INDOMETHACIN INCREASES SUSCEPTIBILITY TO INJURY IN HUMAN GASTRIC CELLS INDEPENDENT OF PG SYNTHESIS INHIBITION

Indomethacin and other nonsteroidal anti-inflammatory drugs are common ly used to indirectly deduce the possible role of PGs in a process bei ng studied. The objective of this study was to determine if indomethac in, 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 mechani sm. The role of intracellular Ca2+ in this damaging process was also a ssessed. Indomethacin pretreatment, although by itself nondamaging, wa s associated with elevated intracellular Ca2+ concentrations and an in creased cellular permeability, an effect that was dependent on extrace llular Ca2+. Furthermore, indomethacin pretreatment significantly pred isposed AGS cells to injury induced by two dissimilar agents (deoxycho late and A-23187), both of which are associated with intracellular Ca2 + accumulation. The addition of exogenous PGs did not reverse the pred isposition to injury induced by indomethacin. The observed effects of indomethacin were dependent on concentration and not on ability to inh ibit PG synthesis. Similar effects were not observed with equipotent c oncentrations of ibuprofen or aspirin. Finally the exacerbation of deo xycholate-induced injury induced by indomethacin was not observed when extracellular Ca2+ was removed. Indomethacin, by disturbing intracell ular Ca2+ homeostasis, predisposes human gastric cells to injury throu gh mechanisms independent of PG synthesis. The current study suggests that data resulting from studies employing only indomethacin as a PG s ynthesis inhibitor should be interpreted with caution.