[The effect of secretin on the cysteamine induced inhibition of alkaline secretion by the duodenal mucosa].
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Biomedical subjects
Publications and source records attributed to K Ohe.
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Disodium glycyrrhizinate (DG) was administered at concentrations of 0.15 (maximum tolerated dose), 0.08, 0.04 or 0% in the drinking-water to groups of 50, 70, 60 and 60 male B6C3F1 mice, respectively. Female groups, each consisting of 50 mice, were given DG in the drinking-water at concentrations of 0.3 (maximum tolerated dose), 0.15, 0.08 or 0%. Treatment was continued for 96 wk and the experiment was terminated at wk 110. There was no difference between treated and control groups in tumour incidence, in the latent period before tumours appeared or in the distribution of different types of tumour. Thus the long-term oral administration of DG to mice did not yield any evidence of chronic toxicity or tumorigenicity.
A case of adrenocortical carcinoma with feminization seen in a man aged 35, is reported. The levels of estron (E1) and estradiol (E2) in the venous blood draining the tumor were high, and it was confirmed by in vitro assay of tumor cells taken from the primary tumor of the left adrenal gland that the tumor produced estrone. The light microscopic examination demonstrated that the primary tumor was composed of mixture of large cells with pleomorphic nuclei and vacuolated cytoplasm and uniform cells with ovoid nuclei and eosinophilic cytoplasm. The electron microscopic examination on the latter cells revealed numerous large and irregularly shaped mitochondria with mostly tubular or lamellar and occasionally vesicular cristae and electron-dense matrix, well-developed smooth-surfaced endoplasmic reticulum in the cytoplasm. However, lipid droplets and lysosomes or lipofuscin granules were scanty. From these findings, it is suggested that cells of the present tumor have characteristics of those in the zona reticularis of the adrenal cortex as well as in the fetal cortex, and the functional property of this tumor is well correlated with its morphological features.
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To determine whether cimetidine increases serum gastrin levels by elevation of intragastric pH or by other mechanisms, the effects of two different H2-receptor antagonists, cimetidine and YM-11170, on serum gastrin levels were compared in rats with controlled intragastric pH. When the intragastric pH was maintained between 4.5 and 5.5, 2-10 mumol/kg of cimetidine increased serum gastrin levels significantly, whereas no significant increase was observed after 0.02-0.1 mumol/kg of YM-11170. This occurred despite the same extent of inhibition of histamine-stimulated acid secretion as with cimetidine. When the intragastric pH was fixed at 5.5, the serum gastrin responses to cimetidine were significantly greater than to saline or YM-11170. Therefore, the increase in serum gastrin levels by cimetidine is due neither to the elevation of intragastric pH nor the result of H2-receptor blockade, but is probably due to a direct action to release gastrin.
To investigate the possible impairment of defensive mechanisms in cysteamine-induced duodenal ulceration, the effect of cysteamine on the neutralization of acid by the duodenum and the back-diffusion of hydrogen ions into the duodenal mucosa has been studied. The results obtained were as follows. (1) The intraduodenal pH started to decrease between 3 and 4 hr after cysteamine injection. (2) By perfusion of the duodenal loop excluding the opening of bile and pancreatic ducts, the amount of hydrogen ions (H+) neutralized was found to be significantly lower in cysteamine-treated animals than in the controls. (3) the back-diffusion of luminal H+ into the duodenal mucosa, estimated by measuring the H+ disappearance from the test solution including 100 mM HCl, was significantly increased by cysteamine. From these findings, it has been concluded that cysteamine reduces the resistance of duodenal mucosa to acid coming from the stomach.
