Correlation between the cytoprotective effect of beta-carotene and its gastric mucosal level in indomethacin (IND) treated rats with or without acute surgical vagotomy.

As to earlier observations that beta-carotene prevents the development of gastric mucosal injury produced by different noxious agent, however, its cytoprotective effect can be abolished by acute surgical vagotomy. The aim of this study was to evaluate the possible correlation between the gastric mucosal cytoprotective effect of beta-carotene and its gastric mucosal level in rats treated with IND. The gastric mucosal damage was produced by the administration of IND (20 mg/kg s.c.). The instillation of beta-carotene and acute surgical vagotomy (ASV) or SHAM operation were carried out 30 min before IND treatment. The rats were sacrificed 4 h after IND application, and the number and severity of gastric mucosal erosions were noted. The blood rats was collected quantitatively, the liver and the gastric mucosa were removed, and the beta-carotene and vitamin A level of the gastric mucosa, serum and liver were measured with HPLC. It was found that: 1. Beta-carotene induced gastric cytoprotection in SHAM-operated rats treated with IND but its effect disappeared after ASV. 2. Although the beta-carotene level of the gastric mucosa increased its concentration was not elevated in the serum of intact and vagotomized animals either. 3. Vitamin A Formation was not detected in the liver of animals with or without ASV. It was concluded that the lack of intake of beta-carotene into the gastric mucosa can not play etiologic role in the failure of gastric cytoprotection of rats with acute bilateral surgical vagotomy.     

Vagal nerve and the gastric mucosal defense

An essential role for an intact vagal nerve has been proven in the development of gastric mucosal cyto- and general protection. On the other hand, chemically-induced (ethanol, HCl, indomethacin) gastric mucosal damage is enhanced after acute surgical vagotomy. The aims of this paper were to study the possible mechanisms of the vagal nerve in the development of gastric mucosal defense. The following questions were addressed: 1) effect of surgical vagotomy on the development of ethanol- (ETOH), HCl-, and indomethacin (IND)-induced gastric mucosal damage; 2) changes in the gastric mucosal defense by scavengers, prostacyclin and other compounds (small doses of atropine and cimetidine: 3) changes in the gastric mucosal vascular permeability due to chemicals; 4) effect of indomethacin in the ETOH and HCl models with and without surgical vagotomy; 5) changes in the gastric mucosal content of prostacyclin and PGE₂ in the ETOH and HCl models after surgical vagotomy; and 6) changes in the role of SH-groups in gastric mucosal defense after surgical vagotomy. It was found that: 1) the gastric mucosal damage produced by chemicals (ETOH, HCl, and indomethacin) was enhanced after surgical vagotomy; 2) the cyto- and general gastric protective effects of β-carotene, prostacyclin, and small doses of atropine and cimetidine disappeared after surgical vagotomy; 3) the vascular permeability due to chemicals (ETOH, HCl, indomethacin) significantly increased after surgical vagotomy in association with an increase in both number and severity of gastric mucosal lesions; 4) IND alone (in animals with an intact vagus) did not produce gastric mucosal lesions (in 1-h experiments), but it aggravated ETOH-induced gastric mucosal damage (both its number and severity); 5) the gastric mucosal levels of prostacyclin and PGE₂ decreased after surgical vagotomy; 6) IND application (after surgical vagotomy) decreased further the tissue levels of prostacyclin and PGE₂ in association with an increase of gastric mucosal damage; and 7) the gastric mucosal protective effects of SH-groups were abolished by surgical vagotomy.     

