Masanori Yamato

Kyoto Pharmaceutical University, Kioto, Kyōto, Japan

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Publications (8)19.15 Total impact

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    ABSTRACT: Reflux esophagitis is caused mainly by excessive exposure of the mucosa to gastric contents. In the present study, we examined the effect of several amino acids on acid reflux esophagitis in rats. After 18 h of fasting, acid reflux esophagitis was induced by ligating both the pylorus and the transitional region between the forestomach and the corpus under ether anesthesia, and the animals were killed 4 h later. The severity of esophagitis was reduced by the oral administration of omeprazole, a proton pump inhibitor, or pepstatin, a specific pepsin inhibitor. The development of esophageal lesions was dose-dependently prevented by L-arginine and glycine, given intragastrically (i.g.) after the ligation, with complete inhibition obtained at 250 mg/kg and 750 mg/kg, respectively, and these effects were not influenced by the prior s.c. administration of indomethacin or L-NAME. By contrast, both L-alanine and L-glutamine given i.g. after the ligation aggravated these lesions in a dose-dependent manner. These amino acids had no effect on acid secretion but increased the pH of the gastric contents to 1.8~2.3 due to their buffering action. The results confirmed an essential role for acid and pepsin in the pathogenesis of acid reflux esophagitis in the rat model and further suggested that various amino acids affect the severity of esophagitis in different ways, due to yet unidentified mechanisms; L-alanine and L-glutamine exert a deleterious effect on the esophagitis, while L-arginine and glycine are highly protective, independent of endogenous prostaglandins and nitric oxide.
    Medical science monitor: international medical journal of experimental and clinical research 12/2011; 18(1):BR9-15. · 1.22 Impact Factor
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    ABSTRACT: Pravastatin, an HMG-CoA reductase inhibitor, exerts anti-inflammatory effects via several mechanisms including induction of endothelial nitric oxide synthase (eNOS). We investigated the effect of pravastatin on Helicobacter pylori-induced gastritis in mice. Mice with or without H. pylori infection received intraperitoneal pravastatin daily for 1 week. Expression of eNOS mRNA and tumor necrosis factor-alpha mRNA and myeloperoxidase activity in gastric tissue was determined. Myeloperoxidase activity was reduced in a dose-dependent manner by pravastatin, with activity inhibited by 53.5 and 73.7% at doses of 0.3 and 1 mg/kg, respectively. At a dose of 1 mg/kg, pravastatin reduced the level of tumor necrosis factor-alpha mRNA by 52.7%, while it did not affect eNOS expression. Pravastatin had no effects on these inflammatory parameters in uninfected mice. Pravastatin did not affect the viability of H. pylori. In conclusion, pravastatin exerts an anti-inflammatory effect on H. pylori-induced gastritis in mice without affecting eNOS expression.
    Digestive Diseases and Sciences 10/2007; 52(10):2833-9. · 2.55 Impact Factor
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    ABSTRACT: Pepsin, a protease activated by gastric acid, is a component of the refluxate, yet the role of pepsin in the pathogenesis of reflux esophagitis has not been well studied. In the present study, we examined the effect of pepstatin, a specific inhibitor of pepsin, on acid reflux esophagitis. Acid reflux esophagitis was induced in rats by ligating both the pylorus and the forestomach for 3 or 4 hr. Pepstatin, ecabet Na (the anti-ulcer drug), and L-glutamine were administered intragastrically after the ligation. Pepstatin or ecabet Na, given intragastrically, significantly prevented esophageal lesions, even though they did not affect basal acid secretion in pylorus-ligated rats. Pepstatin significantly inhibited pepsin activity in vivo and in vitro, while ecabet Na inhibited this activity in vitro. By contrast, L-glutamine given intragastrically aggravated the lesions in a dose-dependent manner, but even in the presence of L-glutamine the development