Stimulatory effect of dibutyryl cyclic GMP on acid secretion in mouse isolated stomach and on histamine release in gastric mucosal cells.

We previously reported that endogenous nitric oxide (NO) is involved in the peripheral control of gastric acid secretion induced by some secretagogues, and that endogenous NO is involved in the acid secretion process via histamine release from histamine-containing cells. However, the stimulus-secretion coupling in the cells remains to be clarified. In the present study, we investigated the effect of dibutyryl cyclic GMP on gastric acid secretion in mouse isolated stomach and on histamine release in gastric mucosal cells, in comparison with those of dibutyryl cyclic AMP. Dibutyryl cyclic GMP (300 microM) produced a slight but significant increase of gastric acid secretion, which was completely inhibited by the histamine-H2 receptor antagonist famotidine. In contrast, dibutyryl cyclic GMP (1 mM) markedly inhibited histamine-induced acid secretion. Dibutyryl cyclic AMP (100 microM) produced a sustained increase of gastric acid secretion. The pretreatment with famotidine partially inhibited dibutyryl cyclic AMP-induced gastric acid secretion. Dibutyryl cyclic GMP and dibutyryl cyclic AMP significantly increased the histamine release from gastric mucosal cells. These results suggest that both intracellular cyclic GMP and cyclic AMP act as second messengers for histamine release in the histamine-containing cells, probably ECL cells. On the other hand, in gastric parietal cells, cyclic AMP has a stimulatory effect on gastric acid secretion, whereas cyclic GMP has an inhibitory effect.     

Endogenous opiates inhibit gastric acid secretion induced by central administration of Thyrotropin-Releasing Hormone (TRH)

Thyrotropin-releasing hormone (TRH) administered intraventricularly (ICV) to rats causes a dose-dependent increase in gastric acid secretion over a range of 0.01 μg to 10 μg in the pyloris ligated rat. The maximum increase in gastric acid secretion occurs in the first hour. This effect of TRH is not mediated by its metabolites, histidyl-proline diketopiperazine or pyroglutamyl-histidyl-proline (acid TRH). β-endorphin, D-alanine-methionine-enkephalin and the leucine-enkephalin precursor, dynorphin, all inhibit TRH-induced gastric acid secretion. Bombesin, which reduces basal gastric acid secretion had no effect on TRH-induced secretion.     

Suppression of gastric acid secretion by intracisternal bombesin does not require the ventromedial hypothalamus

Intracisternal administration of the tetradecapeptide peptide bombesin suppresses gastric acid release. Other studies have shown that the ventromedial hypothalamus (VMH) may have an inhibitory role in gastric regulation. To determine if the inhibition of gastric acid secretion by intracisternally administered bombesin is mediated by the ventromedial hypothalamus, bombesin was injected intracisternally in rats with ventromedial hypothalamic lesions. Neither anterior nor posterior VMH lesions altered the effects of bombesin on gastric acid, concentration, volume, total output, or on serum gastrin. The bombesin-induced rise in gastric pH was very mildly attenuated by both lesions. The previous finding of enhanced gastric acid secretion after anterior VMH lesions was confirmed. The results suggest that the VMH is not crucial in the bombesin-induced inhibition of acid secretion.     

Enzyme histochemistry of tryptase in stomach mucosal mast cells of the mouse.

We investigated the histochemical characteristics of mast cell tryptase in different mouse tissues. By use of peptide substrates, tryptase activity could be demonstrated in unfixed connective tissue mast cells in different tissues, including the stomach. Tryptase activity was better localized after aldehyde fixation and frozen sectioning, and under such conditions was also demonstrated in mucosal mast cells of the stomach but not in those of the gut mucosa. Double staining by enzyme histochemistry followed by toluidine blue indicated that the tryptase activity was present only in mast cells and that all mast cells in the stomach mucosa contained the enzyme. The peptide substrates z-Ala-Ala-Lys-4-methoxy-2-naphthylamide and z-Gly-Pro-Arg-4-methoxy-2-naphthlyamide, which are substrates of choice for demonstrating tryptase in other species, were most effective for demonstrating mouse tryptase. The use of protease inhibitors further indicated that activity present in all mast cells was tryptase. Safranin O did not stain stomach mucosal mast cells, suggesting that the tryptase present in these cells was active in the absence of heparin sulfate proteoglycan.     