Effect of atropine, PGF2 alpha and cimetidine on the beta-carotene induced cytoprotection in ethanol-treated rats

The aim of the study was to evaluate the influence of atropine, PGF2 alpha and cimetidine on the gastric cytoprotective effect of beta-carotene. Mucosal damage was produced by intragastric (i.g.) addition of 96% ethanol in CFY-strain rats of both sexes weighing 180-220 g. Gastric cytoprotection caused by i. g. pretreatment with 1.0 mg/kg beta-carotene 30 minutes before ethanol administration, was observed after 1 hour. Atropine (0.5 mg/kg), cimetidine (50 mg/kg) and PGF2 alpha (200 micrograms/kg) were given intraperitoneally (i.p.) 30 minutes before ethanol administration with and without beta-carotene and the changes in the number and severity of the gastric ulcers were detected. PGF2 alpha did not influence the gastric cytoprotective effect of beta-carotene meanwhile it was inhibited by atropine and markedly by cimetidine. Deleterious effect of cimetidine on the beta-carotene-induced cytoprotection may be explained perhaps by the adverse effect of the two compounds on ATP-cAMP transformation hereby counteracting one another, but more data are needed to the better understanding of drug interactions relating to mucosal cytoprotection.     

Acute and chronic surgical vagotomy (SV) and gastric mucosal vascular permeability in ethanol treated rats.

The role of vagus nerve was studied in the development of gastric mucosal damage induced by ethanol (ETOH). The investigations were carried out on Sprague-Dawley rats. The gastric mucosal damage was produced by i.g. administration of 1 ml 96% ETOH. Acute surgical vagotomy (ASV) was carried out 30 min, chronic surgical vagotomy (CSV) 14 days before the ETOH application. The animals were sacrificed at 0, 1, 5, 15, 60 min after ETOH. Evans blue (EB) (1 mg/100 g) was given i.v. 15 min before autopsy. The number and severity of lesions the EB accumulation of the gastric juice and gastric mucosa were noted. It was found, that: 1. The vascular permeability increased after ETOH treatment at an early state (within 1-5 min) in association to the macroscopic appearance of erosions. 2. The number and extension of lesions, the EB concentrations in gastric juice and gastric mucosa were significantly higher both after ASV and CSV. 3. Surgical vagotomy alone did not increase the vascular permeability. 4. No significant ulcer formation was observed in vagotomized rats without ETOH treatment. It was concluded, that 1. Both ASV and CSV enhanced the development of gastric mucosal injury induced by ethanol. 2. Neither acute nor chronic surgical vagotomy exerted an effect of the development of mucosal injury and vascular permeability without the application of the noxious agent. 3. The further increase of enhanced vascular permeability by vagotomy probably has an etiologic role in the aggravating effect of ASV and CSV on the development of chemical-induced lesions.     

Is acute surgical vagotomy an aggressor to gastric mucosa in pylorus ligated rats with and without indomethacin treatment?

Previously it was proved that intact vagal nerve is basically necessary for the development of gastric cytoprotection. The aims of this study were to receive further data about the role of vagal nerve in the development of gastric mucosal damage. The observations were carried out on Sprague-Dawley rats. Acute bilateral surgical vagotomy was done with pylorus ligation and/or indomethacin (IND) treatment (20 mg/kg, sc.) at the time of operation. The animals were sacrificed 4 h after the operation. The number, the severity (semiquantitative method), the mean size and summed surface (computer assisted quantitative method) of gastric mucosal damage, the H+ output and the mucosal PGE2 level were determined. It has been found that 1) the ASV itself (without IND or pylorus ligation) provoked gastric mucosal damage, which was more severe than in the pylorus ligated animals at 4 h; 2) IND was able to reduce the summed surface of mucosal damage after ASV; 3) ASV aggravated the gastric mucosal damage in pylorus ligated animals in spite of the decreased H+ output; 4) the PGE2 level was lower in vagotomized and vagotomized+pylorus ligated animals then in the control group, and the IND did not cause further decrease in its level after ASV. It has been concluded that the balance between aggressive and defensive factors of gastric mucosa was shifted to the aggressive side in surgically vagotomized animals.     

