S. Fiorucci et al., EFFECT OF NSAIDS ON PEPSINOGEN SECRETION AND CALCIUM MOBILIZATION IN ISOLATED CHIEF CELLS, American journal of physiology: Gastrointestinal and liver physiology, 31(6), 1995, pp. 968-978
Acid and pepsin are thought to play an important role in the process o
f gastrointestinal side effects induced by nonsteroidal anti-inflammat
ory drugs (NSAIDs). Although NSAIDs increase basal gastric acid secret
ion, the effect they exert on pepsinogen secretion is unknown. Because
pepsin plays a key role in many acid-related diseases, we investigate
d whether NSAIDs directly stimulate pepsinogen secretion from isolated
chief cells. Exposure of guinea pig gastric chief cells to indomethac
in (10 mu M) did not reduce cell viability as evaluated by lactate deh
ydrogenase and Cr-51 release and trypan blue incorporation. Indomethac
in (10 mu M) caused two- to threefold increases in pepsinogen secretio
n and intracellular calcium concentrations ([Ca2+](i)). Both effects w
ere concentration dependent. Removal of extracellular Ca2+ or pretreat
ment of the cells with 0.5 mM lanthanum blocked both pepsinogen secret
ion and the [Ca2+](i) increase in chief cells stimulated with 10 mu M
indomethacin. Exposure of isolated chief cells to indomethacin caused
a 90% inhibition of prostaglandin (PG) E(2) generation, but a 12-fold
increase in leukotriene (LT) B-4 release. Incubating chief cells with
exogenously added LTB(4), LTC(4), LTD(4), and LTE(4) provoked a concen
tration-dependent stimulation of pepsinogen release (mean effective co
ncentration of 0.05-0.1 nM). Maximally effective concentrations of all
LTs (10 mu M) increased [Ca2+](i) two- to threefold. Pretreating the
cells with a 5-lipoxygenase inhibitor abolished LTB(4) generation indu
ced by Ca2+ ionophore and indomethacin and reduced indomethacin-induce
d pepsinogen secretion 20%. In conclusion, indomethacin induced a conc
entration-dependent stimulation of pepsinogen secretion and [Ca2+](i)
in isolated chief cells. Indomethacin inhibits PGE(2) generation, but
increases LTB(4) release. This ''lipoxygenase shunt'' may contribute t
o the effect indomethacin exerts on isolated chief cells.