Biomedical subjects

N Misaki

Publications and source records attributed to N Misaki.

At least 19 recordsLinked to original sources

PubMed1995

[Therapeutic effect of IGN-2098, a new antiulcer drug (H2-antagonist), in the ulcer diminishing period against acetic acid-induced gastric ulcer in rats].

The effects of IGN-2098 on the healing process of acetic acid-induced gastric ulcer was investigated in comparison with the other histamine H2-receptor antagonists, famotidine and roxatidine acetate HCl, in rats. Ulcer was induced by the injection of acetic acid solution (20%, 0.05 ml). From the 4th day to 17th day after the ulcer induction, drugs were orally administered twice a day. On the 18th day after the ulcer induction, rats were sacrificed to measure the ulcer index macroscopically and to take pictures of the stomachs. Judging from the photographs, the prominence of ulcer the edge was graded into 4 classes, which showed a significant correlation with the histological amount of connective tissue at the ulcer edge. All drugs accelerated the healing of the ulcer, and the effect of IGN-2098 was the most remarkable. In addition, IGN-2098-treatment exhibited more marked inhibition against the prominence of the ulcer edge as compared with the control group. Based on these results, it is concluded that IGN-2098 may be a useful drug for the clinical treatment of ulcer and that the healing acceleration by IGN-2098 without prominence of the ulcer edge may induce no relapse of the ulcer after healing.

Acetates↗

PubMed1993

Effect of the novel histamine H2-antagonist 5,6-dimethyl-2-[4-[3-(1- piperidinomethyl)phenoxy]-(z)-2-butenylamino]-4(1H)-pyrimidine dihydrochloride on histamine-induced gastric acid secretion in Heidenhain pouch dogs.

Effects of IGN-2098 (5,6-dimethyl-2-[4-[3-(1-piperidinomethyl)phenoxy]- (z)-2-butenylamino]-4(1H)-pyrimidone dihydrochloride, CAS 126869-04-3) a novel histamine H2-antagonist, on histamine-induced gastric acid secretion were investigated in Heidenhain pouch dogs in comparison with those of famotidine, roxatidine acetate HCl and cimetidine. Orally administered IGN-2098 (0.03-1.0 mg/kg), famotidine (0.01-0.3 mg/kg), roxatidine acetate HCl (0.1-1.0 mg/kg) and cimetidine (0.3-3.0 mg/kg) showed dose-dependent inhibition on histamine-induced gastric acid secretion, and ED50 values of IGN-2098, famotidine, roxatidine acetate HCl and cimetidine were 0.077, 0.024, 0.200 and 0.585 mg/kg, respectively. IGN-2098 was effective even at 6 h after administration and ED50 value was 0.315 mg/kg. IGN-2098 was effective also by intravenous route. The inhibitory effect of IGN-2098 on histamine-induced gastric secretion was not affected by the repeated administration of IGN-2098 (1 mg/kg b.i.d. for 14 days). These results show that IGN-2098 is a potent and long acting antisecretory agent and is a useful antisecretory drug for the treatment of peptic ulcer disease.

Administration, Oral↗

PubMed1992

Identification of glucocorticoid responsive elements (GREs) at far upstream of rat NPY gene.

The location of three glucocorticoid responsive elements (GREs) in rat neuropeptide Y (NPY) gene was determined by chloramphenicol acetyltransferase (CAT) assay and nucleotide sequencing. We have reported that mRNA content of rat prepro-NPY is increased by 1.7-fold in NG108-15 cells by 1 microM dexamethasone, suggesting the presence of GRE in the gene. To identify the element, the 5'-flanking DNA of 3.3 kilobases (kb) was isolated from rat NPY gene. When chimeric chloramphenicol CAT plasmids containing various deletions of the NPY upstream sequence were transfected into NG108-15 cells, the region between -2.9 and -2.1 kb relative to the cap site was found to potentiate the transcription of CAT gene in the presence of 1 microM dexamethasone. The nucleotide sequencing of this region revealed three GRE consensus sequences at -2.5, -2.2 and -2.1 kb. The results indicate that these elements present in the far upstream region of the NPY gene confer induction by glucocorticoids.

