Takeuchi K, Suzuki K, Yamamoto H, Araki H, Mizoguchi H, Ukawa H
Department of Pharmacology & Experimental Therapeutics, Kyoto Pharmaceutical University, Yamashina, Japan.
J Physiol Pharmacol. 1998 Dec;49(4):501-13.
Occurrence of gastrointestinal damage and delayed healing of pre-existing ulcer are commonly observed in association with clinical use of nonsteroidal antiinflammatory drugs (NSAIDs). We examined the effects of NS-398, the cyclooxygenase (COX)-2 selective inhibitor, and nitric oxide (NO)- releasing aspirin (NCX-4016) on gastric mucosal ulcerogenic and healing responses in experimental animals, in comparison with those of nonselective COX inhibitors such as indomethacin and aspirin. Indomethacin and aspirin given orally were ulcerogenic by themselves in rat stomachs, while either NS-398 or NCX-4016 was not ulcerogenic at the doses which exert the equipotent antiinflammatory action with indomethacin or aspirin. Among these NSAIDs, only NCX-4016 showed a dose-dependent protection against gastric lesions induced by HCl/ethanol in rats. On the other hand, the healing of gastric ulcers induced in mice by thermal-cauterization was significantly delayed by repeated administration of these NSAIDs for more than 7 days, except NCX-4016. Gastric mucosal prostaglandin contents were reduced by indomethacin, aspirin and NCX-4016 in both normal and ulcerated mucosa, while NS-398 significantly decreased prostaglandin generation only in the ulcerated mucosa. Oral administration of NCX-4016 in pylorus-ligated rats and mice increased the levels of NO metabolites in the gastric contents. In addition, both NS-398 and NCX-4016 showed an equipotent anti-inflammatory effect against carrageenan-induced paw edema in rats as compared with indomethacin and aspirin. These results suggest that both indomethacin and aspirin are ulcerogenic by themselves and impair the healing of pre-existing gastric ulcers as well. The former action is due to inhibition of COX-1, while the latter effect may be accounted for by inhibition of COX-2 and mimicked by NS-398, the COX-2 selective NSAID. NCX-4016, despite inhibiting both COX-1 and COX-2, protects the stomach against damage and preserves the healing response of gastric ulcers, probably because of the beneficial action of NO.
在非甾体抗炎药（NSAIDs）的临床使用过程中，胃肠道损伤的发生以及原有溃疡愈合延迟的情况较为常见。我们研究了环氧化酶（COX）-2选择性抑制剂NS-398和释放一氧化氮（NO）的阿司匹林（NCX-4016）对实验动物胃黏膜溃疡形成和愈合反应的影响，并与吲哚美辛和阿司匹林等非选择性COX抑制剂进行了比较。口服给予的吲哚美辛和阿司匹林在大鼠胃中本身就具有致溃疡作用，而NS-398或NCX-4016在发挥与吲哚美辛或阿司匹林等效抗炎作用的剂量下并无致溃疡作用。在这些NSAIDs中，只有NCX-4016对大鼠由盐酸/乙醇诱导的胃损伤具有剂量依赖性的保护作用。另一方面，除NCX-4016外，反复给予这些NSAIDs超过7天会显著延迟热烧灼诱导的小鼠胃溃疡的愈合。吲哚美辛、阿司匹林和NCX-4016均可降低正常和溃疡黏膜中的胃黏膜前列腺素含量，而NS-398仅在溃疡黏膜中显著降低前列腺素的生成。在幽门结扎的大鼠和小鼠中口服NCX-4016可增加胃内容物中NO代谢产物的水平。此外，与吲哚美辛和阿司匹林相比，NS-398和NCX-4016对大鼠角叉菜胶诱导的爪肿胀均显示出等效的抗炎作用。这些结果表明，吲哚美辛和阿司匹林本身均具有致溃疡作用，且会损害原有胃溃疡的愈合。前一种作用是由于COX-1受到抑制，而后一种作用可能是由于COX-2受到抑制，并可被COX-2选择性NSAID NS-398模拟。NCX-4016尽管同时抑制COX-1和COX-2，但可保护胃免受损伤并维持胃溃疡的愈合反应，这可能是由于NO的有益作用。
