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In this study we investigated functional changes in the femoral artery and ultrastructural alterations in mesenteric vessels and capillaries in the rat model of multiple low dose streptozotocin (STZ)-induced diabetes. Participation of oxidative stress in this model of diabetes was established by studying the effect of the pyridoindole antioxidant stobadine (STB) on diabetes-induced impairment. Experimental diabetes was induced by i.v. bolus of STZ (20 mg/kg) given for three consecutive days to male rats. At the 12(th) week following STZ administration, the animals revealed typical signs of diabetes, such as polyphagia, polydypsia and polyuria. There was no weight gain in the diabetic groups throughout the experiment. No exitus occurred in any group. Diabetes was characterised with high levels of plasma glucose, no significant changes in lipid metabolism, decreased serum levels of glutathione, increased serum levels of the lysosomal enzyme N-acetyl-beta-D-glucosaminidase (NAGA), injured endothelial relaxant capacity of the femoral artery and alterations in ultrastructure of mesenteric arteries and capillaries. Antioxidant STB in the dose of 25 mg/kg body weight i.p. (5 times per week) did not influence glucose levels, however, it mitigated biochemical, functional and ultrastructural changes induced by diabetes, suggesting a role of reactive oxygen species in diabetes-induced tissue damage.

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The effects of pleuran, beta-glucan isolated from Pleurotus ostreatus, were studied in a model of acute colitis in rats. Pleuran was given either as a 2% food component or as 0.44% pleuran hydrogel drink over 4 weeks. Colitis was induced by intraluminal instillation of 4% acetic acid and after 48 h the extent of colonic damage and several biochemical parameters were examined. Pleuran supplementation both in food and in drinking fluid significantly decreased the disposition to colitis. The macroscopic damage score was reduced by 51% or 67% by pleuran diet and pleuran hydrogel drink, respectively. Pleuran did not influence the final body weights of rats but prevented significantly colonic wet weight increase which was observed in the control diet group. The enhanced activity of myeloperoxidase in the inflamed colonic segment was reduced by pleuran diets, reflecting decreased neutrophil infiltration. The colonic damage was accompanied by decreased activities of lysosomal enzymes--acid phosphatase and cathepsin D--in the control untreated group, whereas in the pleuran groups the decrease was significantly attenuated. Both pleuran regimens reduced the content of conjugated dienes in the colon, liver and erythrocytes. In contrast to this fact, activities of antioxidant enzymes in erythrocytes and the colon were not so greatly influenced. Significant increase was found only in the case of SOD activity in sham operated rat erythrocytes under influence of both pleuran regimes and in the case of GST activity in erythrocytes of pleuran hydrogel group. The mechanism of the described protective effect of pleuran is not yet fully understood. Our results indicate that the pleuran-enhanced antioxidant defence of the colonic wall against the inflammatory attack may have come into play.

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In rats with diabetes induced by streptozotocin (STZ), we studied the reactivity of the aorta in response to vasoconstrictor and vasorelaxant agents, changes in conduction velocity in the sciatic nerve, and glutathion (GSH) content in the gastric mucosa as well as the occurrence of spontaneous gastric lesions. STZ-induced diabetes was found to be accompanied by endothelial injury, exhibited by diminished endothelium-dependent relaxation and by increased noradrenaline- and H2O2-induced contraction. Conduction velocity in the nerves from STZ-treated animals was significantly lower compared to that in nerves from control animals. Moreover, gastric hyperaemia, occasional gastric lesions, and a significant depletion of GSH in the gastric mucosa were observed in STZ-treated rats. Our experiments confirmed the suitability of Wistar rats for the model of STZ-induced diabetes.

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The effect of a carbanilic local anesthetic pentacaine [(+/-)-trans-2- (1-pyrrolidinyl)cyclohexyl ester of 3(n)-pentyloxyphenyl-carbanilic acid] and some of its derivatives [K-1905 [(+/-)-trans-2-diethylaminocyclopentyl ester of 3(n)-pentyloxyphenyl-carbanilic acid], K-2002 [(+/-)-trans-2-(1-pyrrolidinyl)cyclohexyl ester of 4(n)-pentyloxyphenyl-carbanilic acid], K-2006 [(+/-)-trans-2-(1-pyrrolidinyl)cyclopentyl ester of 4(n)-pentyloxyphenyl-carbanilic acid], and carbanilates P2 [(+/-)-trans-2-(1-pyrrolidinyl)cyclohexyl ester of 4-methoxy-carbonylphenyl-carbanilic acid], P3 [(+/-)-trans-2-(1-pyrrolidinyl)cyclohexyl ester of 3-methoxy-phenyl-carbanilic acid], and PeJ, the quaternized derivative of pentacaine), as well as that of oxethazaine was studied on longitudinal antral and circular fundic smooth muscle strips of the guinea-pig stomach. All the carbanilates studied relaxed the smooth muscle, attenuated the spontaneous smooth muscle contractions and shifted the acetylcholine, histamine, and BaCl2 cumulative concentration effect curves to the right, reducing their maximum. There was no direct relationship between their relaxing potency and the ability to reduce the action of different stimulants. For the effectiveness of the carbanilates studied, substitution in the lipophilic part of the molecule was more important than in the hydrophilic part and the meta position was more advantageous than the para position. Pentyloxy-derivatives (pentacaine, K-1905, K-2002 and K-2006) were more active than the methylcarbonyloxy (P2)- and methoxy (P3)-derivatives. Opening of the heterocyclic ring (K-1905) in the hydrophilic part of the molecule did not affect significantly the potency of the derivative studied, while quaternization (PeJ) significantly reduced the potency. It is suggested that the carbanilates studied may affect the smooth muscle responses via changes in the membrane fluidity and Ca2+ availability, and that these effects might be partly responsible also for their antiulcer activity.