Animals↗

PubMed1992

[Effects of IGN-2098, a new histamine H2-receptor antagonist, on gastric secretion and gastric and duodenal lesions induced in rats. Comparison with roxatidine].

A new compound, IGN-2098 [5,6-dimethyl-2-[4-<3-(1-piperidinomethyl) phenoxy>cis-butenylamino]-4-(1H)-pyrimidone.2HCl], was found to be a potential histamine H2-receptor antagonist in the guinea pig atrium. IGN-2098, given p.o., significantly and persistently (for more than 12 hr) inhibited the basal gastric secretion in pylorus-ligated rats. The agent also significantly inhibited the basal gastric secretion when given by the s.c.-, i.d.- or i.p.-route. Stimulated gastric secretion in fistula rats in response to histamine, carbachol or pentagastrin was also significantly inhibited with IGN-2098 given s.c. Pretreatment with IGN-2098 (p.o.) significantly protected the gastric mucosa against pylorus ligation-, water-immersion stress-, histamine-, indomethacin-, HCl.aspirin-, and HCl.ethanol-induced gastric lesions. In addition, the agent significantly protected the duodenal mucosa against mepirizole-induced ulcers. Based upon the ED50 values, the antisecretory effects on histamine, carbachol or pentagastrin-stimulated acid secretion were 6.0, 37.0 or 80 times more potent than roxatidine, respectively. As to the anti-lesion effects on HCl.aspirin-induced gastric lesions or mepirizole-induced duodenal ulcers, IGN-2098 was 8.1 or 14.8 times more potent than roxatidine, respectively. These results suggest that IGN-2098 will be a useful drug for the treatment of gastric and duodenal lesions in man.

Animals↗

PubMed1991

A new method for measurement of blood flow, pH, and transmucosal potential difference in rat gastroduodenal mucosa by endoscopy.

A method was developed to measure the mucosal blood flow (BF), mucosal pH (pH), and transmucosal potential difference (PD) in various sites from the oral cavity to the duodenum without surgical operation or damage to the subject rats. These measurements were carried out by using three indicator electrodes, which were attached to the various sites through the suction channel of an endoscope. The hydrogen gas clearance method was used for the measurement of BF. BF values obtained at the fundic, pyloric, and duodenal regions were 119 +/- 17, 69.9 +/- 8.8, and 114 +/- 18 ml/min/100 g (mean +/- SE), respectively. The pH values were lowest at the cardiac portion and the forestomach and highest at the duodenum. PD showed higher values at the stomach and lower values at the pharynx and duodenum. Using this technique, it was possible to measure the BF, pH, and PD repeatedly and safely at various sites in the same rat. Therefore, it was suggested that this method is useful in studying the physiological functions of the stomach and duodenum and the pathogenesis of gastroduodenal ulceration and that this method is applicable to measure the change of the above parameters in the healing process of gastric ulcer in rats.

Animals↗

PubMed1990

Healing of acetic acid-induced gastric ulcer and gastric mucosal PGI2 level in rats.

The present study was designed to investigate the changes in gastric mucosal PGI2 level accompanying the healing of acetic acid-induced gastric ulcers in rats. The ulcers, which were observed with an endoscope, were found to undergo periods of decrease, healing and exacerbation during the rat's lifetime. The phases were categorized as follows: (1) the reduction period (days 3-50 after ulcer induction, corresponding to 7-14 weeks of age), (2) healing period (days 35-150 after ulcer induction, corresponding to 12-29 weeks of age), (3) first exacerbation period (days 35-231 after ulcer induction, corresponding to 12-40 weeks of age), (4) inactive period (days 231-365 after ulcer induction, corresponding to 40-60 weeks of age), and (5) second exacerbation period (days 365-550 after ulcer induction, corresponding to 60-86 weeks of age). In normal rats, the level of gastric mucosal PGI2 gradually increased with aging between 7 and 20 weeks, then decreased up to 40 weeks. The PGI2 level in the 60-week-old rat did not differ from that in the 40-week-old rat. The PGI2 level was the lowest in the 86-week-old rat. In ulcer-bearing rats, the PGI2 level showed the same pattern of change as that in normal rats, but the level was higher. The above results indicated a marked decrease in PGI2 level between 20 and 40 weeks of age and between 60 and 86 weeks of age in normal and ulcer-bearing rats. These periods corresponded closely to the first and second exacerbation periods, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetates↗

PubMed1990

Change in formation of gastric lesions by aspirin during aging in rats.