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To investigate the mechanism of intracellular transmission of three representative stimuli for gastric acid secretion, the dose-response relations of cyclic nucleotides accompanied by acid secretion stimulated by histamine, pentagastrin and bethanechol were comparatively studied using an in vitro preparation of guinea pig gastric mucosa surviving with a constant potential difference and acid secretion sensitive to amytal. The following results were obtained. (1) Both histamine- and pentagastrin-stimulated acid secretion accompanied a significant increase in cyclic AMP contents in the gastric mucosa and in the serosal solution without any increase in cyclic GMP. However, the ratio of the increase in acid secretion to that in cAMP content was significantly greater with pentagastrin than with histamine, indicating that pentagastrin exerts its acid-secreting stimulus with less increase in cyclic AMP. (2) Stimulation with bethanechol resulted in a significant increase in the mucosal cyclic GMP content without any change in cyclic AMP. From these findings, it has been concluded that the above three stimuli were transmitted differently in the target cells, presenting evidence against the common final mediator theory of histamine for gastric acid secretion.
By means of high-performance liquid-chromatography, the putrescine, spermidine and histamine contents in the gastric mucosa were examined during the course of ulceration in rats by the restraint-immersion stress. (1) The putrescine content increased progressively during the course of ulceration with the continuing stress whereas after being released from the stress the content decreased gradually to a significantly lower level than that immediately after 12 hours of the stress. (2) The spermidine content in the gastric mucosa was unchanged during the course of ulceration with continuing stress nor after being released from the stress. (3) The mucosal histamine content decreased significantly after 4 hours under the continuing stress. (3) Extensive histological examination revealed the appearance of regenerating epithelium 36 hours after being released from the stress whereas no such finding was seen before that period. From the above findings, it has been speculated that the increase in the gastric mucosal putrescine content during the course of ulceration induced by restraint-immersion stress is probably due to the stimulated adrenal function by the stress, independently of the regeneration of gastric mucosa.
Transport of L-proline was studied with membrane vesicles prepared from the brush borders of the guinea-pig ileum. The presence of an Na+ gradient from outside to inside of the vesicles stimulated L-proline uptake. Accumulation of amino acid in the vesicles reached a maximum 30 s after incubation, then decreased due to efflux and finally equilibrated at a level nearly identical to that shown in the absence of an Na+ gradient in 30 min. The peak level of the uptake was 3.5-times greater than the final equilibrium level. The equilibrium level of L-proline uptake decreased with increasing medium osmolarity. Extrapolation to infinite medium osmolarity, that is, under the condition of zero intravesicular space, showed no uptake, indicating transport of L-proline into membrane vesicles. The initial rate of uptake for 15 s was enhanced with increasing concentrations of Na+ in the external medium. A small part of the L-proline transport occurred by simple diffusion in addition to Na+-gradient-dependent transport. When L-proline concentrations were varied and transport due to diffusion was subtracted, the initial rate of uptake dependent on Na+ gradient (out greater than in) obeyed Michaelis-Menten kinetics with Km and V values of 0.67 mM and 2.73 nmol/15 s per mg protein, respectively. Evidence was obtained which indicates that L-cysteine is a substract specific for transport through system ASC (alanine-, serine-, and cysteine-preferring) and that transport in the presence of an Li+ gradient (out > in) also takes palce by the ASC system. The uptake of L-proline in the presence of an Na+ gradient (out > in) was inhibited 90% by a large excess of alpha-(methylamino)-isobutyrate, the model substrate specific for the A system (alanine-preferring). This indicates than 90% of Na+-gradient-dependent L-proline uptake is supported by the A system. The remaining 10% of L-proline uptake was found to be catalyzed by the ASC system, since L-proline uptake equivalent to this alpha-(methylamino)-isobutyrate-uninhibited part was demonstrated in the presence of Li+ gradient.
The effect of amytal on energy metabolism and acid secretion in an isolated gastric mucosa of the guinea-pig were studied. Determination of adenine nucleotides, creatine phosphate, pyruvate and lactate in the gastric mucosa showed that amytal depressed the levels of ATP, creatine phosphate and energy charge with elevation of the AMP and pyruvate levels. This treatment inhibited concomitantly acid secretion and active chloride transport detected by short circuit current. The addition of menadione with ascorbate to the medium in the presence of amytal partially restored ATP and energy charge levels and also induced a partial recovery of acid secretion and activ chloride transport. These results suggest that ATP is a direct energy donor for acid secretion in the gastric mucosa of the guinea-pig.
