T. Jávor

Cellular mechanisms of the development of gastric mucosal damage and of gastrocytoprotection induced by prostacyclin in rats. A pharmacological study

Abstract The rat gastric mucosal damage (lesion) can be produced by the topical application of 96% ethanol and its development can be prevented by the administration of prostacyclin (PGI2) in doses which have no inhibitory effect on gastric acid secretion. The bases for this phenomenon are unknown. In this study the following observations were carried out: 1. The effects of different drugs (actinomycin D, atropine, cimetidine, Degranol,2,4-dinitro-phenol, histamine, epinephrine, pentagastrin, prostacyclin, tetracycline) and of bilateral surgical vagotomy were studied on the development of ethanol-induced rat gastric mucosal damage (ulcer); 2. The effect of PGI2 (applied in a dose of 5 μg/kg) was studied on the ulcer preventive effects of different drugs and of surgical vagotomy; 3. The effects of different drugs and of surgical vagotomy were estimated on the development of gastrocytoprotection produced by PGI2. The drugs and surgical vagotomy were applied alone or in a parallel administration with the PGI2 cytoprotective dose of μg/kg, at 30 minutes before giving the ethanol. The animals were killed 1 hr after ethanol administration. The number of gastric lesions (ulcers) were noted and their severities scored. The single application of atropine, cimetidine, Degranol, epinephrine, histamine, pentagastrin and PGI2 decreased significantly the number and severity of ulcers; the other drugs (tetracycline, actinomycin D,2,4-dinitrophenol) diminished the lesions but without statistical significance. The PGI2 ( in a dose of 5 μg/kg) decreased significantly the ulcer preventive effect of Degranol, tetracycline, cimetidine, atropine, epinephrine and of surgical vagotomy; while the effects of actinomycin D, pentagastrin and 2,4-dinitrophenol were significantly increased by PGI2 administration. The cytoprotective effect of PGI2 was decreased significantly when it was given together with Degranol, tetracycline, actinomycin D, cimetidine, atropine, epinephrine and surgical vagotomy. The parallel administration of PGI2 with pentagastrin and 2,4-dinitrophenol increased significantly the extent of PGI2-induced gastrocytoprotection. These data suggest that very complex cellular mechanisms (energy liberations, d e n o v o synthesis of DNA,RNA,protein, oxydative phosphorylation) may be involved in the development of gastric mucosal damage by topical application of ethanol and of gastrocytoprotection produced by PGI2.

Interrelationships between membrane-bound ATP-dependent energy systems,gastric mucosal damage produced by NaOH,hypertonic NaCl, HC1, and alcohol, and prostacyclin-induced gastric cytoprotection in rats

Rat gastric mucosal lesions (ulcers) were produced by topical application of 0.2 M NaOH, 25% NaCl, 0.6 M HCl and 96% ethanol. The animals were sacrificed 1 hr after administration of the different necrotizing agents. The number of gastric lesions (ulcers) was noted and their severities scored. Different doses (5 and 50 micrograms.kg-1) of prostacyclin (PGI2) were given intraperitoneally at 30 minutes before administration of necrotizing agents, and their effects were studied on the number and severity of gastric lesions (ulcers). At the time of killing of animals, the rat gastric fundic mucosa was removed for biochemical examinations. Tissue levels of adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP) and lactate were determined enzymatically, while the tissue content of cyclic adenosine monophosphate (cAMP) was measured by radioimmunoassay. The values of the adenylate pool (ATP + ADP + AMP), the ratio of ATP X ADP-1 and the energy charge (ATP + 0.5 ADP X ATP + ADP + AMP-1) were calculated. All biochemical results were calculated in relation to one mg mucosal protein. It was found that:1. the tissue levels of ATP, cAMP, AMP decreased significantly, while the tissue level of ADP increased (without statistical significance) in all models, during the development of gastric mucosal damage; 2. the tissue level of lactate increased only in the model produced by 0.6 M HCl, while its level was unchanged in the other models during the development of gastric mucosal damage; 3. PGI2 decreased dose-dependently the number and severity of gastric lesions (ulcers); 4. the tissue level of ATP, ratio of ATP X ADP-1 and energy charge were decreased significantly, while the tissue level of ADP was increased significantly by PGI2 in all models; 5. the tissue level of lactate and the adenylate pool remained unchanged during the PGI2 effects. It was concluded that: 1. the development of gastric mucosal damage, produced by topical application of 0.2 M NaOH, 25% NaCl, 0.6 M HCl and 96% ethanol, is associated with an active metabolic adaptation of the gastric fundic mucosa; 2. the metabolic adaptation of the rat gastric fundic mucosa is further increased by PGI2, without resulting in hypoxaemic damage of the gastric mucosa; 3. the feed-back mechanism system - between the membrane-bound ATP-dependent energy systems - is broken during the development of gastric mucosal damage produced by different necrotizing agents, which is modified further by PGI2 at the time of gastric cytoprotection.(ABSTRACT TRUNCATED AT 400 WORDS)