Formation of gastric lesions induced by orally administered aspirin (100 mg/kg) was examined in 4 to 86 week-old Sprague-Dawley male rats. Gastric mucosal prostaglandin I2 level and gastric secretion in basal state were also examined in these rats. Gastric mucosal PGI2 level was measured by bioassay and gastric secretion was collected by the pyloric ligation method for 4 h. Gastric lesions reached the maximum value in 7 week-old, and lowest in 60 week-old. Acid output also reached the maximum value in 7 week-old. As for PGI2 level, it showed the maximum value in 20 week-old, and moderately decreased thereafter. In 86 week-old, PGI2 level was further lowered to about 35% of 20 week-old rats. A linear positive correlation was noted between formation of aspirin-induced gastric lesion and acid secretion. From these results, it was concluded that formation of gastric lesions by aspirin was closely related to acidity of the gastric secretion. It was also suggested that in aged rats, aspirin-induced gastric lesions may at least partly be associated with the reduced PGI2 level.

Aging↗

PubMed1990

[Effect of anti-ulcer drugs and PGE2 on the proliferation of rat gastric cultured cells].

The effects of anti-ulcer drugs and PGE2 on the proliferation of rat gastric cultured cells were investigated. To study the cell proliferation, the rate of incorporation of 3H-thymidine into the cultured cells was measured. ULTROSER G, corresponding to fetal bovine serum, was found to dose-dependently increase the incorporation of 3H-thymidine into the cultured cells at a dose range of 1-4%. The incorporation of 3H-thymidine was highest at 36 hr after the inoculation of cells. Therefore, the effect of the drugs on the proliferation was performed under the condition of 2% ULTROSER G and evaluated at 36 hr. Aldioxa, cetraxate HCl, cimetidine (10(-7)-10(-5) M) and PGE2 (10(-8)-10(-6) M) had no effect on the cell proliferation, while indomethacin (0.35-1.41 x 10(-3) M) inhibited the proliferation in a dose-dependent manner. Aldioxa, cetraxate HCl (10(-5) M) and PGE2 (10(-6), 10(-8) M) antagonized the inhibitory effect by indomethacin at a concentration of 0.5 x 10(-3) M, but cimetidine (10(-7)-10(-5) M) did not. From the above results, it was concluded that this method was useful for investigating the effect of drugs on the proliferation of gastric cultured cells.

Animals↗

PubMed1990

[The effect of aldioxa on the formation of gastritis induced with sodium hydroxide].

The effects of aldioxa and cetraxate hydrochloride on the formative process of gastritis induced with intragastric application of 2% sodium hydroxide were studied. Rats were given food including either aldioxa or cetraxate hydrochloride for 6 weeks after the sodium hydroxide application. After sacrifice, the stomachs were removed, and the gastric mucosa were observed macroscopically and histologically. Gastric mucosal injury was widely induced with sodium hydroxide, being histologically characterized by mucosal hypertrophy, cell infiltration and intestinal metaplasia. These lesions seem to be the early stage of chronic gastritis. The aldioxa group showed a decrease of mucosal hypertrophy and cell infiltration as compared with the control group. In the cetraxate hydrochloride group, the mucosal surface of white gray color and the mucosal bosselation were observed macroscopically. Histologically, these were found to be cell infiltration and cyst formation. Moreover, intestinal metaplasia occurred at high incidence in this group. These findings in the cetraxate hydrochloride group are recognized to be an aggravation of chronic gastritis. From the above results, it is suggested that aldioxa promotes good regeneration of mucosa and should be useful for the clinical therapy of chronic gastritis.

Allantoin↗

PubMed1989

The H-L subgroup of guinea-pig cardiac M2 receptors (M2 beta) regulates inositol phosphate formation.

