Kokoska E R, Smith G S, Deshpande Y, Wolff A B, Miller T A
Theodore Cooper Surgical Research Institute, Department of Surgery, Saint Louis University Health Sciences Center, St. Louis, Missouri 63104, USA.
Am J Physiol. 1998 Oct;275(4):G620-8. doi: 10.1152/ajpgi.1998.275.4.G620.
Indomethacin and other nonsteroidal anti-inflammatory drugs are commonly used to indirectly deduce the possible role of PGs in a process being studied. The objective of this study was to determine if indomethacin, at concentrations comparable to plasma and tissue levels obtained in humans taking therapeutic doses, predisposes human gastric cells to injury through inhibition of PGs or acts through an alternate mechanism. The role of intracellular Ca2+ in this damaging process was also assessed. Indomethacin pretreatment, although by itself nondamaging, was associated with elevated intracellular Ca2+ concentrations and an increased cellular permeability, an effect that was dependent on extracellular Ca2+. Furthermore, indomethacin pretreatment significantly predisposed AGS cells to injury induced by two dissimilar agents (deoxycholate and A-23187), both of which are associated with intracellular Ca2+ accumulation. The addition of exogenous PGs did not reverse the predisposition to injury induced by indomethacin. The observed effects of indomethacin were dependent on concentration and not on ability to inhibit PG synthesis. Similar effects were not observed with equipotent concentrations of ibuprofen or aspirin. Finally, the exacerbation of deoxycholate-induced injury induced by indomethacin was not observed when extracellular Ca2+ was removed. Indomethacin, by disturbing intracellular Ca2+ homeostasis, predisposes human gastric cells to injury through mechanisms independent of PG synthesis. The current study suggests that data resulting from studies employing only indomethacin as a PG synthesis inhibitor should be interpreted with caution.
吲哚美辛和其他非甾体类抗炎药通常被用于间接推断前列腺素（PGs）在某一正在研究的过程中可能发挥的作用。本研究的目的是确定，在与服用治疗剂量药物的人类血浆和组织中所达到的浓度相当的情况下，吲哚美辛是否会通过抑制PGs使人类胃细胞易受损伤，或者通过其他机制发挥作用。同时也评估了细胞内钙离子（Ca2+）在这一损伤过程中的作用。吲哚美辛预处理虽然本身不会造成损伤，但却与细胞内Ca2+浓度升高以及细胞通透性增加有关，这一效应依赖于细胞外Ca2+。此外，吲哚美辛预处理显著使AGS细胞对两种不同试剂（脱氧胆酸盐和A-23187）诱导的损伤更加敏感，这两种试剂都与细胞内Ca2+蓄积有关。添加外源性PGs并不能逆转吲哚美辛诱导的易损伤性。观察到的吲哚美辛的效应取决于浓度，而不是抑制PG合成的能力。使用等效浓度的布洛芬或阿司匹林未观察到类似效应。最后，当去除细胞外Ca2+时，未观察到吲哚美辛加重脱氧胆酸盐诱导的损伤。吲哚美辛通过扰乱细胞内Ca2+稳态，通过独立于PG合成的机制使人类胃细胞易受损伤。本研究表明，仅使用吲哚美辛作为PG合成抑制剂的研究所得到的数据应谨慎解读。
