Shigeru Ueki

Importance of gastric motility in the pathogenesis of indomethacin-induced gastric lesions in rats.

Effects of indomethacin on gastric motility and secretion, and levels of endogenous prostaglandins (PGs) were investigated in rats, in attempts to elucidate the factors involved in the pathogenesis of indomethacin-induced macroscopic gastric lesions. Subcutaneous administration of indomethacin had no effect on the gastric mucosa at doses of 1 and 5 mg/kg, but induced visible lesions dose dependently at over 10 mg/kg within 4 hr. At 25 mg/kg, there were apparent nonhemorrhagic lesions within 1 hr, and these lesions became hemorrhagic with time. Acid secretion was not affected by this agent at either dose level, but pepsin or acid-induced HCO3− secretion was significantly increased or decreased, respectively, at a dose less than 5 mg/kg, which did not induce any lesion. Gastric motility, however, was dose dependently increased after administration of indomethacin, and its effect was significant at 10 mg/kg or greater. Time-course changes in the motility were in parallel with those of the lesion formation. PGE2 and 6-keto PGF1α levels in the corpus mucosa were reduced around 80–90% for more than 4 hr from 30 min after administration of 5 mg/kg or more of indomethacin. When all the above changes caused by indomethacin were plotted for the various doses, a significant correlation (r=0.958, P<0.01) was found between the lesion index and the changes in motility, but not in other factors, including PG levels. These results indicate that gastric motility may be an important factor in the pathogenetic mechanism of indomethacin-induced gastric lesions in rats. A deficiency of endogenous PGs may be a prerequisite for later extension of the lesions.

Gastric motility is an important factor in the pathogenesis of indomethacin-induced gastric mucosal lesions in rats.

Effects of atropine, cimetidine, and 16,16-dimethyl prostaglandin E2 (16,16-dmPGE2) on indomethacin-induced gastric lesions were investigated in rats by correlating their effects on gastric acid and HCO}-3 secretion and motility. Subcutaneously administered indomethacin (25 mg/kg) produced gastric mucosal lesions within 4 hr. In parallel studies, an equivalent dose of indomethacin inhibited gastric HCO}-3 secretion, and stimulated gastric motor activity measured as intraluminal pressure recordings, whereas acid secretion was unaffected. The lesions induced by indomethacin were significantly prevented by three agents: cimetidine (100 mg/kg), which reduced acid secretion; atropine (1 mg/kg), which reduced acid secretion and gastric motility; and 16,16-dmPGE2 (10 μg/kg), which reduced acid secretion and motility and increased gastric HCO−3 secretion. If acid (150 mM HCl) was infused into the stomach (1.2 ml/hr) during indomethacin treatment, only the latter two agents significantly prevented the formation of gastric lesions in response to indomethacin. Since only the effect on gastric motility was common to these two agents (atropine and 16,16-dmPGE2), the increased gastric motility may be an important pathogenetic factor in indomethacin-induced gastric lesions. The presence of acid as well as a deficiency of endogenous PGs may be prerequisite for later extension of the lesions but cannot account for the induction of mucosal lesions in rats following administration of indomethacin.

Influence of prednisolone on gastric alkaline response in rat stomach. A possible explanation for steroid-induced gastric lesion.

Exposure of the rat stomach for 10 min to 1 M NaCl produced an increase of luminal pH (alkaline response) with a concomitant reduction of the transmucosal potential difference (PD) and an increased generation of mucosal prostaglandins of E2 and 6-keto F1α. Prednisolone (3–50 mg/kg), given subcutaneously 4 hr before exposure to 1 M NaCl, dose-dependently inhibited alkaline response without affecting the PD reduction, and at 50 mg/kg completely prevented the increased production of mucosal prostaglandins after exposure to 1 M NaCl. The inhibitory effect of prednisolone on alkaline response was significantly antagonized by pretreatment with 16,16-dimethyl prostaglandin E2 (16,16-dmPGE2) (3 μg/kg) or cycloheximide (1.5 mg/kg). A repeated administration of prednisolone (3–50 mg/kg), once daily for 4 days, produced gastric lesions dose-dependently. At 50 mg/kg, gastric lesions appeared after administration of this drug for more than 2 days, and the inhibition of alkaline response caused by 1 M NaCl became more potent as the days of treatment increased. Either 16,16-dmPGE2 (10–100 μg/kg) or cycloheximide (1 or 3 mg/kg), given daily in two divided doses for 4 days, dose-dependently inhibited formation of gastric lesions in response to prednisolone (50 mg/kg). These results indicate that prednisolone inhibits gastric alkaline response caused by 1 M NaCl by reducing generation of endogenous prostaglandins. The weakened self-defense mechanisms caused by prednisolone may be involved in the pathogenesis of steroid-induced gastric lesions.