Failure of prostacyclin, beta-carotene, atropine and cimetidine to produce gastric cyto- and general mucosal protection in surgically vagotomized rats

Different chemicals (such as ethanol, HCl, drugs) produce gastric mucosal injury. A special type of gastric mucosal defense, which differed from the inhibition of gastric acid secretion, was discovered in response to small doses of prostaglandins. This phenomenon was termed "gastric cytoprotection". Later, the existence of gastric cytoprotection was proved using different compounds, such as vitamin A and other carotenoids, prostacyclin, small doses of anticholinergic and H2-blocking agents. These compounds produce cyto-protection by different mechanisms. In this study we tested the role of vagus nerve on the development of these different types of gastric cytoprotection. These compounds prevent ethanol-induced gastric mucosal injury in rats with intact vagus nerve, but their cyto- and mucosal protective effects disappear in surgically vagotomized rats. These results indicate that the intact vagus nerve is basically necessary for the overproduction of HCl and pepsin secretion, and for the development of gastric cytoprotection, produced by different compounds (e.g. prostacyclin, beta-carotene, small doses of atropine and cimetidine) acting without the presence of inhibition of gastric acid secretion.     

Effects of endothelin-1 on duodenal bicarbonate secretion and mucosal integrity in rats

Effects of endothelin-1 on gastric acid secretion, duodenal HCO3- secretion, and duodenal mucosal integrity were investigated in anesthetized rats, in comparison with those of TY-10957, a stable analogue of prostacyclin. A rat stomach mounted on an ex-vivo chamber or a proximal duodenal loop was perfused with saline, and gastric acid or duodenal HCO3- secretion was measured using a pH-stat method and by adding 100 mM NaOH or 10 mM HCl, respectively. Duodenal lesions were induced by mepirizole (200 mg/kg) given subcutaneously. Intravenous administration of endothelin-1 (0.6 and 1 nmol/kg) caused an increase of duodenal HCO3- secretion with concomitant elevation of blood pressure; this effect was antagonized by co-administrahon of BQ-123 (ET(A) antagonist; 3 mg/kg, i.v.) and significantly mitigated by vagotomy. Likewise, endothelin-1 caused a significant decrease in histamine-stimulated acid secretion, and this effect was also significantly antagonized by BQ-123. Although TY-10957 (10 and 30 mg/kg, i.v.) produced a temporal decrease of blood pressure, this agent caused not only an increase of duodenal HCO3- secretion, independent of vagal nerves, but also a decrease of acid secretion as well. In addition, both endothelin-1 and TY-10957 significantly prevented mepirizole-induced duodenal lesions at the doses that caused an increase of duodenal HCO3- secretion and a decrease of gastric acid secretion. These results suggest that endothelin-1 affects the duodenal mucosal integrity by modifying both gastric acid and duodenal HCO3- secretions, the effects being mediated by ET(A) receptors.     

Peripheral GLP-1 gastroprotection against ethanol: the role of exendin, NO, CGRP, prostaglandins and blood flow

The aim of this study was to investigate the effects of peripherally injected glucagon like peptide-1 (GLP-1) on ethanol-induced gastric mucosal damage and the mechanisms included in the effect. Absolute ethanol was administered through an orogastric cannula right after the injection of GLP-1 (1, 10, 100, 1000 or 10,000 ng/kg; i.p.). The rats were decapitated an hour later, the stomachs removed and the gastric mucosal damage scored. 1000 ng GLP-1 inhibited gastric mucosal damage by 45% and 10,000 ng GLP-1 by 60%. The specific receptor antagonist exendin-(9-39) (2500 ng/kg; i.p.), calcitonin gene related peptide (CGRP) receptor antagonist CGRP-(8-37) (10 microg/kg; i.p.), nitric oxide (NO) synthase inhibitor l-NAME (30 mg/kg; s.c.) and cyclooxygenase inhibitor indomethacin (5 mg/kg; i.p.) inhibited the preventive effect of GLP-1 on ethanol-induced gastric mucosal damage. GLP-1 also prevented the decrease in gastric mucosal blood flow caused by ethanol when administered at gastroprotective doses (1000 and 10,000 ng/kg; i.p.). In conclusion, GLP-1 administered peripherally prevents the gastric mucosal damage caused by ethanol in rats. CGRP, NO, prostaglandin and gastric mucosal blood flow are thought to play a role in this effect, mediated through receptors specific to GLP-1.     

