Kobata Atsushi, Kotani Tohru, Komatsu Yoshino, Amagase Kikuko, Kato Shinichi, Takeuchi Koji
Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, Japan.
Digestion. 2007;75(4):188-97. doi: 10.1159/000108590. Epub 2007 Sep 19.
We investigated the roles of NO/NOS isoforms in the pathogenesis of ischemia/reperfusion (I/R)-induced gastric injury in mouse stomachs.
Under urethane anesthesia, the celiac artery was clamped, and then reperfusion was established 30 min later by removal of the clamp. After a 60-min reperfusion, the stomach was examined for macroscopic lesions.
Following I/R, hemorrhagic lesions were generated in the mucosa, although ischemia alone caused no visible damage. Prior administration of L-NAME (a nonselective NOS inhibitor) significantly aggravated these lesions, in a L-arginine-inhibitable manner. By contrast, the selective iNOS inhibitor 1400W significantly prevented the occurrence of I/R-induced gastric lesions. The mucosal MPO activity was increased after I/R, and this response was enhanced and attenuated by prior administration of L-NAME and 1400W, respectively. Interestingly, the later treatment with L-NAME, given 10 min before reperfusion, significantly reduced the severity of the I/R-induced gastric damage, in a L-arginine-dependent manner. The expression of iNOS mRNA was up-regulated in the stomach following I/R, with an increase of mucosal NO content, and the NO production was significantly inhibited by both L-NAME and 1400W.
Endogenous NO plays a dual role in the pathogenesis of IR-induced gastric damage; NO/cNOS is protective while NO/iNOS is proulcerogenic during I/R.
我们研究了一氧化氮（NO）/一氧化氮合酶（NOS）同工型在小鼠胃缺血/再灌注（I/R）诱导的胃损伤发病机制中的作用。
在氨基甲酸乙酯麻醉下，夹闭腹腔动脉，30分钟后移除夹子建立再灌注。再灌注60分钟后，检查胃的宏观病变。
I/R后，黏膜出现出血性病变，而单独缺血未造成可见损伤。预先给予L-NAME（一种非选择性NOS抑制剂）以L-精氨酸可抑制的方式显著加重了这些病变。相比之下，选择性诱导型NOS（iNOS）抑制剂1400W显著预防了I/R诱导的胃损伤的发生。I/R后黏膜髓过氧化物酶（MPO）活性增加，预先给予L-NAME和1400W分别增强和减弱了这种反应。有趣的是，在再灌注前10分钟给予L-NAME的后期治疗以L-精氨酸依赖的方式显著降低了I/R诱导的胃损伤的严重程度。I/R后胃中iNOS mRNA表达上调，黏膜NO含量增加，L-NAME和1400W均显著抑制了NO的产生。
内源性NO在I/R诱导的胃损伤发病机制中起双重作用；在I/R期间，NO/组成型NOS具有保护作用，而NO/iNOS具有促溃疡作用。