Bicarbonate stimulatory action of nizatidine, a histamine H2-receptor antagonist, in rat duodenums

Nizatidine, a histamine H(2)-antagonist, is known to inhibit acetylcholinesterase (AChE) activity and is used clinically as a gastroprokinetic agent as well as the anti-ulcer agent. We examined whether or not nizatidine stimulates duodenal HCO(3)(-) secretion in rats through vagal-cholinergic mechanisms by inhibiting AChE activity. Under pentobarbital anesthesia, a proximal duodenal loop was perfused with saline, and the HCO(3)(-) secretion was measured at pH 7.0 using a pH-stat method and by adding 10 mM HCl. Nizatidine, neostigmine, carbachol, famotidine or ranitidine was administered i.v. as a single injection. Intravenous administration of nizatidine (3-30 mg/kg) dose-dependently increased the HCO(3)(-) secretion, and the effect at 10 mg/kg was equivalent to that obtained by carbachol at 0.01 mg/kg. The HCO(3)(-) stimulatory action of nizatidine was observed at the doses that inhibited the histamine-induced acid secretion and enhanced gastric motility. This effect was mimicked by neostigmine (0.03 mg/kg) and significantly attenuated by bilateral vagotomy and pretreatment with atropine but not indomethacin. The IC(50) of nizatidine for AChE of rat erythrocytes was 1.4 x 10(-6) M, about 12 times higher than that of neostigmine. Ranitidine showed the anti-AchE activity and increased duodenal HCO(3)(-) secretion, similar to nizatidine, whereas famotidine had any influence on neither AChE activity nor the HCO(3)(-) secretion. On the other hand, duodenal damage induced by acid perfusion (100 mM HCl for 4 h) in the presence of indomethacin was significantly prevented by nizatidine and neostigmine, at the doses that increased the HCO(3)(-) secretion. These results suggest that nizatidine increases HCO(3)(-) secretion in the rat duodenum, mediated by vagal-cholinergic mechanism, the action being associated with the anti-AChE activity of this agent.

Mechanisms of antisecretory action of intragastric FPL-52694: a mast cell stabilizer in anesthetized rats

Mechanisms of antisecretory action of intragastric FPL-52694, a mast cell stabilizer, were investigated in anesthetized rats. In Schilds rat preparation, intravenous FPL-52694 (10 mg/kg) significantly suppressed acid secretion in response to only tetragastrin (20 micrograms/kg, i.v.) (42.1 +/- 19.4%), while intragastric application of FPL-52694 (100 mg/kg) for 30 min produced a marked, unequivocal inhibition (over 70%) in acid secretory responses to histamine (1 mg/kg, i.v.) and carbachol (2.5 micrograms/kg, i.v.) as well as tetragastrin. The inhibitory effect of intragastric FPL-52694 was confirmed in the lumen-perfused rats, where acid secretion (24-25 mumol/10 min) induced by intravenous infusion of histamine (8 mg/kg/h) was abolished for 1 h after exposure of the stomach for 30 min to this agent. Inhibition of histamine-stimulated acid secretion by intragastric FPL-52694 was much greater and lasted longer (2 h) as compared with xylocaine (4% solution), but significantly mitigated by pretreatment of the rats with subcutaneous administration of indomethacin (3 mg/kg). Furthermore, application of FPL-52694 but not of xylocaine to the stomach caused a reduction of transmucosal potential difference, an increase of luminal appearance of HCO-3 (1-2 mumol/10 min), and an enhancement of H+ back-diffusion, although no damage was appreciated in the mucosa. These results suggest that antisecretory action of intragastric FPL-52694 may involve local mechanisms such as neutralization of acid with HCO-3, a loss of acid due to H+ back-diffusion, and inhibition of acid production mediated by endogenous prostaglandins, but is not related to the local anesthetic activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Prostaglandin E1誘導体Misoprostol, (±)-methyl(11α, 13E)-11, 16-dihydroxy-16-methyl-9-oxoprost-13-en-1-oate，のラットの各種胃および十二指腸損傷に対する効果

Male Sprague-Dawley rats (230-280 g), either fasted for 15-24 hr or non-fasted prior to experiments, were used. Misoprostol (3-100 micrograms/kg, p.o.) dose-dependently inhibited the development of 150 mM HCl X aspirin (100 mg/kg)-, 150 mM HCl X 60% ethanol-, and aspirin (150 mg/kg)-induced gastric lesions. Misoprostol (30, 100 micrograms/kg, p.o.), given twice daily for 4 days, significantly inhibited prednisolone (50 mg/kg given once daily for 4 days)-induced gastric lesions. Misoprostol (30 or 2 X 300 micrograms/kg, p.o.) also significantly inhibited water-immersion stress (21 degrees C, 10 hr)-induced gastric lesions or mepirizole (200 mg/kg)-induced duodenal lesions, respectively. In contrast, misoprostol (30-300 micrograms/kg, p.o.) had no effects on indomethacin (25 mg/kg)- and mepirizole (200 mg/kg)-induced gastric lesions. Misoprostol (30 micrograms/kg, p.o.) had no effect on gastric secretion in pylorus-ligated preparations (4 hr), but it (100 or 300 micrograms/kg, p.o.) significantly increased the volume and pepsin output. Gastric motility, either normal or enhanced with indomethacin (25 mg/kg), was inhibited by misoprostol (30 or 300 micrograms/kg, p.o.). Misoprostol (30 micrograms/kg, i.d.) significantly stimulated duodenal HCO3- secretion. Mechanisms by which misoprostol inhibits various gastric lesions remain unknown. However, the stimulatory activity on duodenal HCO3- secretion appears to be involved in the preventive effect of misoprostol on the development of duodenal lesions. The effects of cimetidine and 16,16-dimethyl PGE2 were also studied and compared with those of misoprostol.