Effects of TRH on gastric acid secretion: a model for human study.

The possible effects of TRH administration on different parameters of gastric function were studied in 10 patients with different gastrointestinal complaints. Basal (BAO) and pentagastrin stimulated (6 micrograms pentagastrin/kg bw sc) maximal (MAO) acid output were determined and serum levels of TSH, total and free thyroxine (T4 and FT4), triiodothyronine (T3) were measured. After determinations of BAO and MAO and the hormones indicated above, one group of patients received a TRH injection (0.2 mg protirelin) intravenously. The second group of patients was injected with atropine (atropinum sulfuricum, 1 mg, iv). At different times following the injections in both groups of patients BAO, MAO and serum levels of TSH, total and free T4, T3, gastrin were determined. Injection of TRH resulted in an increase in TSH and with some delay in thyroxine and gastric acid levels. Atropine treatment was followed by a decrease in gastric acid secretion and a small decrease in TSH and no changes in the values of the other studied hormones. The results suggest a complex interrelationship between TRH, vagal system and pentagastrin-dependent gastric acid secretion operating in human subjects.

Molecular biochemistry and pharmacology of peptic ulcer treatment. A review.

The membrane-bound ATP-dependent energy systems (ATP-membrane ATPase-ADP and ATP-adenylate cyclase-cAMP) play an essential role in the physiological regulation of the gastrointestinal mucosa and its damage in rat and man. A good, physiologically, hormonally and pharmacologically well controlled and regulated feedback system exists between the two energy systems. The significant increase of ATP transformation into ADP or cAMP represents a causative metabolic background of the development of gastric, duodenal and jejunal ulcer (damage) in man and rat. The ulcer preventive effects of vitamin A, beta-carotene, atropine, cimetidine, prostacyclin I2, and surgical vagotomy were studied in connection with their effects on the membrane-bound ATP-dependent energy systems of the gastric, duodenal and jejunal mucosa in man and rat. Atropine and cimetidine were applied in cytoprotective and antisecretory doses, and the tissue levels of ATP, ADP, AMP, cAMP and lactate were measured. The results indicated that the disturbed equilibrium between the two energy supply systems can be modified (normalized) by drugs and surgical vagotomy; the drug effect depends on the actual biochemism of the gastroduodenal mucosa; the values of affinities (pD2) and intrinsic activities (alpha) of the different drugs differ in relation to membrane-bound ATP-splitting enzymes; the changes in the membrane-bound ATP-dependent energy systems of the damaged rat gastric mucosa, produced by vitamin A and beta-carotene, depend on their cytoprotective doses which are connected with their cytoprotective effects; the biochemical changes induced by drugs (given in cytoprotective and anti-secretory doses) differ only quantitatively but not qualitatively; the drug effects on the membrane-located ATP-splitting enzymes (membrane ATPase and adenylate cyclase) in human gastric, duodenal and jejunal mucosa are similar to those in rats, but their affinities (pD2) and also their intrinsic activities (alpha) differ to the enzyme systems.

Effect of indomethacin on glucose absorption and insulin release in patients with impaired glucose tolerance.

Determinations of the levels of blood glucose and of serum insulin-like activity were made in 12 patients with impaired glucose absorption treated with indomethacin 4 x 25 mg for a day. By comparing the results with untreated control patients, it was found that the peak blood level of glucose, and the serum level of insulin-like activity, could be significantly decreased by this oral administration of indomethacin. The decrease of blood level of glucose appeared 0.5 h before the decrease of insulin-like activity in these patients with impaired glucose tolerance.

Biochemical background of the development of gastric mucosal damage in pylorus-ligated plus aspirin-treated rats.

Gastric mucosal damage was produced in rats after pyloric ligation by intragastric administration of 200 mg/kg aspirin diluted in 2 ml 150 mmol/l HCl. The animals in the control group received 2 ml saline solution, or submitted to pyloric ligation only. The animals were killed 4 h after the pyloric ligation, when the number and severity of gastric lesions (ulcers), and the gastric fundic mucosal level of adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP), cyclic adenosine monophosphate (cAMP) and lactate, were noted and measured. The adenylate pool (ATP + ADP + AMP) and the energy charge (ATP + 0.5ADP). (ATP + ADP + AMP)-1 were calculated. It was found that: the gastric H+ output decreased significantly in the pylorus-ligated plus aspirin-treated animals; the number and severity of gastric lesions increased significantly in the pylorus-ligated aspirin-treated animals; the extent of ATP transformation into the ADP decreased significantly in the pylorus-ligated aspirin-treated animals; the extent of ATP transformation into the cAMP decreased significantly during the aspirin treatment; the values of adenylate pool and of "energy charge" remained unchanged in the different groups of animals. It is concluded that: the decreased H+ output in the pylorus-ligated plus aspirin-treated group can be obtained by the decreased extent of ATP transformation into the ADP by membrane ATPase, and the biochemical changes in the gastric mucosa indicate a decreased energy turnover.