Development of 'pharmacological denervation phenomenon' in patients treated with atropine

Abstract The parotid secretion of patients subjected to chronic atropine treatment was examined before, during 2–4 weeks, and after the course of treatment. The basal and reflex secretions (to 0.5 and 5.0% citric acid applied locally) were measured as well as the secretions in response to acetylcholine, norepinephrine and histamine. During the course of treatment there was a decrease in the inhibitory effect of atropine on the parotid secretion, which was not caused by a change in its absorption, metabolism or excretion. During the atropine treatment there was an increase in the basal and submaximal reflex secretions and in the secretion produced by norepinephrine; a smaller increase was observed in response to acetylcholine. 3–5 days after the end of atropine treatment, the basal, submaximal reflex and norepinephrine-induced secretions returned to pretreatment level; the acetylcholine-induced secretion was also reduced but to a lesser degree. From these data the authors conclude that a pharmacological denervation phenomenon develops in human beings. This indicates that there is an alteration in the balance of the mediator-effector system which is reversible, for in 3–5 days after the atropine treatment the pharmacological denervation phenomenon disappears and the original state is re-established.

Development of drug cross-tolerance in patients treated chronically with atropine.

Abstract Studies were carried out on the quantitative inhibitory effect of a quaternary parasympatholytic compound (Gastrixone: 8-methyl-tropinium-bromide-xanthene-9-carboxilate) upon the basal and reflex parotid secretion in patients treated chronically with atropine before, during (2–4 weeks) treatment and 3–6 days after cessation of treatment. A significant decrease in the inhibitory effect of Gastrixone was observed during the course of treatment. This was shown to be a reversible process since the original effect returned 3–6 days after the end of atropine treatment. No alterations in absorption, metabolism and excretion of Gastrixone were found during the atropine treatment. These results suggest the development of drug cross-tolerance to Gastrixone during the course of atropine treatment. The hypothesis is put forward, based on experiments on cholinesterase activity, that the site of the drug cross-tolerance phenomenon is at the receptor level, the alteration of cholinergic receptor structure being induced by prolonged atropine treatment.

Interrelationships between the Gastric Secretory Responses, Prostaglandin E2 Inhibition and Serum Level of Immunoreactive Gastrin in Pylorus-Ligated and Antrectomized Rats

The effects of prostaglandin E2 (PGE2) have been studied on the gastric secretion and the serum level of immunoreactive gastrin in pylorus-ligated and antrectomized rats. It has been observed that: (1) a significant inhibition of gastric secretion (volume and acid output) was caused by PGE2, applied in doses of 75, 150 and 300 microgram/kg body weight, subcutaneously, in both pylorus-occluded and antrectomized rats: PGE2 inhibition of gastric secretion was more pronounced in rats with antrectomy; (2) no significant changes were found in the serum gastrin levels of both pylorus-ligated and antrectomized rats, and (3) no significant changes in serum levels of immunoreactive gastrin were produced by different doses of PGE2, in comparison with their marked inhibitory effects on gastric H+ secretion. It was concluded that there is no essential role of the immunoreactive gastrin, originated from the antral part of the stomach, neither in development of gastric hypersecretion nor in PGE2-produced inhibition on gastric secretion of the pylorus-occluded rats.

