Mesenteric ischemia/reperfusion-induced intestinal and vascular damage: effect of stobadine.

This study examined the effects of the pyridoindole compound stobadine on intestinal and vascular injury following mesenteric ischemia/reperfusion (I/R) in rats. Ischemia was induced by occlusion of the superior mesenteric artery (SMA) for 60 min, followed by 30 min reperfusion. To characterize gut impairment, some parameters of intestinal damage and biochemical variables, such as GSH content, activity of a lysosomal enzyme N-acetyl-beta-D-glucuronidase and activity of gamma-glutamyl transpeptidase, were determined. Vascular I/R-induced damage was evaluated as changes in acetylcholine evoked relaxation of mesenteric artery rings under isometric conditions. A method of amplified chemiluminescence (CL) was used to detect production of reactive oxygen species (ROS). Following I/R, pronounced intestinal injury of various intensities was observed, with maximal changes occurring in the terminal ileum. The effect of I/R was expressed mainly as increased vascular permeability, with protein leakage and subsequent hemorrhagic injury of the intestine as well as impaired endothelium-dependent SMA relaxation. Vessel dysfunction was manifested by a decrease of the maximal relaxation response to acetylcholine. An increase of CL, indicative of increased ROS production, was observed in both intestinal and vascular tissue. A novel antioxidant, stobadine, was found to reduce the increased vascular permeability and the extent of small intestine injury caused by I/R, to improve biochemical alterations accompanying I/R, to protect endothelial-dependent relaxation of mesenteric arteries, and to attenuate the CL response. The observed beneficial effect of stobadine indicates its possible application in the preventive and/or therapeutic approach to I/R-induced pathologies.

Contribution to safe anti-inflammatory therapy with indomethacin.

Non-steroidal anti-inflammatory drugs possess not only therapeutic but also adverse effects, mainly on the gastrointestinal tract. The aim of this pilot study was to establish the ulcerogenic dose caused by daily administration of indomethacin to male Lewis rats. Further, the model of rat adjuvant arthritis (AA) was used to evaluate the protective effect of stobadine dipalmitate against indomethacin-induced gastroenteropathy. Indomethacin was administered subcutaneously in the daily dose of 5, 7, 10, 20 and 30 mg/kg b.w. Survival of the animals and damage of gastric and intestinal mucosa were monitored, and some biochemical parameters were determined. In AA rats stobadine dipalmitate was administered orally in the daily dose of 15 mg/kg. For the chronical experiments on AA rats the subcutaneous indomethacin dose of 5 mg/kg was selected as the therapeutic dose and the dose of 7 mg/kg was chosen as the adequate dose for gastropathy induction. The additive adverse effect of arthritis induction and indomethacin administration was demonstrated on the basis of gastric mucosa damage observations. The supposed stobadine gastro-protection was not confirmed.

Gut and vessel alterations induced by mesenteric ischaemia/reperfusion in rats.

A rat model of transient occlusion of the superior mesenteric artery was used to study the intestinal and vascular injury induced by ischaemia/ reperfusion (I/R). A pronounced intestinal injury was observed, ranging from hyperaemia to severe haemorrhagic necrosis and bleeding. The length of the damaged intestinal segments reached 58.6% of the small intestine with a decrease of the wet weight in the I/R group. Sham operation resulted in 100% survival, I/R decreased survival to 40% after 24 h. Following I/R a significant increase of vascular permeability was observed in the small intestine. Gamma-glutamyl transpeptidase activity decreased aborally in sham operated rats and I/R reduced it further in all parts of the small intestine. I/R resulted in damaged endothelium-dependent relaxation of mesenteric artery rings. This was manifested by decreased maximal responses of arterial preparations to acetylcholine as well as decreased pD2 values. The results confirmed and specified the presumed effect of I/R on the small intestine and on vascular functions.

Differences between gastric antiulcer effects of trapencaine enantiomers.

