was observed. Moreover, addition of dibutyryl cAMP suppressed hepatocyte death. A rise in [Ca2+]i, which preceded cell death, was prevented by PGI2 analogues or dibutyryl cAMP. CONCLUSIONS: The increase in cellular cAMP followed by suppression of [Ca2+]i elevation might be the major cause of the cytoprotective effect of PGI2 analogues in superoxide-induced hepatocyte injury.

Animals↗
PubMed1994

Effect on gastric mucus of the proton pump inhibitor leminoprazole and its cytoprotective action against ethanol-induced gastric injury in rats.

The effect of leminoprazole ((+-)-2-[[2-(isobutyl-methylamino)benzyl]sulfinyl]-1H-benzimidazol e, NC-1300-O-3, CAS 104340-86-5), a new compound being developed as an inhibitor of the gastric mucosal proton pump (H+,K(+)-ATPase), on gastric mucus secretion was studied by a biochemical method measuring the gastric mucin content in rats. Oral administration of leminoprazole (30 mg/kg) strongly inhibited the hemorrhagic lesions induced by 60% ethanol containing 0.15 mol/l HCl (acid-ethanol) administered 1 h later. Leminoprazole significantly inhibited the acid-ethanol-induced reduction of the mucin content in the surface mucosa including the mucus gel layer, but no significant effect could be obtained on the reduction of mucin present in the deep layer of the corpus and antral mucosa. Leminoprazole given to rats not treated with acid ethanol accelerated the secretion of deep mucosal mucus and increased significantly the content of soluble mucus which was recovered from the gastric luminal contents to about 200% of control, but failed to produce any significant change in the mucus content present in the surface mucosal and the mucus gel layers. The effect of leminoprazole on gastric mucus secretion might contribute to healing the peptic ulcer diseases and may be involved in the cytoprotective mechanism of this drug.

2-Pyridinylmethylsulfinylbenzimidazoles↗