Takeuchi K, Yasuhiro T, Asada Y, Sugawa Y
Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, Japan.
Digestion. 1998 Jul-Aug;59(4):298-307. doi: 10.1159/000007506.
We examined the effect of NO synthase inhibitor on the functional and ulcerogenic responses to aspirin (ASA) in rat stomach. The animals were given ASA (20-80 mM) orally with or without HCl (10-50 mM) and killed 2 h later. NG-nitro-L-arginine methyl ester (L-NAME) was given i.v. 5 min before aspirin. In the functional study, a rat stomach was mounted on an ex vivo chamber under urethane anesthesia, perfused with saline, and transmucosal potential difference (PD), luminal pH, acid secretion and mucosal blood flow (GMBF) were measured simultaneously. ASA alone caused gastric damage in a dose-related manner; mostly nonhemorrhagic lesions. Pretreatment with L-NAME worsened such lesions and caused severe hemorrhagic lesions. Coadministration of HCl with ASA also potentiated gastric lesions in a concentration-dependent manner, changing nonhemorrhagic into hemorrhagic damage, and the worsening effect of L-NAME disappeared when 80 mM ASA was given together with HCl at >20 mM. In chambered stomachs, the mucosal application of ASA (80 mM, 30 min) caused a marked reduction in PD and a slight decrease in acid secretion, with minimal change in GMBF. L-NAME blocked the reduced acid response following ASA and caused stimulation of acid secretion with no effect on PD and GMBF. These effects of L-NAME were all antagonized by coadministration of L-arginine and significantly mitigated by sensory deafferentation or pretreatment with cimetidine or FPL-52694. These results suggest that (1) intragastric administration of ASA causes a release of NO, which reduces the development of hemorrhagic lesions by decreasing acid secretion, and (2) L-NAME worsens gastric damage by increasing acid secretion in ASA-treated stomachs, the process being dependent on endogenous histamine and sensory neurons.
我们研究了一氧化氮合酶抑制剂对大鼠胃中阿司匹林（ASA）功能及致溃疡反应的影响。给动物口服ASA（20 - 80 mM），同时或不同时给予HCl（10 - 50 mM），2小时后处死。在给予阿司匹林前5分钟静脉注射NG-硝基-L-精氨酸甲酯（L-NAME）。在功能研究中，将大鼠胃置于氨基甲酸乙酯麻醉下的离体腔室中，用生理盐水灌注，同时测量跨黏膜电位差（PD）、腔内pH值、酸分泌和黏膜血流量（GMBF）。单独使用ASA以剂量相关方式导致胃损伤；大多为非出血性病变。用L-NAME预处理会使此类病变恶化并导致严重出血性病变。HCl与ASA共同给药也以浓度依赖方式增强胃损伤，将非出血性损伤转变为出血性损伤，当80 mM ASA与>20 mM HCl一起给药时，L-NAME的恶化作用消失。在有腔胃中，黏膜应用ASA（80 mM，30分钟）导致PD显著降低，酸分泌略有减少，GMBF变化最小。L-NAME阻断了ASA后酸反应的降低，并导致酸分泌增加，对PD和GMBF无影响。L-精氨酸共同给药可拮抗L-NAME的这些作用，感觉去传入、西咪替丁或FPL-52694预处理可显著减轻这些作用。这些结果表明：（1）胃内给予ASA会导致一氧化氮释放，通过减少酸分泌降低出血性病变的发生；（2）L-NAME通过增加ASA处理胃中的酸分泌使胃损伤恶化，该过程依赖于内源性组胺和感觉神经元。