Effect of acute surgical vagotomy on the mucosal content of 6-keto-PGF1 alpha, PGE2 and glutathione after intragastric 96% ethanol treatment in rats.

It has been observed earlier that gastric cytoprotection produced by PGI2, beta-carotene, small doses of atropine or cimetidine has failed in surgically vagotomized rats. This phenomenon may be in connection with endogenous prostaglandins (PGs) and glutathione (GSH) level of the gastric mucosa. The aims of the study were to evaluate the effect of vagus nerve on the gastric mucosal 6-keto-PGF1 alpha, PGE2 and glutathione after intragastric 96% ethanol (ETOH) treatment. The observations were carried out on CFY rats. The gastric mucosal damage was produced by intragastric administration of 1 ml 96% ETOH. Acute bilateral surgical vagotomy (ASV) was carried out 30 min prior to ETOH application. The animals were sacrificed 1, 5, 15 or 60 min after ETOH installation. The number and the severity of gastric mucosal lesions were noted and 6-keto-PGF1 alpha, PGE2 an GSH contents of gastric mucosa were measured. It has been found that: 1. the number and the severity of gastric mucosal lesions were increased after ASV compared to those with intact vagal nerve, 2. 96% ETOH treatment increased both the gastric mucosal PGs and GSH levels, 3. 6-keto-PGF1 alpha peaked at 5 min PGE2 and GSH peaked at 15 min after ETOH treatment, 4. ASV decreased the gastric mucosal PGs content and delayed the peaks of PGE2 and GSH. It has been concluded that the decreased content of PGs and the delayed GSH increase may play a pathological role in the failure of gastric cytoprotection of rats after ASV.     

Gastric mucosal damage induced by arecoline seizure in rats

In an attempt to know the relation of seizure and gastric mucosal damage, we challenged arecoline (ACL) centrally to induce seizure and investigated gastric hemorrhagic injury in acid-irrigated stomachs of rats. The protective effects of several drugs also were evaluated. After deprivation of food for 24 h, rats were received laparotomy under diethylether-anesthesia. Both pylorus sphincters and carotid esophagus were ligated. The forestomach was equipped with a cannula for gastric irrigation. After recovery from anesthesia (approximately 1 h), the stomach was irrigated for 2 h with an acid solution containing 100 mM HCl and 54 mM NaCl or the same volume of normal saline. Intracerebroventricular (i.c.v.) ACL (0, 1, 3 or 10 mg/kg dissolved in 10 microl of CSF) was challenged to rats immediately after gastric irrigation. The seizure in rats was produced by ACL in a dose-related manner. The ulcerogenic parameters such as decrease of gastric mucosal glutathione levels and increase of histamine concentrations and lipid peroxide generations as well as the raise of luminal hemoglobin contents and exacerbated mucosal lesions were obtained depending on the doses of ACL challenged. These ulcerogenic parameters produced in ACL (10 mg/kg, i.c.v.) seizure rats were markedly ameliorated by gastric vagotomy or central anticholinergics. Intraperitoneal ketotifen, zinc sulfate, diphenhydramine or cimetidine also produced significant (p<0.05) inhibitions of these ulcerogenic parameters in ACL seizure rats. In conclusion, central ACL seizure may produce gastric oxidative stress and hemorrhagic lesions via vagal nervous activation and histamine release in acid-irrigated stomachs of rats.     

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.     