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The antiulcer, gastroprotective, and antisecretory effects of selected carbanilates were tested in rats. The compounds K-1905 and K-2002 were found to have beneficial effects similar to those of pentacaine in phenylbutazone- and ethanol-induced gastric injury and in cysteamine-induced duodenal lesions; their antisecretory activity was also comparable to pentacaine in pylorus-ligated rats. Compounds P2 and P3 were generally less effective than pentacaine, and compound P1 was gastrotoxic. Thus pentyloxy-substitution on the benzene ring of the parent structure (K-1905 and K-2002) is more suitable for antiulcer and gastroprotective activity than methoxy-substitution on the meta-position (P3) or alkyloxy-substitution on the para-position (P2, P1). The results indicate that the two carbanilates K-1905 and K-2002 can be considered prospective antiulcer drugs.

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The effect of selected carbanilates on the rat gastric mucus was tested after oral administration. The compounds K 1905 and K 2002 were found to increase gastric mucus content in nonstressed rats while compound P 2 was ineffective. The activity of K 1905 was comparable with that of the parent drug trapencaine. Cold-restraint stress decreased the gastric mucus content and induced haemorrhagic erosions in the glandular stomach. With the exception of compound P 2 pretreatment with carbanilates dose-dependently diminished the extent of stress-induced gastric damage and prevented the depletion of mucus after stress. The results indicate that pentyloxy-substitution in the meta and in the para position on the benzene ring of the parent structure (K 1905 and K 2002, respectively) seems to be more suitable for mucus enhancing activity than alkyloxy-substitution on the para position (P 2). The observed increased mucus secretion might be partly responsible for the gastroprotective action of the drugs tested.

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The in vivo effect of indomethacin and three H2-receptor antagonists-cimetidine, ranitidine, and famotidine-on gastric damage and on the activity of lysosomal enzymes and on proteins was examined in rat gastric mucosa and serum. The activities of the lysosomal enzymes N-acetyl-beta-glucosaminidase (NAGA), acid phosphatase (APh), and beta-D-glucuronidase (GLU) decreased significantly in gastric mucosa 2, 4, 6 and 12 h after subcutaneous administration of indomethacin (20 mg/kg). The serum activities of the lysosomal enzymes were unchanged. A decrease of protein in gastric mucosa was observed 4 and 6 h after indomethacin administration. Pretreatment with cimetidine and ranitidine reduced dose-dependently the length of gastric lesions induced by indomethacin, as well as the decrease in lysosomal enzyme mucosal activities. Famotidine, in spite of its antiulcer effect, failed to prevent the release of NAGA and APh, yet proved to inhibit GLU release. The results suggest that, in addition to their gastroprotective effect, H2-receptor antagonists may contribute to lysosomal membrane protection in indomethacin-induced gastric injury.

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The efficacy of vinpocetine (CAS 42971-09-5) to prevent gastric mucosal damage induced by several noxious agents and its antisecretory effect were studied in rats. Vinpocetine administered orally or intraperitoneally inhibited the development of gastric lesions induced by 96% ethanol in a dose-dependent way. The highest protective activity was observed when vinpocetine was given intraperitoneally 30 min before ethanol, and its effect was still significant when administered 120 min before ethanol exposure. Oral administration of vincamine also displayed gastroprotective action in this model. Pretreatment with indometacin counteracted the protective action of vinpocetine against ethanol-induced damage, suggesting the involvement of a prostaglandin-mediated mechanism. The protective effect of vinpocetine was compared with that of prostaglandin E2, sucralfate, and tripotassium dicitrate bismuthate. The antiulcer activity of vinpocetine was demonstrated also in gastric injury induced by phenylbulazone and in chronic gastric ulcer induced by acetic acid. Histamine-stimulated gastric acid secretion in pylorus-ligated rats was partially inhibited by vinpocetine administered intraduodenally. The activity of vinpocetine established in these experiments is indicative of its potential clinical value as a gastroprotective agent.

