Akima Miyoshi

Changes of colonic vasoactive intestinal peptide and cholinergic activity in rats with chemical colitis

The vasoactive intestinal peptide concentration was examined in the colonic wall and portal venous plasma of rats with chemical colitis by radioimmunoassay, and the colonic localization was determined with immunocytochemistry. Colonic acetylcholine esterase activity was also measured, and the response of vasoactive intestinal peptide to acetylcholine administration was determined. Colitis was induced by administration of dextran sulfate for three months. The chemical colitis was histologically similar to active human ulcerative colitis. We observed a significant increase of immunostained neurons and nerve fibers and a significant rise in the colonic wall vasoactive intestinal peptide content in chemical colitis rats, while plasma concentrations of the peptide did not change significantly. Colonic acetylcholine esterase activity was significantly elevated in colitis rats compared with control rats. Systemic administration of acetylcholine significantly increased the colonic and plasma vasoactive intestinal peptide concentrations in colitis rats. These findings demonstrated a positive association between colitis activity and an increase of vasoactive intestinal peptide and suggested that increased vagal tone promoted the peptides release.

Dyspepsia and Dyspepsia Subgroups in Japan: Symptom Profiles and Experience with Cisapride: General Discussion

In 240 patients with symptoms of dyspepsia, recruited consecutively and investigated in 12 hospitals in Japan, 24.2% were diagnosed having organic dyspepsia; 75.8% had functional dyspepsia, of whom 63.2% were diagnosed by the investigator having dysmotility-like, 13.7% ulcer-like, 11.5% reflux-like, and 11.5% non-specific dyspepsia. There was, however, considerable overlap of symptom profiles. Cisapride therapy initiated in functional dyspeptic patients resulted in moderate or marked improvement in 79.1% of the patients with the highest response rates for dysmotility-like (85.2%), reflux-like (81.0%), and non-specific dyspepsia (76.1%) (versus 52.0% for ulcer-like dyspepsia).

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.

Antral gastrin and somatostatin concentrations in peptic ulcer patients.

As an attempt to approach the pathogenesis of peptic ulcer disease, antral gastrin and somatostatin concentrations were studied in normal subjects, patients with duodenal ulcer and gastric ulcer. In the patients with peptic ulcer, antral somatostatin concentrations were significantly lower than those in normal subjects. In non-ulcer subjects, including normal subjects and patients with atrophic gastritis, antral somatostatin concentrations were correlated inversely with the degree of antral gastritis, while in the patients with peptic ulcer, especially in duodenal ulcer, they were low, irrespective of histological picture of antral mucosa. In the patients with duodenal ulcer, low antral somatostatin concentrations with high antral gastrin/somatostatin ratio may cause increased serum gastrin levels and increased gastric acid secretion. From the above findings, it has been concluded that low antral somatostatin levels may be related to the pathogenesis of duodenal ulcer disease.

Increased serum pepsinogen I and recurrence of duodenal ulcer

To determine whether the serum pepsinogen I (PG I) level would be a suitable marker for selecting patients at risk for duodenal ulcer recurrence and, thus, would benefit from maintenance therapy, we treated duodenal ulcer patients with H2-receptor antagonists. After healing 140 ulcer patients we assessed the recurrence rate at 1 year with and without maintenance therapy. The annual recurrence rates in duodenal ulcer patients with hyper-PGI (95 ng/ml or more), with 66 ng/ml less than or equal to PGI less than 95 ng/ml, and with PGI less than 66 ng/ml were 87.0%, 27.3%, and 17.9%, respectively, when they did not receive maintenance therapy. In patients with hyper-PGI the recurrence rate was significantly lower in patients receiving maintenance therapy than in patients not receiving maintenance therapy, whereas in patients with PGI less than 66 ng/ml the recurrence rate was as low as 20% regardless of maintenance therapy. These results indicate that maintenance therapy with half the dose of H2-receptor antagonist is not required by patients with PGI less than 66 ng/ml, whereas those with hyper-PGI may be good candidates for long-term maintenance therapy.

Distribution of neurokinin A-like and neurokinin B-like immunoreactivity in human peripheral tissues.

Using specific radioimmunoassay and immunocytochemistry for neurokinin A (NKA) and neurokinin B (NKB), distribution and localization of the two peptides in human peripheral tissues were studied. Both NKA-like immunoreactivity (NKA-LI) and NKB-like immunoreactivity (NKB-LI) were present in the walls of the gut and gall bladder and in the pancreas. In the gut, the values for NKA-LI were 0.56-35.73 pmol/g wet weight, while those in pancreas and gall bladder were 0.64-0.68 and 0.36 pmol/g wet weight, respectively. The values of NKB-LI were 0.45-2.66 pmol/g wet weight in the gut, 0.93-1.65 pmol/g wet weight in the pancreas, and 0.30 pmol/g wet weight in the gall bladder. The immunocytochemical reactivity to both peptides was localized to ganglia of the submucosal and myenteric nerve plexuses in the gut wall, and to neurons in the muscle layer and mucosa of the gut wall. Weak but positive NKA-LI appeared in nerve cells of the pancreas, while NKB-LI was not detectable in the pancreas. Conversely, in the gall bladder wall, NKA-LI was undetectable while a very faint NKB-LI was found in the muscle layer. The localization of NKA corresponded closely to that of NKB in the tissues although the relative concentrations of the peptides varied from organ to organ.

β-Endorphinlike immunoreactivity and somatostatinlike immunoreactivity in normal gastric mucosa, muscle layer, and adenocarcinoma

beta-Endorphinlike immunoreactivity and somatostatinlike immunoreactivity were detected in the mucosa and muscle layer of normal gastric antrum and corpus and in moderately differentiated adenocarcinoma derived from the antral mucosa. The concentration of beta-endorphinlike immunoreactivity in the normal gastric tissues was 4-15 pmol/g wet wt tissue; this value varied from 9.64 to 241.39 pmol/g wet wt tissue (81.38 +/- 37.82 pmol/g wet wt tissue) in adenocarcinomas. The concentration of somatostatinlike immunoreactivity was 18-25 pmol/g wet wt tissue in normal gastric mucosa, whereas it was 1-2 pmol/g wet wt tissue in adenocarcinomas. Gel exclusion chromatography of beta-endorphinlike immunoreactivity revealed two peaks corresponding to beta-endorphin and beta-lipotropin. In normal mucosa and in the whole layer of antrum, the major peak was eluted near the position of beta-lipotropin, and the minor broad peak was eluted near the position of beta-endorphin. In contrast, in adenocarcinoma, beta-endorphinlike immunoreactivity was eluted broadly at the position of beta-endorphin and the other smaller peak was at the position of beta-lipotropin. Gel exculsion chromatography of somatostatinlike immunoreactivity also showed different patterns between antral mucosa and adenocarcinoma. This study revealed the presence of the opioid peptide, beta-endorphinlike immunoreactivity, not only in normal gastric tissue but also in adenocarcinomas with highly increased concentration and different elution patterns in combination with decreased concentration of somatostatinlike immunoreactivity.

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.