Changes of gastric mucosal biochemistry in ethanol-treated rats with and without acute surgical vagotomy

The biochemical background of ethanol-(ETOH) induced gastric mucosal damage was studied in rats with intact vagus and after acute surgical vagotomy. Observations were carried out on Sprague-Dawley (CFY) strain rats of both sexes. Gastric mucosal lesions were produced by intragastric administration of 1 ml 96% ethanol. Bilateral truncal surgical vagotomy was carried out 30 min before ETOH administration. The number and severity of gastric mucosal lesions was noted 1 h after ETOH administration. Biochemical measurements (gastric mucosal level of ATP, ADP, AMP, cAMP and lactate) were carried out from the total homogenized gastric mucosa. The adenylate pool (ATP + ADP + AMP), energy charge ((ATP + 0.5 ADP)/(ATP + ADP + AMP)) and ratio of ATP/ADP were calculated. It was found that: 1) ATP transformation into ADP increased, while ATP transformation in cAMP decreased in ethanol-treated animals with intact vagus nerve, while these transformations were quite the opposite in vagotomized animals; 2) no significant changes were found in the tissue level of lactate: and 3) the extent of biochemical changes was significantly less after surgical vagotomy. It is concluded that an intact vagus is basically necessary for the metabolic adaptation of gastric mucosa.     

Stimulation of gastric acid secretion by progesterone metabolites as neuroactive steroids in anesthetized rats.

The effect of neuroactive progesterone metabolites, 5alpha- and 5beta-pregnan-3alpha-ol-20-one, and their stereoisomers at the 3 C site, 5alpha- and 5beta-pregnan-3beta-ol-20-one, on gastric acid secretion was investigated in urethane-anesthetized rats. Both 5alpha- and 5beta-pregnan-3alpha-ol-20-one dose-dependently (0.3-3 mg x kg(-1), i.v.) stimulated gastric acid secretion with an early onset of action. Their potency and efficacy were almost the equivalent of one another. In contrast, their stereoisomers did not have a significant effect even at 10 mg x kg(-1) (i.v.). The 5beta-pregnan-3alpha-ol-20-one (3 mg x kg(-1), i.v.)-stimulated gastric acid secretion was remarkably inhibited by bilateral vagotomy or pretreatment with atropine (1 mg x kg(-1), i.v.). An antagonist of the GABA(A) receptor, picrotoxin, at 3 and 6 mg x kg(-1) (i.v.), significantly inhibited the 5beta-pregnan-3alpha-ol-20-one (3 mg x kg(-1), i.v.)-stimulated gastric acid secretion. These results indicate that naturally occurring neuroactive steroids, 5alpha- and 5beta-pregnan-3alpha-ol-20-one, stimulate gastric acid secretion in a stereoselective and dose-dependent manner in urethane-anesthetized rats. It is likely that the action of these neuroactive steroids is of central origin and that interaction with GABA(A) receptors and stimulation of vagal pathway are involved in its mechanism of action.     

Vagus-mediated activation of mucosal mast cells in the stomach: effect of ketotifen on gastric mucosal lesion formation and acid secretion induced by a high dose of intracisternal TRH analogue.

TRH analogue, RX 77368, injected intracisternally (i.c.) at high dose (3 microg/rat) produces gastric mucosal lesion formation through vagal-dependent pathway. The gastric mucosal hyperemia induced by i.c. RX 77368 was shown to be mediated by muscarinic vagal efferent fibres and mast cells. Furthermore, electrical vagal stimulation was observed to induce gastric mucosal mast cell degranulation. The aim of the study was to assess the influence of ketotifen, a mast cell stabilizer, on RX 77368-induced gastric lesion formation and gastric acid secretion. RX 77368 (3 microg, i.c.) or vehicle (10 microL, i.c.) was delivered 240 min prior to the sacrifice of the animals. Ketotifen or vehicle (0.9% NaCl, 0.5 mL) was injected intraperitoneally (i.p.) at a dose of 10 mg x kg(-1) 30 min before RX 77368 injection. The extent of mucosal damage was planimetrically measured by a video image analyzer (ASK Ltd., Budapest) device. In the gastric acid secretion studies, the rats were pretreated with ketotifen (10 mg x kg(-1), i.p.) or vehicle (0.9% NaCl, 0.5 mL, i.p.), 30 min later pylorus-ligation was performed and RX 77368 (3 microg, i.c.) or vehicle (0.9% NaCl, 10 microL, i.c.) was injected. The rats were killed 240 min after i.c. injection, and the gastric acid secretion was measured through the titration of gastric contents with 0.1 N NaOH to pH 7.0. RX 77368 (3 microg, i.c.) resulted in a gastric mucosal lesion formation involving 8.2% of the corpus mucosa (n = 7). Ketotifen elicited an 85% inhibition on the development of mucosal lesions (n = 7, P < 0.001) whereas ketotifen alone had no effect on the lesion formation in the mucosa (n = 7). The RX 77368 induced increase of gastric acid secretion was not influenced by ketotifen pretreatment in 4-h pylorus-ligated animals. Central vagal activation induced mucosal lesion formation is mediated by the activation of mucosal mast cells in the stomach. Mast cell inhibition by ketotifen does not influence gastric acid secretion induced by i.c. TRH analogue in 4-h pylorus-ligated rats.     

