EFFECT OF NSAIDS ON PEPSINOGEN SECRETION AND CALCIUM MOBILIZATION IN ISOLATED CHIEF CELLS

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.