Rainsford K D
Division of Biomedical Sciences and Biomedical Research Centre, Sheffield Hallam University, England, UK.
J Pharm Pharmacol. 1999 Mar;51(3):331-9. doi: 10.1211/0022357991772330.
The leukotrienes, platelet activating factor and intracellular calcium have been implicated in the development of gastro-intestinal lesions induced by non-steroidal anti-inflammatory drugs (NSAIDs) but the relative significance of these inflammatory mediators in lesion formation has not been established in sensitive and specific models of gastro-intestinal ulceration. In the present study the effects of drugs affecting 5-lipoxygenase activity, the actions of platelet activating factor and intracellular calcium on the development of gastric and intestinal ulceration induced by NSAIDs were investigated in highly sensitive models of ulcerogenicity induced by treatment with either the cholinomimetic, acetyl-beta-methyl choline chloride, in mice (gastric mucosal lesions) or adjuvant-induced polyarthritis in rats (gastric and intestinal mucosal lesions) as well as in normal mice (intestinal mucosal lesions). The 5-lipoxygenase inhibitors, such as MK-886 (3-[1-(4-chlorobenzyl)-3-t-butyl-thio-5-isopropylindol-2-yl]-2,2-+ ++dimethylpropanoic acid), given at doses shown to reduce the indomethacin-induced increase in mucosal leukotriene B4 concentrations were found to partially prevent the development of gastric and intestinal lesion induced by indomethacin and gastric lesions from aspirin, but the same doses of MK-886 did not affect gastric lesions from diclofenac. Pretreatment with these inhibitors at both 3-5 h and 0-0.25 h was required to achieve protection against gastric mucosal damage from indomethacin. Immediate prior administration of platelet activating factor antagonists (e.g. WEB-2086) with the 5-lipoxygenase inhibitors did not affect gastric or intestinal lesions induced by indomethacin. The calcium antagonist, verapamil, was slightly protective against gastric and intestinal lesions induced by indomethacin. Gastric lesions were further prevented by combinations of a single dose of verapamil with a platelet activating factor antagonist but not combined with a 5-lipoxygenase inhibitor; other combinations of verapamil with lipoxygenase inhibitors or platelet-activating factor antagonists being without inhibitory effects on gastric or intestinal lesions compared with the drugs alone. These results show that 5-lipoxygenase products and intracellular calcium play a major role in acute gastric and intestinal damage by the NSAIDs, but platelet-activating factor has little or no appreciable involvement.
白三烯、血小板活化因子和细胞内钙已被认为与非甾体抗炎药（NSAIDs）所致胃肠道损伤的发生有关，但在胃肠道溃疡的敏感和特异模型中，这些炎症介质在损伤形成中的相对重要性尚未明确。在本研究中，利用高度敏感的致溃疡模型，研究了影响5-脂氧合酶活性的药物、血小板活化因子的作用以及细胞内钙对NSAIDs所致胃和肠道溃疡形成的影响。这些致溃疡模型包括：用拟胆碱药氯化乙酰-β-甲基胆碱处理小鼠诱发胃黏膜损伤；用佐剂诱导大鼠多关节炎诱发胃和肠道黏膜损伤；以及正常小鼠诱发肠道黏膜损伤。5-脂氧合酶抑制剂，如MK-886（3-[1-(4-氯苄基)-3-叔丁基硫代-5-异丙基吲哚-2-基]-2,2-二甲基丙酸），给予能降低吲哚美辛所致黏膜白三烯B4浓度的剂量时，发现可部分预防吲哚美辛所致胃和肠道损伤以及阿司匹林所致胃损伤，但相同剂量的MK-886对双氯芬酸所致胃损伤无影响。需要在3 - 5小时和0 - 0.25小时用这些抑制剂预处理，才能预防吲哚美辛所致胃黏膜损伤。5-脂氧合酶抑制剂与血小板活化因子拮抗剂（如WEB-2086）立即联合预先给药，不影响吲哚美辛所致胃或肠道损伤。钙拮抗剂维拉帕米对吲哚美辛所致胃和肠道损伤有轻微保护作用。单剂量维拉帕米与血小板活化因子拮抗剂联合可进一步预防胃损伤，但与5-脂氧合酶抑制剂联合则无此作用；维拉帕米与脂氧合酶抑制剂或血小板活化因子拮抗剂的其他联合与单独用药相比，对胃或肠道损伤无抑制作用。这些结果表明，5-脂氧合酶产物和细胞内钙在NSAIDs所致急性胃和肠道损伤中起主要作用，但血小板活化因子几乎没有或没有明显参与。
