Nishio Hikaru, Hayashi Yujiro, Terashima Shun, Takeuchi Koji
Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8414, Japan.
Life Sci. 2006 Sep 13;79(16):1523-30. doi: 10.1016/j.lfs.2006.04.013. Epub 2006 May 26.
Nitric oxide (NO) plays a role in regulating the mucosal integrity of the stomach. However, its part in the mucosal defense of the inflamed stomach remains unclear. In the present study, we examined the effects of various NO synthase (NOS) inhibitors on gastric ulcerogenic and acid secretory responses following daily exposure of the stomach to iodoacetamide and investigated the role of each NOS isozyme in gastric protection from subchronic mucosal irritation. Gastric mucosal irritation was induced in rats by addition of 0.1% iodoacetamide to drinking water, and the gastric mucosa was examined on the 6th day. L-NAME (a nonselective NOS inhibitor: 20 mg/kg) or aminoguanidine (a selective iNOS inhibitor: 20 mg/kg) was given s.c. twice 24 h and 3 h before the termination of iodoacetamide treatment. Giving iodoacetamide in drinking water for 5 days produced minimal damage in the stomach with an increase in myeloperoxidase (MPO) activity and lipid peroxidation. Iodoacetamide treatment up-regulated the expression of iNOS mRNA and NO production in the stomach, without affecting nNOS expression. Both L-NAME and aminoguanidine markedly aggravated gastric lesions induced by iodoacetamide treatment, with a further enhancement in MPO activity and lipid peroxidation. Basal acid secretion as determined in pylorous-ligated stomachs was decreased following iodoacetamide treatment, but the response was significantly restored by both L-NAME and aminoguanidine. These results suggest that endogenous NO derived from both cNOS and iNOS is involved in mucosal defense of the inflamed stomach, partly by decreasing acid secretion, and contributes to maintaining mucosal integrity under such conditions.
一氧化氮（NO）在调节胃黏膜完整性方面发挥作用。然而，其在炎症胃黏膜防御中的作用仍不清楚。在本研究中，我们检测了各种一氧化氮合酶（NOS）抑制剂对胃每日暴露于碘乙酰胺后的致胃溃疡和酸分泌反应的影响，并研究了每种NOS同工酶在胃免受亚慢性黏膜刺激保护中的作用。通过在饮用水中添加0.1%碘乙酰胺诱导大鼠胃黏膜刺激，并在第6天检查胃黏膜。在碘乙酰胺治疗结束前24小时和3小时，皮下注射L-NAME（一种非选择性NOS抑制剂：20mg/kg）或氨基胍（一种选择性诱导型NOS抑制剂：20mg/kg）两次。在饮用水中给予碘乙酰胺5天，对胃产生的损伤最小，同时髓过氧化物酶（MPO）活性和脂质过氧化增加。碘乙酰胺治疗上调了胃中诱导型NOS mRNA的表达和NO的产生，而不影响神经元型NOS的表达。L-NAME和氨基胍均显著加重了碘乙酰胺治疗诱导的胃损伤，同时MPO活性和脂质过氧化进一步增强。碘乙酰胺治疗后，幽门结扎胃中测定的基础酸分泌减少，但L-NAME和氨基胍均显著恢复了该反应。这些结果表明，来自组成型NOS和诱导型NOS的内源性NO参与了炎症胃的黏膜防御，部分是通过减少酸分泌，并有助于在这种情况下维持黏膜完整性。