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 μg 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.     

Effects of ethanol on gastric acid secretion and gastric mucosal cyclic AMP in the rat.

The effect of ethanol on the secretion of gastric acid and the content of cyclic AMP of the gastric mucosa was studied in rats. Intravenously, ethanol (10 to 800 mg/kg) had no effect on the output of acid. Upon local application into the stomach, ethanol (1 to 10%) caused a concentration-dependent inhibition of the output of gastric acid. The effect was evident within 5 min. At the concentration of 1 %,ethanol decreased the rate of acid secretion maximally by about 30%. At the concentration of 3 %, the maximal inhibition was about 70 %. At the concentration of 10 %, ethanol caused a total cessation of the output of acid within 20 to 60 min.Five and 25 min after the administration of 10 % ethanol into the stomach, the gastric mucosal content of cyclic AMP was decreased by approximately 50 %. Also in vitro, the mucosal content of cyclic AMP was decreased by ethanol within 5 min. The decrease was about 30 % with 2.5 % ethanol, approximately 60 % with 10 % ethanol, and approximately 45 % with 20 % ethanol. Alcohol inhibited the activity of the cyclic AMP phosphodiesterase of the gastric mucosa in a competitive manner. The K_i-value was 0.16 M which would correspond to an alcohol concentration of 9.1 % (v/v). Ethanol caused a concentration-dependent inhibition of the activity of the gastric mucosal adenyl cyclase. By 0.166 M (9.4 %) alcohol the inhibition was nearly 100 %.It is concluded that the ethanol-induced decrease of cyclic AMP in the gastric mucosa is due to a decreased formation of the nucleotide. The accompanying inhibition of the output of acid by ethanol is consistent with the view that cyclic AMP is an intracellular regulator of the gastric acid secretion. In view of the role of cyclic AMP in the control of the integrity of the cells, it is suggested that the ethanol-induced damage of gastric mucosa might also be, at least partly, due to the decreased mucosal content of cyclic AMP.     

Inhibition of gastric acid secretion and mucosal blood flow induced by intraventricularly applied neurotensin in rats

To investigate the central effect of neurotensin in gastric functions, changes in gastric acid secretion and mucosal blood flow (MBF) following administration were examined in rats anesthetized with urethane. Neurotensin in doses 1–10 μg/animal injected into the lateral ventricle decreased the basal value of both gastric acid output and MBF. This effect of neurotensin on these gastric parameters was completely blocked by pretreatment of animals with reserpine (2 mg/kg, i.p., 24 hr) or 6-OH-dopamine (250 μg/animal, intraventricularly, 10–14 days). These results indicate that exogenously applied neurotensin induces an inhibition of gastric functions by a central mechanism and suggest that an interaction exists between central catecholamines and the effect of neurotensin on gastric functions.     

Uptake and methylation of histamine by dispersed gastric mucosal cells and its possible influence on acid secretion

Inactivation of histamine by gastric mucosal tissue was examined in dispersed rabbit gastric mucosal cells. Mucosal cells were incubated with [14C]histamine. The formed radioactive metabolites were separated and identified by thin layer co-chromatography and quantitated, in both the cellular and extracellular mediums. Gastric mucosal cells internalized histamine, most of which was immediately methylated primarily to N tau-methylhistamine and released. Cellular histamine product accumulation reached a plateau. The rate of histamine methylation increased with increasing extracellular histamine concentration, moving towards a plateau above 5 microM. Histamine methylation was greatly decreased but not abolished at 4 degrees C, in the absence of Na+ and by phlorizin (0.5 mM), an inhibitor of Na(+)-dependent co-transport. Inhibition of histamine N-methyltransferase decreased intracellular methylhistamine content dose dependently without increasing intracellular histamine. The secretagogues pentagastrin and carbachol did not influence histamine metabolism but ethanol inhibited methylation. The data suggest that gastric mucosal cells take up histamine by a Na(+)-dependent and Na(+)-independent process. The histamine uptake capacity appears to be linked to the methylation activity within the cell. The decrease in histamine uptake and metabolism caused by ethanol could potentially increase histamine concentrations near the target cells and be the reason for the stimulatory effect of ethanol on acid secretion.     