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)

Interrelationships between membrane-bound ATP-dependent energy systems, gastric mucosal damage produced by NaOH, hypertonic NaCl, HCl, 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)

Membrane-bound ATP-dependent energy systems and the development of the gastric mucosal damage in rats produced by 0.2 M NaOH, 25% NaCl, 0.6 M HCI and 96% ethanol.

Damage to the gastric fundic mucosa was produced in rats by intragastric administration of 1 ml 0.2 M NaOH, 25% NaCl, 0.6 M HCl or 96% ethanol; a control group received 1 ml saline solution. The animals were killed 1 h later, and the number and severity of ulcers (lesions) noted. The gastric fundic mucosa were excised and frozen, and assayed enzymatically for adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP) and lactate, while the tissue level of cyclic adenosine monophosphate (cAMP) was estimated by radioimmunoassay. It was found that: (i) the number and severity of gastric lesions (ulcers) increased significantly in all the groups treated by the 4 necrotizing agents, (ii) the extent of ATP breakdown into ADP increased significantly, while the ATP transformation into cAMP by adenylate cyclase, and of cAMP into AMP by phosphodiesterase, decreased, (iii) the tissue level of lactate increased only in the 0.6 M HCl groups. It was concluded that: (i) the mucosal damage develops in consequence of a very active metabolic adaptation of the rat gastric fundic mucosa, notably the significantly increased ATP transformation into ADP, which is not the consequence of hypoxaemia, (ii) the feed-back mechanism system between the membrane-bound ATP-dependent energy systems is broken as the mucosal damage develops, the main changes being a significantly increased ATP transformation into ADP, a significantly decreased ATP transformation into cAMP, and significant alterations by neural, hormonal and pharmacological influences in the membrane-bound ATP-dependent energy systems.

Some metabolic and biochemical alterations during the development of stress ulcers in rats forced to swim.

Swimming of the rats in the water below body temperature (23 degrees C) for a period of 5 hours resulted in a number of acute haemorrhagic lesions, principally erosions, in the glandular part of the stomach. The objective of this study was to establish the possible roles of some hormonal, biochemical and metabolic factors in the pathogenesis of stress ulcer produced in rats forced to swim. It was found that (i) prior ligation of the pylorus caused a considerable decrease of both the incidence and the severity of the ulcers resulting from the swim-stress, (ii) a significant decrease of the gastric secretion and rectal temperature resulted during the swim-stress condition, (iii) metabolic acidosis developed during the forced swimming period, (iv) considerable increases of the plasma corticosterone and blood glucose concentration also developed, (v) the gastric mucosal level of cAMP also increased, and (vi) a prior period of starvation increased the incidence and severity of the acute ulcers resulting from the swim-stress. It was concluded that various humoral, biochemical and metabolic factors play important roles in the development of stress ulceration in rats forced to swim.

Membrane-bound ATP-dependent energy systems and gastric cytoprotection by prostacyclin, atropine and cimetidine in the rat.

The effects were studied of different doses of prostacyclin (PG12), atropine and cimetidine on the gastric secretory responses of four-hour pylorus-ligated rats and on the gastric mucosal damage produced by intragastric administration of 0.6 M HCl, to determine the cytoprotective doses of PG12, atropine and cimetidine. In another series of observations, gastric mucosal damage was produced by intragastric administration of 0.6 M HCl and the effects were studied of cytoprotective doses of PG12, atropine and cimetidine on the number and severity of gastric lesions, in connection with the biochemical changes of the rat gastric fundic mucosa. The drugs were given intraperitoneally 30 min before the application of the necrotizing agent, and the animals were killed one hour later. During the experiments, the tissue levels of adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP) and lactate were measured enzymatically, and the tissue content of cyclic adenosine monophosphate (cAMP) was determined by radioimmunoassay. The specimens were taken from the gastric fundic mucosa of groups of animals treated with saline solution (absolute control), with 0.6 M HCl (pathological control) and with 0.6 M HCl plus PG12, atropine and cimetidine (given in cytoprotective doses). The ratio of ATP.ADP-1, adenylate pool (ATP + ADP + AMP) and energy charge (ATP + 0.5 ADP.ATP + ADP + AMP-1) were calculated in all groups of animals. It was found that: (i) PG12 (in a dose of 5 micrograms.kg-1) atropine (in a dose of 0.025 mg.kg-1) and cimetidine (in a dose of 2.5 micrograms.kg-1) have cytoprotective effects; (ii) the gastric fundic mucosal damage produced by intragastric administration of 0.6 M HCl appears as a result of a positive metabolic adaptation of the gastric fundic mucosa; (iii) the development of gastric cytoprotection by PG12, atropine and cimetidine give rise to very different changes in the tissue levels of ATP, ADP, AMP and cAMP.(ABSTRACT TRUNCATED AT 400 WORDS)

The relationships between indomethacine-induced gastric ulcer, ulcer protection by cimetidine and prostacyclin and the cAMP system of the gastric fundic mucosa in the rat.