Deficiency of glucocorticoid production delays the healing of acute gastric mucosal erosion and chronic ulcers in rats

Effects of glucocorticoid deficiency followed by corticosterone replacement on the healing of gastric erosions and chronic gastric ulcers have been investigated in rats. Glucocorticoid deficiency was induced by adrenalectomy performed after the formation of gastric erosions or ulcers. Gastric erosions were produced by indomethacin (35 mg/kg, i.p.) or by 6 h immobilization at temperature 8 degrees C, chronic gastric ulcers were induced by 60% acetic acid. All ulcerogenic stimuli caused an increase in corticosterone production. Adrenalectomy created corticosterone deficiency and delayed the healing of gastric erosions and chronic gastric ulcers. The effect of adrenalectomy was more evident in the indomethacin ulcerogenic model. Replacement by corticosterone prompted the healing of gastric erosions and ulcers in adrenalectomized animals. These data suggest a participation of endogenous glucocorticoids in a restoration of gastric mucosal integrity.     

Interrelationships between the membrane-bound ATP-dependent energy systems of the gastric mucosa and the gastric cytoprotective effect of beta-carotene on the development of gastric mucosal damage produced by 0.6 M HCl in rats

The effects of different doses (0.01-0.1-1.0-10.0/mg/kg-1) of beta-carotene were studied on gastric secretory responses of 4 hr pylorus-ligated rats: development of gastric mucosal damage (as assessed by number and severity of lesions) produced by intragastric administration of 0.6 M HCl; tissue level of adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP), adenylate pool (ATP + ADP + AMP), ratio of ATP X ADP-1, "energy charge" (ATP + 0.5 ADP X X (ATP + ADP + AMP)-1) (during the development of gastric mucosal damage by 0.6 M HCl and of gastric cytoprotection by beta-carotene. It was found that beta-carotene did not decrease the gastric secretory responses of 4 hr pylorus-ligated rats; The development of gastric mucosal damage could be decreased dose-dependently by the administration of beta-carotene; the ATP transformation could be decreased by beta-carotene; the tissue levels of cAMP and AMP could be increased significantly and dose-dependently by beta-carotene; the ratio of ATP X ADP-1 could be increased significantly and dose-dependently by beta-carotene; the values of adenylate pool and "energy charge" remained unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of the position of the side chain hydroxy group on the gastric antisecretory and antiulcer actions of E1 prostaglandin analogs.

The influence of transposing the C-15 hydroxy group of prostaglandin E1 methyl ester (PGE2ME) on gastric antisecretory and antiulcer actions was investigated. The compound (+/-)15-deoxy- 16alpha, beta-hydroxy PGE1ME (SC-28904) was equipotent to the reference standard PGE1ME in suppressing histamine-stimulated gastric secretion in the Heidenhain pouch (HP) dog. In contrast to PGE1ME, SC-28904 was longer acting when administered intravenously and also showed significant oral activity in the histamine-stimulated gastric fistula dog. SC-28904 was also equipotent to PGE1ME (range of active doses of 0.5 to 5.0 mg/kg, s.c.) in inhibiting forced-exertion gastric ulceration in rats. The compound (+/-)15-deocy-17alpha, beta-hydroxy PGE1ME (SC-30963) was an inactive antisecretory agent in the dog at the 1.0 mg/kg i.v. bolus dose. This dose was 100 times greater than the active antisecretory dose of PGE1ME. Likewise, SC-30693, when administered subcutaneously at a 5.0 mg/kg dose, was also totally inactive in preventing gastric ulcers induced by forced exertion in rats. The important implications of this work are that some of the receptor sites for the PGE1 molecule could easily accomodate the side chain hydroxy group either in the C-15 or C-16 position. Moreover, the hydroxy group in the latter position significantly improved the biological activity of PGE1ME.     

