Hisanaga Y, Goto H, Tachi K, Hayakawa T, Sugiyama S
Department of Internal Medicine, Faculty of Medicine, University of Nagoya, Japan.
Aliment Pharmacol Ther. 1996 Dec;10(6):933-40. doi: 10.1046/j.1365-2036.1996.108279000.x.
Nitric oxide (NO) is a potent cytoprotective substance of gastric mucosa. FK506, an immunosuppressive drug, shows anti-gastric ulcer effects equivalent to famotidine, an H2 blocker, in rats. This study was designed to evaluate the cytoprotective mechanism of FK506 on gastric mucosa in relation to the changes in NO synthase activity.
Gastric lesions were induced in rats by water immersion stress. Changes in NO synthase activity during water immersion stress treatment, and effects of FK506 on NO synthase activity were determined enzymatically. Gastric mucosal interleukin (IL)-1 beta and IL-2 were measured by immunoradiometric assay. Gastric mucosal blood flow was measured by hydrogen gas clearance technique.
FK506 mitigated gastric lesions developed by water immersion stress. Stress-induced lesions were exacerbated by NG-monomethyl-L-arginine (L-NMMA), a specific inhibitor of NO synthase, while sodium nitroprusside, a NO donor, mitigated the lesions. Water immersion stress increased NO synthase activity in the early phase (0.5 h after stress treatment) and decreased it in the late phase (6 h after). Decrease in NO synthase activity in the late phase was significantly mitigated by FK506, though it did not affect changes in NO synthase activity in the early phase. Water immersion stress increased gastric mucosal IL-1 beta and IL-2 contents 6 h after stress treatment, and these increases were prevented by FK506. FK506 itself did not affect gastric mucosal blood flow. L-NMMA treatment significantly decreased gastric mucosal blood flow. In contrast, gastric mucosal blood flow was significantly increased by sodium nitroprusside.
Increase in NO synthase activity might contribute to cytoprotection, and a decrease in activity might be a harmful factor for the gastric mucosa. Preservation of NO synthase activity by FK506 might be involved in FK506's protective effects on the gastric mucosa.
一氧化氮（NO）是胃黏膜一种强大的细胞保护物质。免疫抑制药物FK506在大鼠中显示出与H2受体阻滞剂法莫替丁相当的抗胃溃疡作用。本研究旨在评估FK506对胃黏膜的细胞保护机制与一氧化氮合酶活性变化的关系。
通过水浸应激诱导大鼠胃损伤。采用酶法测定水浸应激处理过程中一氧化氮合酶活性的变化以及FK506对一氧化氮合酶活性的影响。采用免疫放射分析法测定胃黏膜白细胞介素（IL）-1β和IL-2。采用氢气清除技术测定胃黏膜血流量。
FK506减轻了水浸应激所致的胃损伤。一氧化氮合酶的特异性抑制剂NG-单甲基-L-精氨酸（L-NMMA）加剧了应激诱导的损伤，而一氧化氮供体硝普钠减轻了损伤。水浸应激在早期（应激处理后0.5小时）增加一氧化氮合酶活性，在后期（应激处理后6小时）降低其活性。FK506显著减轻了后期一氧化氮合酶活性的降低，尽管它不影响早期一氧化氮合酶活性的变化。水浸应激在应激处理后6小时增加胃黏膜IL-1β和IL-2含量，而FK506可阻止这些增加。FK506本身不影响胃黏膜血流量。L-NMMA处理显著降低胃黏膜血流量。相反，硝普钠使胃黏膜血流量显著增加。
一氧化氮合酶活性增加可能有助于细胞保护，而活性降低可能是胃黏膜的有害因素。FK506对一氧化氮合酶活性的保留可能参与了FK506对胃黏膜的保护作用。