尖顶羊肚菌对急性酒精性胃黏膜损伤保护作用研究

研究尖顶羊肚菌菌丝体水提液对酒精引起的大鼠急性胃黏膜损伤的保护作用。以95%乙醇诱导的大鼠胃黏膜损伤为模型,测定各组胃黏膜损伤指数,并测定胃黏膜超氧化物歧化酶（SOD）、丙二醛（MDA）、谷胱甘肽（GSH）含量,采用幽门结扎法,测定大鼠胃酸、胃蛋白酶与胃黏液分泌的量。结果表明羊肚菌中、高剂量能明显降低胃黏膜损伤指数（p＜0.05）;羊肚菌不能抑制胃酸的分泌（p＞0.05）,但是能增加胃蛋白酶与胃黏液的分泌（p＜0.05）;95%乙醇能引起胃黏膜SOD活性与GSH的降低,MDA含量的增加,给予羊肚菌能明显抑制这一现象。结果说明羊肚菌对急性酒精性胃黏膜损伤的保护作用是与增加胃黏液分泌与提高机体抗氧化能力有关。     

The effect of neurotensin and secretin on gastric acid secretion and mucosal blood flow in man

Neurotensin stimulates pancreatic secretion directly and by potentiating the effect of secretin. Neurotensin also inhibits gastric secretion. Secretin inhibits gastric secretion as well, but whether it also interacts with neurotensin is not known. Secretin is known to inhibit gastric mucosal blood flow (GMBF). The effect of neurotensin on GMBF is not known. Acid secretion (triple lumen perfused orogastric tube) and GMBF ([14C]aminopyrine clearance) were therefore measured in 6 subjects during neurotensin, secretin and neurotensin plus secretin infusions. Neurotensin plus secretin reduced acid secretion by a median 130 (range 34-394) mumol/min which was significantly greater than either neurotensin at 36 (7-67) mumol/min or secretin 54 (20-347) mumol/min alone (P less than 0.05). This effect appeared independent of GMBF. Neurotensin plus secretin reduced GMBF by 14 (12-27) ml/min but not significantly more than neurotensin at 11 (3-20) ml/min or secretin 18 (2-27) ml/min alone. Further, there was no correlation between changes in acid output and GMBF during infusion of the peptides. We conclude that the inhibitory effects of neurotensin and secretin on gastric secretion are at least additive and together they may function as an 'enterogastrone'.     

Direct effect of prolactin, induced by TRH injection, on ovarian oestradiol secretion in the ewe

The effect of sustained high plasma levels of prolactin, induced by repeated 2-h i.v. injections of thyrotrophin-releasing hormone (TRH; 20 micrograms), on ovarian oestradiol secretion and plasma levels of LH and FSH was investigated during the preovulatory period in the ewe. Plasma levels of progesterone declined at the same rate after prostaglandin-induced luteal regression in control and TRH-treated ewes. However, TRH treatment resulted in a significant increase in plasma levels of LH and FSH compared to controls from 12 h after luteal regression until 5 to 6 h before the start of the preovulatory surge of LH. In spite of this, and a similar increase in pulse frequency of LH in control and TRH-treated ewes, ovarian oestradiol secretion was significantly suppressed in TRH-treated ewes compared to that in control ewes. The preovulatory surge of LH and FSH, the second FSH peak and subsequent luteal function in terms of plasma levels of progesterone were not significantly different between control and TRH-treated ewes. These results show that TRH treatment, presumably by maintaining elevated plasma levels of prolactin, results in suppression of oestradiol secretion by a direct effect on the ovary in the ewe.     