To investigate the possible role of pepsin in ulceration induced by hydrogen ion back-diffusion, the ratio of alkali-labile pepsinogen to total pepsinogen was studied during the course of aspirin- and taurocholate-induced gastric ulceration in comparison with the changes in the ion permeability and histological findings. The results obtained were as follows. (1) The increase in the ulcer index was observed between 1 and 2 hr with intragastric aspirin and between 2 and 4 hr with intragastric taurocholate. (2) The back-diffusion of luminal hydrogen ions, observed as a significant decrease in hydrogen ion net flux, occurred immediately in both cases with aspirin and with taurocholate. (3) A significant increase in the ratio of alkali-labile to total pepsinogen in the homogenate of gastric mucosa was observed at 30 min with aspirin and at 60 min with taurocholate. (4) Histological examination revealed the degeneration of mucosal cells spreading from the luminal surface into the mucosa, which fell off after 120 min with aspirin. These findings indicate that the activated pepsin is involved in the ulcer formation caused by the hydrogen ion back-diffusion, although the origin of the activated pepsin is not clear at the present time.
Using the isolated guinea pig gastric mucosa perfused in vitro with a constant acid secretion and potential difference, the cyclic AMP (cAMP) contents in the gastric mucosa and in the serosal solution were measured during the course of acid secretion stimulated by histamine or dibutyryl cyclic AMP (db-cAMP). (1) The acid-secreting response of the gastric mucosa to histamine was reproduced by addition of db-cAMP. (2) The acid secretion stimulated by db-cAMP was not inhibited. (3) The increase in mucosal cAMP content was accompanied by histamine-stimulated acid secretion. (4) The increase in the mucosal cAMP content preceded the increase in acid secretion stimulated by histamine. From these findings, it has been concluded that cAMP plays an important role in the mechanism of histamine-stimulated acid secretion, including the morphological transformation of parietal cells, although its role as the intracellular mediator of the stimuli for the hydrogen ion pump itself requires further investigation.
To clarify the mechanism of initiation of the hydrogen ion backdiffusion, the effects of aspirin and taurocholate, two representative gastric mucosal barrier breakers, on the potential difference, secretory activity, energy metabolism, and the hydrogen ion permeability of guinea pig gastric mucosa was studied in vitro. 1) The ATP content and energy charge of the gastric mucosa showed a statistically significant reduction when the potential difference decreased to one-half of that before addition. 2) The mucosal acid secretion was reduced by addition of the barrier breaker. 3) However, the hydrogen ion backdiffusion, as measured by titrating the acid appearing in the serosal solution, became detectable when the potential difference decreased to one-fourth of that before addition. It has been concluded, therefore, that the primary action of gastric mucosal barrier breakers is to damage the energy metabolism of the mucosal cells, and that the hydrogen ion backdiffusion takes place as the result of cellular death caused by the impairment of energy metabolism.
In order to investigate the possible involvement of gastrointestinal hormones in functional disorders of the digestive tract, serum motilin, neurotensin and gastrin levels in their response to oral intake of fat and glucose were examined in patients with irritable colon syndrome and dumping syndrome. The following results were obtained. (1) Basal serum motilin levels were higher in patients with irritable colon syndrome than in normal subjects, and remained high after ingestion of either 50 g of butter or 50 g of glucose. (2) No consistent response in serum neurotensin levels was found in patients with irritable colon syndrome or in normal subjects. (3) An immediate increase in serum gastrin levels was found in response to fat ingestion both in patients with irritable colon syndrome and in normal subjects, but there was no difference between these two groups. (4) In a patient with typical dumping syndrome, a markedly high level of fasting serum motilin was found, and the level increased further after the oral intake of glucose. These findings suggest that motilin may be involved in the irritable colon syndrome and dumping syndrome.
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