Kato S, Suzuki K, Ukawa H, Komoike Y, Takeuchi K
Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University Misasagi, Yamashina, Japan.
Dig Dis Sci. 2001 Aug;46(8):1690-9. doi: 10.1023/a:1010601520497.
The gastric toxic effects of aspirin (ASA) and NCX-4016, a nitric oxide (NO)-releasing ASA, were compared in normal, cirrhotic, and arthritic rats. Oral administration of ASA (100 mg/kg) produced hemorrhagic lesions on the gastric mucosa in normal rats. The gastric ulcerogenic response to ASA was significantly worsened in both cirrhotic rats induced by N-nitrosodiethylamine and in arthritic rats induced by Freund's complete adjuvant. By contrast, NCX-4016 at 190 mg/kg (a dose equimolar to 100 mg/kg of ASA) did not induce damage in normal rat stomachs but caused slight lesions in the gastric mucosa of both cirrhotic and arthritic rats. Plasma salicylate levels following administration of ASA or NCX-4016 were not different between normal, cirrhotic, and arthritic rats, although the latter drug gave significantly lower values in any group of rats as compared to the former. Acid secretion was significantly increased in both cirrhotic and arthritic rats. ASA with 150 mM HCl caused severe gastric lesions in normal rats, the degree of damage being significantly greater than that induced by ASA alone. Coadministration of NOR-3, a NO donor, significantly prevented the development of gastric lesions induced by ASA, irrespective of whether or not ASA was given together with HCl. Gastric mucosal application of ASA (100 mg/kg) for 30 min caused a marked reduction of transmucosal potential difference (PD) with a minimal effect on gastric mucosal blood flow in both normal and cirrhotic rats, while that of NCX-4016 did not cause a PD reduction and produced a marked increase in the mucosal blood flow in both groups of rats. These results suggest that gastric mucosal susceptibility to ASA-induced damage is increased in both cirrhotic and arthritic rats (the process being partly accounted for by acid hypersecretion in these animals), NCX-4016 has even less gastric toxicity in both cirrhotic and arthritic rats, and the gastric-sparing effect of NCX-4016 is due, at least partly, to an increase of gastric mucosal blood flow, mediated by NO released from this drug.
在正常大鼠、肝硬化大鼠和关节炎大鼠中比较了阿司匹林（ASA）和NCX - 4016（一种释放一氧化氮（NO）的ASA）的胃毒性作用。给正常大鼠口服ASA（100mg/kg）会在胃黏膜上产生出血性病变。在由N - 亚硝基二乙胺诱导的肝硬化大鼠和由弗氏完全佐剂诱导的关节炎大鼠中，对ASA的胃溃疡形成反应均显著恶化。相比之下，190mg/kg的NCX - 4016（与100mg/kg ASA等摩尔的剂量）在正常大鼠胃中未引起损伤，但在肝硬化和关节炎大鼠的胃黏膜中导致了轻微病变。给予ASA或NCX - 4016后，正常大鼠、肝硬化大鼠和关节炎大鼠的血浆水杨酸盐水平没有差异，尽管与前者相比，后一种药物在任何一组大鼠中的水平都显著较低。肝硬化大鼠和关节炎大鼠的胃酸分泌均显著增加。150mM HCl与ASA一起给药会在正常大鼠中引起严重的胃损伤，损伤程度明显大于单独使用ASA所诱导的损伤。同时给予NO供体NOR - 3可显著预防由ASA诱导的胃损伤的发生，无论ASA是否与HCl一起给药。在正常大鼠和肝硬化大鼠中，将ASA（100mg/kg）应用于胃黏膜30分钟会导致跨黏膜电位差（PD）显著降低，而对胃黏膜血流的影响最小，而NCX - 4016不会导致PD降低，并且在两组大鼠中均使黏膜血流显著增加。这些结果表明，肝硬化大鼠和关节炎大鼠对ASA诱导损伤的胃黏膜易感性增加（该过程部分归因于这些动物的胃酸分泌过多），NCX - 4016在肝硬化和关节炎大鼠中的胃毒性甚至更低，并且NCX - 4016的胃保护作用至少部分归因于该药物释放的NO介导的胃黏膜血流增加。
