AJP - Gastrointestinal and Liver Physiology, Vol 268, Issue 6 968-G978, Copyright © 1995 by American Physiological Society

ARTICLES

Effect of NSAIDs on pepsinogen secretion and calcium mobilization in isolated chief cells

S. Fiorucci, L. Santucci, P. Gresele, O. Luinetti and A. Morelli
Dipartimento di Medicina Clinica, Patologia e Farmacologia, Universita degli Studi di Perugia, Italy.

Acid and pepsin are thought to play an important role in the process of gastrointestinal side effects induced by nonsteroidal anti-inflammatory drugs (NSAIDs). Although NSAIDs increase basal gastric acid secretion, the effect they exert on pepsinogen secretion is unknown. Because pepsin plays a key role in many acid-related diseases, we investigated whether NSAIDs directly stimulate pepsinogen secretion from isolated chief cells. Exposure of guinea pig gastric chief cells to indomethacin (10 microM) did not reduce cell viability as evaluated by lactate dehydrogenase and 51Cr release and trypan blue incorporation. Indomethacin (10 microM) caused two- to threefold increases in pepsinogen secretion and intracellular calcium concentrations ([Ca2+]i). Both effects were concentration dependent. Removal of extracellular Ca2+ or pretreatment of the cells with 0.5 mM lanthanum blocked both pepsinogen secretion and the [Ca2+]i increase in chief cells stimulated with 10 microM indomethacin. Exposure of isolated chief cells to indomethacin caused a 90% inhibition of prostaglandin (PG) E2 generation, but a 12-fold increase in leukotriene (LT) B4 release. Incubating chief cells with exogenously added LTB4, LTC4, LTD4, and LTE4 provoked a concentration-dependent stimulation of pepsinogen release (mean effective concentration of 0.05-0.1 nM). Maximally effective concentrations of all LTs (10 microM) increased [Ca2+]i two- to threefold. Pretreating the cells with a 5-lipoxygenase inhibitor abolished LTB4 generation induced by Ca2+ ionophore and indomethacin and reduced indomethacin-induced pepsinogen secretion 20%. In conclusion, indomethacin induced a concentration-dependent stimulation of pepsinogen secretion and [Ca2+]i in isolated chief cells. Indomethacin inhibits PGE2 generation, but increases LTB4 release. This "lipoxygenase shunt" may contribute to the effect indomethacin exerts on isolated chief cells.

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