Effects of serotonin and stress on the state of the gastric mucosa in rats with the intact and transsected vagus nerve

In experiments on vagotomized and intact rats with the use of two models of experimental gastric ulceration (injection of serotonin and stress) it was demonstrated that the inhibitory action of vagotomy on haemorrhagic gastric effectiveness was more pronounced in stress than after serotonin application. Vagotomy decreased stress-induced erosive lesions but increased serotonin-induced erosions that may be a result of the increase of gastric tissue sensitivity to this amine which developed simultaneously with significant decrease of its level in gastric wall after vagotomy. Serotonin-antagonist peritol decreased stress-induced gastric disturbances in vagotomized rats more significantly than in intact rats; this suggested the great role of serotonin in anti-ulcerogenic effect of vagotomy.     

Comparison of gastric and intestinal antisecretory and protective effects of prostacyclin and its stable thia-imino-analogue (Hoe 892) in conscious rats

The effects of prostacyclin (PGI2) and its stable thia-thimo-analogue (Hoe 892) on gastric and intestinal secretions and gastric mucosal lesions have been determined in conscious rats. Both PGI2 and Hoe 892 given subcutaneously (s.c.) reduced dose-dependent gastric acid secretion, the ID50 (dose producing 50% inhibition) being about 48.6 and 11.8 micrograms/kg, respectively. In contrast, intragastric (i.g.) PGI2 and Hoe 892 did not cause any change in gastric acid secretion at doses ranging from 1 to 100 micrograms/kg. Both PGI2 and Hoe 892 reduced significantly intestinal fluid secretion (antienteropooling activity). PGI2 and Hoe 892 given i.g. or s.c. reduced dose-dependent gastric ulcer formation induced by acidified aspirin (ASA), Hoe 892 being somewhat less potent than PGI2. Both PGI2 and Hoe 892 were equally effective against gastric mucosal necrosis induced by absolute ethanol and this effect was observed both after i.g. and s.c. administration of these agents. We conclude that stable thia-imino-PGI2 analogue, Hoe 892, has similar gastric and intestinal antisecretory and protective activity as PGI2 and may be useful in the prevention of gastric damage by various noxious agents.     

MDL-646, a new synthetic E1-prostaglandin with local protective effects on the gastric mucosa

The gastric protection, diarrheogenic and arterial hypotensive effects of MDL-646, a PGE1 derivative, have been studied in rats. The compound administered p.o. or i.v. was able to inhibit the macroscopic damage to gastric mucosa produced by noxious stimuli (ethanol and indomethacin). In the stomach perfusion test with the anesthetized rat, intravenously administered MDL-646 reduced histamine- or pentagastrin-stimulated gastric secretion. After intraduodenal administration (i.d.) doses at least 40-50 times greater were necessary for an antisecretory effect. In conscious rats with chronic gastric fistulas, intragastrically administered (i.g.) MDL-646 affected both acid concentration and volume of unstimulated gastric secretion. In experimental models for gastric lesions, MDL-646 was much more potent after oral (p.o.) (15-30 times) than after i.v. administration. (ED50 micrograms/kg: vs. alcohol lesions, 0.05 p.o. and 0.7 i.v.; vs. indomethacin ulcers, 7.0 p.o. and 195 i.v.). Our data would fit the hypothesis that it was a local effect on the gastric mucosa. The mechanism of this effect is not known. The supposed local activity coupled with the antisecretory effects and the good tolerability make it interesting to test MDL-646 as an anti-ulcer agent in man.