of esophageal lesions was totally prevented by coadministration of pepstatin or ecabet Na. L-Glutamine increased the pH of gastric contents to approximately 2.0, the optimal pH for the proteolytic activity of pepsin in vitro. In addition, intragastric administration of exogenous pepsin worsened the severity of esophageal damage. These results suggest that pepstatin is highly effective against acid reflux esophagitis, without influencing acid secretion, while L-glutamine aggravated these lesions by increasing the pepsin activity by shifting the intraluminal pH to the optimal pH range for proteolytic action. It is assumed that pepsin plays a major pathogenic role in the development of acid reflux esophagitis.
    Digestive Diseases and Sciences 03/2006; 51(2):303-9. · 2.55 Impact Factor
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    ABSTRACT: We investigated the roles of prostaglandin (PG) E2 and cyclooxygenase (COX) isoenzymes in the mucosal defense of the esophagus, using subtype-selective EP agonists and antagonists as well as various COX inhibitors, in an acute rat esophagitis model. The animals were used after fasting for 18 h. Acid reflux esophagitis was induced by ligating both the pylorus and the transitional region between the forestomach and the glandular portion under ether anesthesia, and the damage was examined 3 or 4 h later. The esophageal lesions were significantly aggravated by prior administration of indomethacin and SC-560 (a selective COX-1 inhibitor) but not rofecoxib (a selective COX-2 inhibitor). PGE2 prevented these lesions at lower doses, yet the protective effect disappeared at a high dose. This biphasic effect was mimicked by 17-phenyl PGE2 (EP1 agonist) and antagonized by ONO-AE-829 (EP1 antagonist), while neither EP2, EP3, nor EP4 agonists had any effect on the esophageal lesions. PGE2 and 17-phenyl PGE2 had no effect on the acid secretion, but significantly increased the pepsin secretion, in a dose-dependent manner. The development of the esophageal lesions was totally prevented by pepstatin, a specific inhibitor of pepsin, and markedly aggravated by exogenous pepsin. We conclude that endogenous PGs derived from COX-1 are involved in the mucosal defense of the esophagus and that PGE2 has a biphasic influence on esophageal injury, depending on the dose: a protective effect at low doses and a deleterious effect at high doses, both mediated by EP1 receptors--the latter effect of PGE2 may be brought about by stimulation of the pepsin secretion.
    Digestion 02/2005; 72(2-3):109-18. · 2.03 Impact Factor
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    ABSTRACT: Endogenous prostaglandins (PGs) are involved in adaptive gastric protection against acute injury, and cyclooxygenase (COX)-1 is responsible for the production of PGs in this phenomenon. In the present study, we examined the effect of various COX inhibitors on gastric ulcerogenic and acid secretory responses following daily exposure of the stomach to iodoacetamide (IA) and investigated the role for COX isozyme in gastric protection under subchronic mucosal irritation. Gastric mucosal irritation was induced by addition of 0.1% IA to drinking water, and the gastric mucosa was examined on the 6th day. Indomethacin (5 mg/kg) or SC-560 (selective COX-1 inhibitor, 5 mg/kg) or rofecoxib (selective COX-2 inhibitor, 5 mg/kg) was given p.o. twice 24 hr and 3 hr before the termination of IA treatment. Giving IA in drinking water for 5 days produced minimal damage in the stomach. The damage was significantly worsened by indomethacin, resulting in hemorrhagic lesions. Both SC-560 and rofecoxib also aggravated such lesions, although the effect of rofecoxib was more pronounced. Treatment with IA decreased acid secretion in pylorus-ligated stomachs, and this change was significantly reverted by indomethacin as well as SC-560 and rofecoxib. Mucosal PGE2 content was increased following IA treatment, with apparent expression of COX-2 mRNA in the stomach, and the increased PGE2 production was significantly suppressed by SC-560 and rofecoxib as well as indomethacin. These results suggest that endogenous PGs derived from both COX-1 and COX-2 are involved in the mucosal defense of the inflamed stomach, partly by decreasing acid secretion and contribute to maintaining the mucosal integrity under such conditions.