Effect of nimesulide on gastric acid secretion in the mouse stomach in vitro

Nimesulide, a selective inhibitor of cyclooxygenase-2, has been reported to cause less gastric damage, compared to other NSAIDs. We investigated the effect of nimesulide on basal gastric acid secretion, a contributing factor in NSAID-induced gastric damage, and histamine, pentagastrin, 5-methylfurmethide, isobutyl methylxanthine or high K(+) stimulated acid secretion in the isolated mouse stomach. The stomachs, removed from mice, were transferred into an organ bath and continuously perfused. Changes in pH following the addition of secretagogues were measured by a pH electrode system. The effects of nimesulide on basal and secretagogues-stimulated acid secretion were compared to those of indomethacin. Nimesulide (1 microM to 100 microM) produced a rightward concentration-dependent shift and reduction of maximum acid secretion of all the agonist-stimulated acid secretion curves. Indomethacin was only effective at the higher concentration of 100 microM. Compared to their effects singly, nimesulide (20 microM) and famotidine (0.15 microM) together caused a further shift without further reduction in maximum acid output of the histamine-stimulated curve, suggesting that nimesulide was not acting at the histamine H(2)-receptor. Nimesulide concentration-dependent reduction of stimulated acid secretion in the isolated mouse stomach was not by antagonism of the histamine H(2) receptor and is probably beyond the level of adenylate cyclase stimulation. A direct effect on the calcium channel is demonstrated.     

Mucosal mast cells. II. Effects of anti-allergic compounds on histamine secretion by isolated intestinal mast cells

Functional mast cells have been isolated from the lamina propria of the small intestine of rats infected with the nematode Nippostrongylus brasiliensis. The cells released histamine on challenge with specific antigen, anti-rat IgE, concanavalin A, and calcium ionophores but were less responsive than peritoneal mast cells (MMC) from the same animals. Intestinal mucosa mast cells (PMC) were refractory to the action of the basic secretagogues peptide 401 from bee venom and compound 48/80. The anti-allergic compounds disodium cromoglycate (less than or equal to 10(-3) M), AH 9679 (less than or equal to 10(-4) M), and theophylline (less than or equal to 10(-2)) did not inhibit antigen-induced histamine secretion by MMC, although these compounds were effective against PMC. In contrast, doxantrazole (10(-5) to 10(-3) M) inhibited the secretion of histamine from both MMC and PMC in a comparable dose-dependent fashion. Thus, we have established that mast cells from different sites are functionally heterogeneous not only in their response to various stimuli for histamine secretion, but also in their responses to different pharmacologic modulators of secretion. It cannot be assumed that anti-allergic compounds effective against mast cells in one tissue site or organ will be equally efficacious against mast cells in other sites. The extent of this functional heterogeneity must be established, and its investigation may provide new insights into the biochemical events involved in mast cell secretion.     

L-type amino acids stimulate gastric acid secretion by activation of the calcium-sensing receptor in parietal cells

Parietal cells are the primary acid secretory cells of the stomach. We have previously shown that activation of the calcium-sensing receptor (CaSR) by divalent (Ca(2+)) or trivalent (Gd(3+)) ions stimulates acid production in the absence of secretagogues by increasing H(+),K(+)-ATPase activity. When overexpressed in HEK-293 cells, the CaSR can be allosterically activated by L-amino acids in the presence of physiological concentrations of extracellular Ca(2+) (Ca(o)(2+); 1.5-2.5 mM). To determine whether the endogenously expressed parietal cell CaSR is allosterically activated by L-amino acids, we examined the effect of the amino acids L-phenylalanine (L-Phe), L-tryptophan, and L-leucine on acid secretion. In ex vivo whole stomach preparations, exposure to L-Phe resulted in gastric luminal pH significantly lower than controls. Studies using D-Phe (inactive isomer) failed to elicit a response on gastric pH. H(+)-K(+)-ATPase activity was monitored by measuring the intracellular pH (pH(i)) of individual parietal cells in isolated rat gastric glands and calculating the rate of H(+) extrusion. We demonstrated that increasing Ca(o)(2+) in the absence of secretagogues caused a dose-dependent increase in H(+) extrusion. These effects were amplified by the addition of amino acids at various Ca(o)(2+) concentrations. Blocking the histamine-2 receptor with cimetidine or inhibiting system L-amino acid transport with 2-amino-2-norbornane-carboxylic acid did not affect the rate of H(+) extrusion in the presence of L-Phe. These data support the conclusion that amino acids, in conjunction with a physiological Ca(o)(2+) concentration, can induce acid secretion independent of hormonal stimulation via allosteric activation of the stomach CaSR.     