The spatial arrangement of single stereoisomers may influence pharmacodynamic, pharmacokinetic and toxicological properties of a drug. Trapencaine (I. N. N.), (+/-)-trans-2-(pyrrolidin-1-yl)cyclohexylester of 3-(n)-pentyloxycarbanilic acid, was developed as an antiulcer drug with gastroprotective, local anaesthetic and spasmolytic effects. Limited information is available about the potential pharmacodynamic differences of the enantiomers of trapencaine. Therefore, the enantiomers of (+/-)-trans- or cis-2-(pyrrolidin-1-yl)cyclohexylester of 3-(n)-pentyloxy carbanilic acid were synthesised and tested on models of acute gastric damage induced by indomethacin and/or ethanol. A difference was found between their antiulcer effect, with the (+)-trans-enantiomer being the most effective and the (-)-cis-enantiomer the least effective in the models used.

Effects of pleuran (beta-glucan isolated from Pleurotus ostreatus) on experimental colitis in rats.

The effects of pleuran, beta-1,3 glucan isolated from Pleurotus ostreatus, were studied in a model of acute colitis induced by intracolonic administration of acetic acid. There was a reduction of the colonic damage score, colonic wet weight and wet/dry weight ratio 48 h after single luminal 2% pleuran suspension pretreatment. Similar results were obtained after repeated intraperitoneal administration of pleuran in doses of 30 and 100 mg/kg. Pleuran given orally as a 10% food component over 4 weeks was effective in reducing the extent of mucosal damage, but did not prevent the increase of myeloperoxidase in the injured colonic segment. In the segment without macroscopic evidence of inflammation, myeloperoxidase activity was significantly lower as documented by histological examination. The results indicate a possible role of this immunomodulator in the treatment of ulcerative colitis.

Effect of N-acetylcysteine on colitis induced by acetic acid in rats.

(1) To verify the proposed role of reactive oxygen species (ROS) in ulcerative colitis, the effect of an antioxidant N-acetylcysteine (NAC) was studied in acetic acid (AA)-induced colonic inflammation. (2) Depending on the dose used, NAC administered intracolonically was found to reduce the extent of colonic damage, along with a decrease in myeloperoxidase (MPO) activity, colonic wet weight and wet/dry weight ratio. (3) NAC attenuated the enhanced vascular permeability and prevented the depletion of colonic reduced glutathione (GSH) caused by AA administration. (4) The findings indicate that NAC may prove beneficial in the treatment of colitis.

Protective effect of stobadine in experimental colitis.

To assess the possible role of reactive oxygen species in inflammatory bowel disease, the effect of the antioxidant and free radical scavenger stobadine was studied in acetic acid-induced experimental colitis. Stobadine administered locally into the colon was found to reduce the extent of colonic mucosal injury, abolish the increase in myeloperoxidase activity, attenuate the enhanced vascular permeability, and prevent the depletion of reduced glutathione. The attempt to reduce pharmacologically excessive free radical production and oxidative damage in the inflamed colonic mucosa may be regarded as a complementary treatment of ulcerative colitis.

Effects of histamine H1 antagonist dithiaden on acetic acid-induced colitis in rats.

To assess the possible involvement of mast cells and/or their mediators in inflammatory bowel diseases, the effect of the histamine H1 antagonist Dithiaden was studied on a model of acetic acid-induced colitis in rats. Dithiaden pretreatment by intracolonic administration was found to reduce the extent of acute inflammatory colonic injury. This was manifested by a decrease in the score of gross mucosal injury, by lowered colonic wet weight and by diminished myeloperoxidase activity reflecting reduced leukocyte infiltration. Vascular permeability and gamma-glutamyl transpeptidase activity, elevated by acetic acid exposure, were decreased after Dithiaden pretreatment. The results indicate that locally administered Dithiaden may protect the colonic mucosa against an acute inflammatory attack by interfering with the action of the major mast cell mediator histamine.

Gastric transmucosal potential difference: effect of antisecretory and gastroprotective drugs.