    Journal of physiology and pharmacology: an official journal of the Polish Physiological Society 04/2004; 55(1 Pt 2):193-205. · 2.72 Impact Factor
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    ABSTRACT: We investigated the preferential role of cyclooxygenase (COX) isozymes in various functional changes of the rat stomach after exposure to taurocholate (TC) as a mild irritant. Under urethane anesthesia, a rat stomach mounted in an ex vivo chamber was perfused with saline or acid (50 mM HCl), and transmucosal potential difference (PD), gastric mucosal blood flow (GMBF), and acid secretion were measured before and after exposure of the stomach to 20 mM TC for 30 min. Indomethacin, 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethylpyrazole (SC-560) (a selective COX-1 inhibitor), or rofecoxib (a selective COX-2 inhibitor) was given intraduodenally 30 min before the TC treatment. Mucosal application of TC caused a marked reduction in PD, followed by a decrease of acid secretion and an increase of GMBF. Previous administration of indomethacin did not affect the reduction in PD but significantly mitigated the two other responses induced by TC, resulting in a delay in the recovery in PD. These effects were mimicked by SC-560 but not rofecoxib, although neither of these drugs had any effect on the reduction in PD. Perfusion of TC-treated stomachs with 50 mM HCl caused only minimal damage, yet this treatment produced gross lesions in the presence of indomethacin or SC-560. Mucosal exposure to TC increased prostaglandin E2 production, but the response was inhibited by both indomethacin and SC-560 but not rofecoxib. These results suggested that COX-1 but not COX-2 is a key enzyme for regulating the functional alterations of the stomach and for maintaining the mucosal integrity after barrier disruption.
    Journal of Pharmacology and Experimental Therapeutics 12/2003; 307(2):713-9. · 3.86 Impact Factor
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    ABSTRACT: We examined the effect of lafutidine, a novel histamine H(2)-receptor antagonist, on acid reflux esophagitis in rats in relation to capsaicin-sensitive afferent neurons. The esophagitis was induced in rats by ligating both the pylorus and forestomach for 4 h. Lafutidine (1 - 30 mg/kg) and cimetidine (100 mg/kg) were administered either intragastrically or intraduodenally, while capsaicin (1 - 30 mg/kg) was administered intragastrically after the dual ligation. Intragastrical administered lafutidine at >3 mg/kg significantly prevented the hemorrhagic esophageal damage induced by the dual ligation, and this effect was mimicked by neither capsaicin nor cimetidine given intragastrically, but totally abolished by sensory deafferentation. In contrast, lafutidine and cimetidine given intraduodenally were both protective against the esophageal damage in a sensory deafferentation-resistant manner. The acid secretion in pylorus-ligated stomachs was significantly inhibited by these agents given intraduodenally, but not intragastrically. Vanilloid receptor subtype 1 (VR1) was expressed abundantly in the stomach, but very weakly expressed in the esophagus as assessed by Western blotting. These results suggest that lafutidine is effective against the esophageal lesions induced by acid reflux through inhibition of acid secretion and capsaicin-sensitive afferent neurons. The latter mechanism, not shared by cimetidine, may be due to the interaction of lafutidine with unidentified sites on sensory neurons other than VR1.
    Journal of Pharmacological Sciences 09/2003; 93(1):55-61. · 2.11 Impact Factor
  • Journal of Pharmacological Sciences 01/2003; 93(1):55-61. · 2.11 Impact Factor

Publication Stats

100 Citations
19.15 Total Impact Points


  • 2003–2011
    • Kyoto Pharmaceutical University
      • Laboratory of Pharmacology and Experimental Therapeutics
      Kioto, Kyōto, Japan
  • 2007
    • Osaka City University
      • Department of Gastroenterology
      Ōsaka, Ōsaka, Japan