Keiji Ohe

Cysteamine-induced inhibition of acid neutralization and the increase in hydrogen ion back-diffusion in duodenal mucosa

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.

Na+-gradient-dependent transport of L-proline and analysis of its carrier system in brush-border membrane vesicles of the guinea-pig ileum.

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.

Increase in pepsin content in gastric mucosa during the course of aspirin-and taurocholate-induced gastric ulceration in rats

To investigate the possible role of pepsin in ulceration induced by hydrogen ion backdiffusion, 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 ucler 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.

Cysteamine-induced inhibition of mucosal and pancreatic alkaline secretion in rat duodenum

To determine the effect of cysteamine on the alkaline secretion by the duodenal epithelium, pancreas, and Brunners glands in relation to the pathogenesis of duodenal ulceration, the alkaline secretion by various types of duodenal loops was comparatively studied. The results obtained were as follows: (1) Cysteamine significantly reduced both mucosal and pancreatobiliary alkaline secretion in the proximal duodenum of rats. (2) The ratio of contribution of pancreatobiliary alkaline secretion to total neutralization of acid in the proximal duodenum was 55.9% under continuous perfusion. (3) There was no significant difference between the amounts of alkali per unit volume of the proximal and distal duodenal loops. (4) The alkaline substance secreted by the proximal duodenal mucosa was confirmed to be the bicarbonate. From these findings, it has been concluded that the impairment of bicarbonate secretion by the mucosal epithelium of proximal duodenum, not by Brunners glands, plays a causative role in cysteamine-induced duodenal ulceration.

Block of acid secretion by amytal and its partial reversal by menadione with ascorbate in the gastric mucosa of the guinea-pig

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.

Cyclic nucleotide response to acid-secreting stimuli in guinea pig gastric mucosa in vitro.

SummaryTo 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 signific antly 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 are transmitted differently in the target cells, presenting evidence against the common final mediator theory of histamine for gastric acid sercetion.

The increase in putrescine content in the gastric mucosa of rats with ulcerations induced by restraint-immersion stress

SummaryBy means of high-performance liquid-chromatography, the putrescine, spermidine and histamine contents in the gastric mucosa were examined during the course of ulceration induced 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.

[Obesity and liver dysfunction in UOEH employees--multiple regression analysis of the annual physical checkup data of 1991].

For the purpose of evaluating the significance of obesity as a risk factor toward various chronic geriatric diseases, a multiple regression analysis was performed on the annual physical checkup data of UOEH employees in 1991. The following results were obtained. (1) The average obesity index of the UOEH employees showed a progressive and significant increase in the 10 years from 1981 to 1991. (2) A close relation between the obesity index and serum GPT was recognized by elevation of the standard partial regression coefficients of serum GPT to obesity index and that of the obesity index to serum GPT when the data from all 1591 UOEH employees were analysed in one group. This finding was derived from a significant contribution of obesity to the liver dysfunction in the young male obese population under 30 years of age. (3) Systolic blood pressure was related to age rather than the obesity index, indicating that the development of hypertension is more closely related to aging than obesity. (4) No significant relation was found between the serum total cholesterol level and the obesity index in any group analysed. From the above findings, it can be suggested that the obesity in young male employees is more closely related to liver dysfunction than other abnormalities.

Defensive Mechanism in Peptic Ulcer and Assessment of Anti-ulcer Agents

ABSTRACT Defensive mechanism of gastric mucosa was studied. (1) In guinea pig gastric mucosa in vitro, reduction in ATP content occurred preceeding the back diffusion of mucosal acid induced by aspirin or taurocholate. (2) The hydrogen ion permeability increases before the increase in activated pepsin in rat gastric mucosa with aspirin-induced ulceration. (3) Increase in the hydrogen ion permeability was specific for the presence of erosions and intestinal metaplasia in gastric ulcer patients. (4) Anti-ulcer agents showed different patterns in inhibiting the events leading to aspirin-induced ulceration in rats. From these findings, it has been concluded that the increase in hydrogen ion permeability is the consequence of cellular damage in the gastric mucosa and to cause erosions which forms the background for ulceration.

Proceedings Of The 21St Autumn Meeting From October 15th-17th, 1979-Maebashi, Japan

When the peripheral blood lymphocytes from patients with various types of hepatitis were stimulated in vitro with liver specific protein, lymphocyte transformation and MIF production were detectable in many cases, especially in chronic active hepatitis. The macrophage activating factor (MAF), a kind of lymphokines, was also detected in the culture medium of activated lymphocytes from patients who showed positive blastogenesis. The activated macrophages by MAF were shown to be cytotoxic to the separated liver cells causing the marked inhibition of albumin synthesis. MAF-containing culture supernatants of these active lymphocytes activated guinea pig macrophages which inhibited the albumin biosynthesis of the isolated liver cells. These observations suggest that the macrophagemediated cytotoxicity may play and role in pathogenesis of chronic active hepatitis.