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The potential involvement of increased mucus secretion in the antiulcer activity of a cytoprotective agent, pentacaine, and of the H2-antagonist ranitidine was studied in stressed rats. Cold-restraint stress decreased the gastric mucus content and induced haemorrhagic erosions in the stomach. Pretreatment with pentacaine and ranitidine dose-dependently diminished the extent of stress-induced gastric damage. Pentacaine prevented the depletion of mucus after stress, while ranitidine failed to affect it. In non-stressed rats only pentacaine was able to enhance mucus secretion. The stimulating effect of pentacaine on gastric mucus secretion may account for some of its antiulcer properties.

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The influence of the proximal selective vagotomy (PSV) on the origin and the extent of experimental gastric ulcer were investigated in rats. The lesions of the gastric mucosa were caused in three groups: by stress through swimming-test, by application of phenylbutazone, and by ischemia (ligature of the left gastric and the right gastroepiploic vessels). The PSV practised a protective influence on the pharmacodynamic etiology, however, not on the stress ulcer. The areas of the ischemic gastric ulcers were larger on an average of 40% after PSV than in the control animals. The difference was not statistically significant. In case the PSV caused besides hyposecretion and hypo-acidity even passive hyperemia caused in the denervated part of the stomach then these did not produce any sufficient defence against the origin of stress ulcers and ischemic lesions.

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Gastric mucosal damage caused by the administration of ulcerogenic agents resulted in different changes in lipid peroxidation. An increase in malondialdehyde level was observed after ethanol exposure, whereas suppression of lipid peroxidation occurred after dosing with indomethacin. Changes in lipid peroxides associated with ethanol- but not indomethacin-induced injury were prevented by pretreatment with pentacaine and cimetidine.

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Pentacaine was found to prevent the development of acute haemorrhagic lesions induced by ethanol in rats in a dose-dependent way. Electron microscopy in the untreated group showed extensive disruption of the surface epithelium and deep necrosis of the mucosa after ethanol exposure. Degranulation or even complete destruction of mast cells was observed. The microvasculature exhibited several signs of derangement. After pentacaine treatment, these signs were absent and no degranulation of mucosal mast cells was observed. The mast cell-mediated effect of pentacaine appears to be only one component of its gastroprotective action.

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The action of pentacaine, a new prospective antiulcer drug with gastric cytoprotective activity, on gastric acid secretion was analysed and compared with the action of other antisecretory drugs. The drugs were given orally or intraduodenally to Wistar rats after pylorus ligation. The gastric acid secretion was studied under basal or stimulated (histamine, pentagastrin, carbachol) conditions. Oral administration of pentacaine, oxethazaine and procaine, in contrast to atropine, had no influence either under basal or stimulated conditions. However, intraduodenal administration of pentacaine significantly suppressed both the basal and stimulated gastric secretion. The present study suggests that the mechanism of antisecretory activity of pentacaine differs from that of anticholinergic and antihistaminergic drugs.

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The influence of the proximal selective vagotomy (PSV) on the local blood flow in the gastric wall was investigated. No significant changes of the microcirculation were established in the mucosa of the corpus ventriculi (secretory area). The blood flow in the antrum pylorus was increased temporarily 24 hours after PSV and it was normalized again 4 and 7 days later. Pentagastrin led to a significant increase of the blood flow in the gastric wall of a control group and also in the operative group 24 hours after PSV. Pentagastrin was without any influence on the microcirculation after PSV are no cause for ulcer relapses.

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The absorption rate of the beta-adrenoceptor blocking drug, exaprolol, from the gastrointestinal tract was studied using in-situ methods in the rat and dog. Exaprolol was rapidly absorbed from the small and large intestine of rats and from the ileum of dogs. The cardiac output and regional blood flow decreased in rats to approximately one half of the original values within 30 min of the in-situ experiment. The logarithm of the amount vs time plots from dogs were linear, whereas with rats a curvilinearity appeared apparently because of the blood flow-limited absorption kinetics of this highly lipophilic drug. The data obtained suggest that exaprolol is suitable for administration in sustained release form.

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After i.v. administration to rats of polysaccharide-protein complex, isolated from Candida albicans, a decrease of cardiac output was observed from 20 sec to 240 min postinjection, followed by a recovery at 360 min. Concomitantly the regional blood flow was maintained in heart and lungs, moderately decreased in intestine, liver and adrenals and markedly reduced in skin, muscle, spleen and kidney.

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