In previous studies, we showed that cardiac muscarinic receptors (M2) are composed of two subgroups, M2 alpha and M2 beta, with different affinities for agonists and that the M2 alpha subgroup is coupled with inhibition of adenylate cyclase. We now studied which subgroup was responsible for the formation of inositol mono- (IP), bis- (IP2), tris- (IP3) and tetrakis- (IP4) phosphates in guinea pig heart. Carbachol (1 mM) significantly stimulated the formation of all four IPs in [3H]myoinositol-preloaded slices of guinea-pig ventricles. Acetylcholine (1 mM) also stimulated the formation of IP2, IP3 and IP4. However, oxotremorine (1 mM) only slightly stimulated the formation of IP2, and pilocarpine did not stimulate the formation of any IP. The pED50 values of carbachol for IP2 and IP3 formation were 3.76 and 4.23, respectively, which coincided with the pKd values of the low-affinity agonist binding site (L site) measured by competition of carbachol with [3H]quinuclidinyl benzilate [( 3H]QNB) binding while the pKd value for inhibition of adenylate cyclase coincided with the pKd value of the high-affinity agonist binding site (H site). Treatment of animals with pertussis toxin decreased the formation of IP2 and IP3 by carbachol to 66 and 54%, respectively, but resulted in complete inhibition of adenylate cyclase. These results suggested that muscarinic stimulation of the formation of IPs was manifested through a different receptor subgroup (M2 beta) and GTP binding protein different from those for inhibition of adenylate cyclase.

Acetylcholine↗

PubMed1989

Heterologous desensitization of bradykinin-induced phosphatidylinositol response and Ca2+ mobilization by neurotensin in NG108-15 cells.

The heterologous desensitization of the bradykinin (BK)-induced increase in intracellular Ca2+ concentration ([Ca2+]i) by neurotensin was studied in neuroblastoma x glioma hybrid NG108-15 cells. The addition of neurotensin to the cells resulted in an increase in [Ca2+]i and an increase in the formation of inositol phosphates in Ca2+-free medium. Pretreatment of the cells with neurotensin resulted in 43% decrease in the BK-induced increase of [Ca2+]i. The increase in [Ca2+]i induced by ionomycin, which causes Ca2+ release from the intracellular pool, was not decreased by pretreatment with neurotensin. This indicates that the inhibitory effect of neurotensin on the BK-induced increase of [Ca2+]i was not due to depletion of the intracellular Ca2+ pool. Pretreatment with neurotensin also caused a 47% decrease in the BK-induced formation of inositol trisphosphates (IP3). This decrease was not due to depletion of phosphatidylinositol bisphosphates. Neurotensin did not inhibit [3H]BK binding to cell membranes. These results show that neurotensin desensitizes the BK responses of NG108-15 cells, heterologously, perhaps by changes in phospholipase C and/or guanine nucleotide-binding protein (G-protein).

Animals↗

PubMed1989

Cyclic AMP-dependent protein kinase interferes with GTP gamma S stimulated IP3 formation in differentiated HL-60 cell membranes.

The effects of addition of activated cyclic AMP-dependent protein kinase (PKA) on the function of islet-activating protein (IAP)-sensitive GTP-binding (G) protein were studied in the plasma membranes of 3H-inositol-labeled differentiated human leukemic (HL-60) cells. Pretreatment of the membranes with activated PKA (0.1 mg/ml) in the presence of MgATP for 15 min. at 37 degrees C decreased GTP gamma S-stimulated inositol trisphosphate (IP3) formation by about 30%, but had no influence on Ca2+-stimulated IP3 formation. And autoradiography in the phosphorylation experiments of solubilized HL-60 cell membranes by PKA showed some 32P incorporated bands, and among them one of the major bands showed the migration at 40 kDa supporting that the G protein coupling with PI response was phosphorylated by PKA. These results showed that pretreatment with activated PKA inhibited the mediating function of the G protein between the fMLP receptor and phospholipase C by its phosphorylation.

Calcium↗

PubMed1989

Blockade of ACh receptors by PrBCM causes deficits in shuttle avoidance performance.

Studies were made examining the effect of blockade of muscarinic acetylcholine (mACh) receptors in the cerebral cortex of rats on their shuttle avoidance after training. Rats were given a session of shuttle avoidance tests once a day for 12 days. Then the irreversible antagonist of mACh receptors, propylbenzilylcholine mustard (PrBCM), was injected bilaterally into the cerebral cortex of rats showing avoidance rates of more than 75% in the last session, and avoidance rates were examined 24 hr later. The avoidance rates of the rats treated with 100 micrograms PrBCM were lower than those in the last session before treatment. The amount of mACh receptors in the cerebral cortex was decreased by PrBCM treatment, as shown by [3H]quinuclidinyl benzilate (QNB) binding studies performed just after measurement of the avoidance response. The present study indicates that cholinergic neurotransmission in rat cerebral cortex is involved in performing a learned shuttle avoidance.