Gastric ulcer was provoked by indomethacine (20 mg/kg s.c.) in rats. The ulcer protection by prostacyclin and cimetidine as well as the changes of tissue cAMP level in the gastric fundic mucosa--during ulcer-provocation and ulcer protection--were studied. The animals received prostacyclin (125, 250 and 500 micrograms/kg) and cimetidine (2.5 and 50 mg/kg) together with indomethacine. Evaluation of the results was undertaken 4 hours after the administration of the provoking agent. The number and severity of the ulcers as well as the cAMP level of the gastric fundic mucosa were measured. The following results were obtained: (1) cAMP level of the gastric fundic mucosa remained unaltered at the time of ulcer provocation; (2) cimetidine and prostacyclin reduced the number and severity of the ulcers in a dose-dependent manner; (3) cAMP level of the gastric fundic mucosa was reduced after cimetidine and prostacyclin treatment in a dose-dependent manner, the extent of which however did not show any correlation with the degree of ulcer-preventive action. The experimental results indicate that (1) the development of indomethacine-induced gastric ulcer is independent of the ATP--adenylate cyclase--cAMP system of the gastric fundic mucosa; (2) the ulcer protective action of cimetidine and prostacyclin is independent of tissue cAMP system of the gastric fundic mucosa in this model.

Effects of drugs on the production of stress ulcer in the rat.

The authors studied the effect of drugs with different mechanisms of action on the prevention of stress ulcer production in the rat. Stress ulcer was induced by a method developed by the authors: intact, starved rats were swum in water at 23 degrees C for 5 hours. Atropine (0.1-0.5 and 1.0 mg/kg i.m.), cimetidine (1.0-5.0 and 25 mg/kg i.p.), prostacyclin (PGI2) (5.0-25.0 and 100 micrograms/kg i.p.) and phentolamine (0.35-1.75-3.5 and 7.0 mg/kg i.m.) were shown to decrease the production of stress ulcers significantly, in a dose-dependent fashion. Propranolol (0.35-1.75-3.5 and 7.0 mg/kg i.m.) did not influence the production of stress ulcers. The finding that drugs with different actions could considerably reduce or prevent the production of stress ulcer appears to indicate the complexity of the neural, hormonal and biochemical processes involved in the pathogenesis. On the basis of the present results the authors suggest the use of a preventive therapeutic regimen in clinical practice with an appropriate combination of drugs.

The role of the ATP--adenylate cyclase--cAMP system and its pharmacological regulation in the development of gastric hypersecretion and ulceration.

The role and pharmacological regulation of the ATP-adenylate-cyclase--cAMP system were studied in the mucosa of the gastric fundus, and in the forestomach, of pylorus-ligated rats to elucidate the development of gastric hypersecretion and ulceration. (1) cAMP content of the tissue of the fundus mucosa and of the forestomach decreased before the significant increase of gastric H+ output and ulcer development; (2) the gastric H+ outputs depended on the breakdown of ATP in the fundus mucosa; (3) the gastric H+ secretion was inhibited in a dose-dependent way by theophylline, epinephrine and cimetidine; (4) the inhibition of gastric H+ secretion by epinephrine , theophylline or epinephrine plus theophylline associated with a significant increase in the mucosal cAMP of the gastric fundus (5) the significant increase in gastric H+ secretion due to histamine associated with a significant decrease in fundic mucosal cAMP; (6) the gastric H+ secretion could be inhibited dose-dependently by ADP, AMP, cyclic 2', 3'-AMP and cAMP; (7) the inhibition of gastric H+ secretion by cimetidine developed without and with histamine application in pylorus-ligated rats; (8) the histamine on gastric H+ secretion could not be stimulated further with theophylline (9) no significant correlation was found between the mucosal cAMP level and the gastric H+ secretion and/or between the decrease of mucosal cAMP content and gastric H+ secretion. It has been concluded that in pylorus-ligated rats (1) the gastric H+ secretion is an ATP-dependent process; (2) the cAMP system has an inhibitory effect as regards the development of gastric hypersecretion and of ulceration; (3) histamine and cimetidine show no close correlation with the cAMP system; (4) an extracellular and intracellular feed-back mechanism system exists between th ATP-membrane-bound ATPase-ADP and the ATP--adenylate cyclase--cAMP systems in the background of the development of gastric hypersecretion and ulceration.