Department of Pathophysiology, Faculty of Pharmaceutical Sciences, Doshisha Women's College of Liberal Arts, Kodo, Kyotanabe, Kyoto, 610-0395, Japan.
Departments of Medicine, School of Medicine, University of California Los Angeles, B114, R217, West LA VAMC, 11301 Wilshire Blvd., Los Angeles, CA, 90025, USA.
Dig Dis Sci. 2020 Sep;65(9):2580-2594. doi: 10.1007/s10620-020-06157-x. Epub 2020 Mar 5.
BACKGROUND/AIMS: We examined the effects of proton pump inhibitors (PPIs) on gastric antral ulcers induced by non-steroidal anti-inflammatory drugs in re-fed mice and the role of capsaicin-sensitive afferent nerves (CSANs) in the protective effects of PPIs on the antral mucosa.
Male mice were administered indomethacin after 2 h of re-feeding of diet after a 24-h fast, and gastric lesions were examined 24 h after indomethacin dosing. The effects of PPIs (lansoprazole and omeprazole), histamine H-receptor antagonists (H-RAs, famotidine, ranitidine), capsaicin and misoprostol on the formation of antral ulcers induced by indomethacin were examined. Functional ablation of CSANs was caused by pretreatment of mice with a high dose of capsaicin.
Indomethacin produced lesions selectively in the gastric antrum in re-fed conditions. Formation of antral ulcers was not affected by H-RAs, but inhibited by PPIs, capsaicin and misoprostol. The anti-ulcer effect of lansoprazole was 30 times stronger than that of omeprazole. Antral ulcers induced by indomethacin were markedly aggravated in mice with ablated CSANs. The effects of PPIs and capsaicin on ulcer formation were inhibited by ablation of CSANs, pretreatment with a capsaicin receptor antagonist (capsazepine/ruthenium red) and an inhibitor of nitric oxide synthesis (L-NAME). However, the inhibitory effect of misoprostol was not prevented by the ablation of CSANs or drugs.
The results suggested that CSANs play an important role in protection of the antral mucosa and that both lansoprazole and omeprazole are capable of preventing NSAID-induced antral ulcers by activating CSANs.
背景/目的：我们研究了质子泵抑制剂（PPIs）对重新喂养的小鼠中由非甾体抗炎药引起的胃窦溃疡的影响，以及辣椒素敏感传入神经（CSANs）在 PPIs 对胃窦黏膜保护作用中的作用。
雄性小鼠在禁食 24 小时后重新喂养饮食 2 小时后给予吲哚美辛，并在吲哚美辛给药后 24 小时检查胃损伤。研究了 PPIs（兰索拉唑和奥美拉唑）、组胺 H 受体拮抗剂（H-RAs，法莫替丁，雷尼替丁）、辣椒素和米索前列醇对吲哚美辛诱导的胃窦溃疡形成的影响。通过用高剂量辣椒素预处理小鼠，导致 CSANs 的功能消融。
吲哚美辛在重新喂养条件下选择性地在胃窦中产生病变。H-RAs 对胃窦溃疡的形成没有影响，但 PPIs、辣椒素和米索前列醇可抑制溃疡形成。兰索拉唑的抗溃疡作用比奥美拉唑强 30 倍。CSANs 消融的小鼠中，吲哚美辛诱导的胃窦溃疡明显加重。PPIs 和辣椒素对溃疡形成的作用被 CSANs 的消融、辣椒素受体拮抗剂（辣椒素/钌红）和一氧化氮合酶抑制剂（L-NAME）预处理所抑制。然而，米索前列醇的抑制作用不受 CSANs 消融或药物的影响。
结果表明 CSANs 在胃窦黏膜保护中起重要作用，兰索拉唑和奥美拉唑均可通过激活 CSANs 预防 NSAID 诱导的胃窦溃疡。
