Indomethacin increases susceptibility to injury in human gastric
cells independent of prostaglandin synthesis inhibition.
Kokoska, Evan R., Gregory S. Smith, Yashwant Deshpande, Andrew B.
Wolff, and Thomas A. Miller.
Theodore Cooper Surgical Research Institute, Department of Surgery,
Saint Louis University Health Sciences Center, St. Louis, MO
63104
APStracts 5:0144G, 1998.
Indomethacin and other nonsteroidal anti-inflammatory drugs (NSAIDs)
are commonly used to indirectly deduce the possible role of
prostaglandins (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 calcium (Ca++) in this damaging process was also
assessed. Indomethacin pretreatment, although by itself non-damaging,
was associated with elevated intracellular Ca++ concentrations and an
increased cellular permeability, an effect which was dependent upon
extracellular Ca++. Furthermore, indomethacin pretreatment
significantly predisposed AGS cells to injury induced by two
dissimilar agents (deoxycholate and A23187), both of which are
associated with intracellular Ca++ accumulation. The addition of
exogenous PGs did not reverse the predisposition to injury induced by
indomethacin. The observed effects of indomethacin were dependent
upon concentration and not upon 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 Ca++ was removed. Indomethacin, by disturbing
intracellular Ca++ homeostasis, predisposes human gastric cells to
injury through mechanisms independent of PG synthesis. The current
work suggests that data resulting from studies employing only
indomethacin as a PG synthesis inhibitor should be interpreted with
caution.
Received 27 January 1998; accepted in final form 21 May 1998.
APS Manuscript Number G35-8.
Article publication pending Am. J. Physiol. (Gastrointest. Liver
Physiology).
ISSN 1080-4757 Copyright 1998 The American Physiological Society.
Published in APStracts on 16 June 1998