Animals↗

PubMed1989

Relapse of acetic acid-induced gastric ulcer and gastric mucosal prostaglandin I2 level in rats.

The healing process of acetic acid-induced gastric ulcer in rats was observed with an endoscope for 365 d after ulcer induction. The ulcers were induced by acetic acid solutions of various concentrations (2.5 (I), 5.0 (II), 10 (III) and 20% (IV); 0.05 ml). On day 3, a positive correlation was observed between the ulcer index (UI) and the concentration of acetic acid solution. On day 365, cumulative healing rates in groups I, II, III and IV amounted to 100, 100, 58.3 and 51.7%, respectively. The cumulative relapse rates in groups I, II, III and IV were 0, 13.6, 66.7 and 58.6%, respectively. Significant correlations were observed between initial UI values and cumulative healing or cumulative relapse rate. On day 365, rats were divided into two groups, a healed group and non-healed group, and the gastric mucosal prostaglandin I2 (PGI2) level was measured by bioassay. The PGI2 level around ulcers in ulcer-induced rats was higher than in normal rats, and it was higher in non-healed rats than in healed rats. Moreover, the PGI2 level was higher in those groups which showed a higher cumulative relapse rates. The above results indicated that the initial ulcer size and the PGI2 level around the ulcer might correlate to ulcer healing or exacerbation.

Acetates↗

PubMed1989

Healing process of acetic acid-induced gastric ulcer and gastric mucosal prostaglandin E generation level in rats.

The prostaglandin E (PGE) generation level (PGE level) in the gastric mucosa was investigated in relation to the healing and relapse of acetic acid-induced gastric ulcers in the rat. The PGE level around ulcers showed higher levels after ulcer induction and decreased during the ulcer diminishing period. Thereafter, the PGE levels showed an inclination to increase during the ulcer exacerbation period. In reulcerated rats, PGE levels were significantly higher. In conclusion, a high level of PGE may indicate an ulcer exacerbation state.

Acetates↗

PubMed1989

In vitro measurement of the pH gradient and thickness of the duodenal mucus gel layer in rats.

The mucus bicarbonate barrier of the duodenum has lately been reported to be one of the most important defensive factors for the duodenal mucosa. We established an in vitro system for evaluating the mucus bicarbonate barrier in the rat duodenum. Our method allows direct measurement of the pH gradient as well as the thickness of the mucus gel layer of the rat duodenum in vitro. The obtained results suggest that alkali secretion in response to acid-loading as well as the thickness of the duodenal mucus gel layer are greater than those in the stomach.

Animals↗

PubMed1989

Effect of the luminal hydrogen ion on alkali and mucus secretion in the rat stomach.

This study was designed to investigate the effect of luminal H+ on alkali and mucus secretion in the isolated rat stomach. At various luminal pHs, the thickness and the pH gradient of the mucus gel layer were measured. The maximum pH and calculated alkali secretion showed that the latter was stimulated in parallel with an increase in luminal H+ concentration, especially when the luminal pH became less than 3.5. Mucus secretion, however, was not significantly affected by the luminal H+ concentration. These results suggest that alkali and mucus secretion in the stomach are not regulated by the same mechanism, but different ones.

Alkalies↗

PubMed1989

Role of the mucus gel layer in the healing of acetic acid-induced gastric ulcers in rats.

Changes in the pH gradient and thickness of the mucus gel layer in the healing of acetic acid-induced gastric ulcers in rats were investigated. The maximum of the pH gradient and the thickness of mucus gel layer at the edge of ulcers and in the regenerated mucosa were higher, decreased gradually with the healing of the ulcers and finally reached normal values. This indicates that mucus and bicarbonate are secreted actively from the mucosa surrounding an ulcer and that they play an important role in protection of the base of ulcers and in acceleration of the healing of the ulcers.

Acetates↗