Biochemical Analysis of the Stomach Wall in Normal Rats

The rat stomach wall was analysed biochemically. The biochemical extraction was carried out according to the Schneider, Schmidt-Thannhausers method. Acid-soluble inorganic phosphate, acid-soluble organic phosphate, phospholipid phosphate, ribonucleic acidic phosphate, deoxyribonucleic acidic phosphate, phosphoproteid inorganic phosphate were measured colorimetrically according to Briggss method. The nucleic acids were estimated by measuring the phosphate and sugar components. The biochemical analysis was made both from the total stomach, and also separately from glandular stomach and the rumen. It is concluded that these two parts of the rats stomach differ biochemically.

A Biochemical-cellular-morphological Explanation of the Development of Gastric Ulcer in Shay Rats

Seven hours after pyloric ligation the acid-soluble organic phosphates increased both in the glandular and membranaceous stomach wall, whereas a pronounced decrease was found 24 hours after pyloric ligation in both parts of the stomach. The phospholipid phosphates were increased in the glandular and membranaceous parts of the stomach both at 7 and 24 hours after pyloric ligation. The deoxyribonucleic acid was less increased in the glandular than in the membranaceous stomach wall 24 hours after pyloric ligation, whereas the ribonucleic acid was only increased in the membranaceous stomach wall 7 and 24 hours after pyloric ligation.

Some effects of prolonged treatment with atropine on the stomach wall of the rat: (a biochemical-pharmacological approach of the effects of vagal exclusion — vagotomy and atropine treatment — on cellular-molecular level)

Abstract A biochemical-pharmacological analysis of the stomach wall was made in rats chronically treated with atropine. The acid-soluble inorganic and organic phosphates, phospholipid phosphates, ribonucleic acid and deoxyribonucleic acid were measured from the membranous (rumenal) and glandular (pyloric) parts of the stomach wall. It was observed that 1) the glandular part and the membranous part of the stomach wall did not react similarly to prolonged (25 days) atropine treatment; 2) “short term” (reversible) and “long term” (irreversible) biochemical process were present in the glandular part of the stomach wall ten days after cessation of prolonged (25 days) atropine treatment. A biochemical-cellular-morphological theory was made to explain the difference between a “chemical” and a “surgical” vagotomy and for the development of drug tolerance on the stomach wall at the cellular-molecular level.

Biochemical Analysis of Vagotomized Stomach Wall in Rats

The authors carried out a biochemical analysis of vagotomized rat stomach wall 2–3 weeks after a bilateral vagotomy. The biochemical extraction was performed by the Schneider-Schmidt-Thannhauser method. The phosphate fractions were measured colorimetrically according to Briggs. The nucleic acids were measured on the basis of phosphate and sugar components according to Seibert and Brown. The following compounds were determined: acid-soluble organic and inorganic phosphates, phospholipidphosphate, ribonucleic acidic phosphate, deoxyribonucleic acidic phosphate, phosphoproteid inorganic phosphate, ribonucleic acid and deoxyribonucleic acid from the whole, the glandular and the membranaceous stomach. These were compared with the some constituents of the normal rat stomach. After vagotomy a decrease was observed in acid-soluble inorganic phosphate, in organic acid-soluble phosphate, in phosphoprotein inorganic phosphate of the glandular, membranaceous and the total stomach. The phospholipid phosphate did not d...

ROLE OF THE FUNCTIONAL STATE OF THE GASTRIC MUCOSA IN RELATION TO DEVELOPMENT OF EPINEPHRINE EFFECTS ON RAT STOMACH

Publisher Summary The pathogenesis of peptic ulcer is a controversial subject. It is controversial partly because its causes are unknown, its etiology is only poorly understood, and the accumulated evidence suggests a complex, multifactorial pathogenesis. In the last few years, many papers dealt with the role of the sympathetic nervous system and catecholamines on gastric secretion, gastric mucosal circulation, and ulcer formation. This chapter discusses the role of the functional state of the gastric mucosa in relation to development of epinephrine effects on rat stomach. Acute gastric mucosal lesions and hemorrhages frequently occur in patients and experimental animals under various stress situations and after administration of ulcerogenic drugs. It is known that the activity of the membrane ATPase, prepared from gastric mucosa is significantly decreased by epinephrine.