Effect of various adenine derivatives on gastric acid secretion in the isolated rat stomach

The adenine derivatives adenosine 5'-triphosphate (ATP), adenosine 5'-diphosphate (ADP), adenosine 5'-monophosphate (AMP) and adenosine (AD), in concentrations of 10(-3)M and 10(-4)M caused significant and dose-related modifications in the basal acid secretion from isolated whole rat stomach. The first three purine derivatives, ATP, ADP and AMP significantly increased the spontaneous acid secretion. On the other hand, AD caused a significant reduction in the basal acid secretion. When ATP, ADP, AMP and AD were assayed in the presence of the adrenergic and cholinergic blocking agents, ergotamine, 10(-6)M, propranolol, 5 X 10(-7)M and atropine, 10(-6)M, all these purine derivatives, including AD, caused a significant increase in the basal acid secretion.     

Further analysis of prostacyclin's effect on rat gastric mucosal nucleic acid content.

Graded single and multiple oral doses of prostacyclin enhance, in a direct dose-dependent manner, the DNA and RNA content of rat gastric (antral and fundic) mucosa, resulting in a decreased RNA/DNA ratio. This latter phenomenon is a convincing sign of new cell formation. The arithmetical (theory of functions) analysis of the data resulted in equations, defined mathematically, of prostacyclin's dose-dependent effect.     

Development of mucosal mast cells after injection of a single connective tissue-type mast cell in the stomach mucosa of genetically mast cell-deficient W/Wv mice

Mast cells may be classified into at least two phenotypically distinct populations: connective tissue-type mast cells (CTMC) and mucosal mast cells (MMC). Mast cells in the peritoneal cavity of mice are typical CTMC, whereas mast cells in the mucosa of the stomach show morphologic characteristics of MMC. We investigated whether CTMC may change to MMC. A single peritoneal mast cell of WBB6F1-+/+ mice was identified under the phase-contrast microscope, picked up with the micromanipulator, and injected into the stomach wall of genetically mast cell-deficient WBB6F1-W/Wv mice. The cells with histochemical and electron microscopical features of MMC developed in the mucosa, and those with histochemical features of CTMC in the muscularis propria. This directly demonstrates that a certain proportion of CTMC may function as a bipotent precursor for both MMC and CTMC.     

The influence of food,beverages and NSAIDs on gastric acid secretion and mucosal integrity.

Gastric acid secretion is stimulated by all foods, especially proteins, and many beverages, the most potent beverages are milk and fermented substances such as beer and wine. The effects of food on mucosal integrity have been little studied, whereas non-steroidal anti-inflammatory drugs are well known to induce tissue injury.     

Activity of oxyntomodulin on gastric acid secretion induced by histamine or a meal in the rat

Conscious rats with chronic gastric fistula were trained for drinking a 14-ml milk meal. The activity of an intestinal hormone, oxyntomodulin (OXM), was studied in this model and compared to that observed when histamine was the stimulus. Under histamine (0.25 mg·kg⁻¹·h⁻¹) stimulation, OXM at doses (60–120 pmol·kg⁻¹·h⁻¹) that induced physiological circulating levels inhibited gastric acid secretion up to 50%. Under meal stimulation, OXM reduced up to 29% acid secretion at doses (1–1.5 nmol·kg⁻¹·h⁻¹) inducing supraphysiological levels. We conclude that at physiological concentrations OXM cannot counteract the complex processes triggered by a meal. OXM would be a component of enterogastrone, a combination of several intestinal hormones acting in synergy. The OXM action is related to pathways recognizing the C-terminal 19–37 moiety of the molecule.