1. Ion transport and electrical resistance of the gastric mucosa are responsible for the generation of the transmucosal potential difference (PD), which is considered an index of mucosal integrity. 2. The aim of the present work was to study the effect of some antisecretory and gastroprotective agents on PD in stomachs damaged by ethanol. 3. Control PD values measured in anesthetized rats were 35 to 40 mV (mucosa negative). Oral administration of 96% ethanol or intragastric instillation of 20% ethanol induced an abrupt fall in PD from the basal values of 40.4+/-1.0 mV and 39.6+/-0.1 mV to 14.6+/-2.5 mV and 11.7+/-1.3 mV, respectively. 4. Oral and/or topical pretreatment with the antisecretory agents ranitidine and timoprazole, as well as with the gastroprotective agents PGE2 and pentacaine, but not with an aluminum- and magnesium-containing antacid and with sucralfate, reduced the maximal drop of PD caused by ethanol. 5. After the administration of concentrated ethanol, hemorrhagic lesions were formed in the glandular stomach. 6. With the exception of ranitidine, all the drugs tested prevented the development of lesions after ethanol administration. 7. The results indicate that the gastric barrier can be protected by various drugs that act through different mechanisms.

Gastroprotective effect of stereoisomeric cis- and trans-2-(1-pyrrolidinyl) and 2-(1-pyrrolidinylmethyl)cyclohexyl alkoxycarbanilates in rats.

The effect of cis- and trans-isomers of 2-(1-pyrrolidinyl) and of 2-(1-pyrrolidinylmethyl)cyclohexyl alkoxycarbanilates was tested in acute gastric injury induced by phenylbutazone and/or 96% ethanol administration in rats. In both models a more pronounced antiulcer and gastroprotective activity was observed after pretreatment with the trans-isomer of 2-(1-pyrrolidinyl)cyclohexyl ester of 3(n)-pentyloxycarbanilic acid. Its cis-isomer, by comparison, was less effective against ethanol-induced gastric injury and failed to prevent the gastric damage induced by phenylbutazone. After introducing a methylene group into the hydrophilic part of the molecule, there was a loss of stereospecific difference, with both stereoisomers exerting a similar gastroprotective activity.

Indomethacin induced changes in mucosal lysosomal enzyme activity: effect of H2 antagonists.

Indomethacin induced gastric damage in rats was accompanied by a decrease in mucosal activities of three lysosomal enzymes tested, with serum levels remaining unchanged. Petreatments with cimetidine (100 mg/kg b.w.) and ranitidine (30 mg/kg b.w.) were found partially to prevent the decrease of N-acetylglucosaminidase and acid phosphatase, as well as of beta-glucuronidase, while the latter was also prevented by famotidine (10 mg/kg b.w.). All the H2 antagonists tested reduced dose-dependently the extent of gastric injury induced by indomethacin and reversed the changes in protein levels. The stabilisation of lysosomal membranes and thus the prevention of lysosomal leakage may be one of the favourable additional mechanisms of antiulcer activity of H2 antagonists.

Gastric antiulcer activity of pentacaine: possible mechanism of action.

The effect of pentacaine on different models of gastric and duodenal damage and on gastric acid secretion was studied after oral and parenteral administration. A proportional involvement of local and systemic effects of pentacaine was found in phenylbutazone-induced and cold-resistant stress-induced lesions, whereas in ethanol-induced lesions oral administration was the only effective way. On the other hand, duodenal lesions and gastric acid secretion were substantially affected by parenteral administration. The possible mechanisms involved in these differences are discussed.

Efficacy of combined ranitidine and pentacaine treatment in experimentally induced gastric damage in rats.

Combined treatment with the H2 antagonist ranitidine and the cytoprotective agent pentacaine was studied in acute gastric lesions induced by phenylbutazone and stress, in chronic gastric ulcers induced by acetic acid, and in Shay's model of gastric secretion stimulated by histamine. In all experimental settings, the effect of the combined treatment was more pronounced than the effect of each drug alone. The resulting antiulcer or antisecretory activity appeared to be additive or, in some cases, synergistic. If confirmed clinically, the combination of ranitidine and pentacaine may prove useful in the treatment of peptic ulcer disease.