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

S. Fiorucci, L. Santucci, P. Gresele, O. Luinetti, A. Morelli

Research output: Contribution to journalArticle

Abstract

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 μM) did not reduce cell viability as evaluated by lactate dehydrogenase and 51Cr release and trypan blue incorporation. Indomethacin (10 μM) caused two- to threefold increases in pepsinogen secretion and intracellular calcium concentrations ([Ca 2+](i)). Both effects were concentration dependent. Removal of extracellular Ca 2+ or pretreatment of the cells with 0.5 mM lanthanum blocked both pepsinogen secretion and the [Ca 2+](i) increase in chief cells stimulated with 10 μM 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 concentration-dependent stimulation of pepsinogen release (mean effective concentration of 0.05-0.1 nM). Maximally effective concentrations of all LTs (10 μM) increased [Ca 2+](i) two- to threefold. Pretreating the cells with a 5-dipoxygenase inhibitor abolished LTB 4 generation induced by Ca 2+ ionophore and indomethacin and reduced indomethacin-induced pepsinogen secretion 20%. In conclusion, indomethacin induced a concentration-dependent stimulation of pepsinogen secretion and [Ca 2+](i) in isolated chief cells. Indomethacin inhibits PGE 2 generation, but increases LTB 4 release. This 'lipoxygenase shunt' may contribute to the effect indomethacin exerts on isolated chief cells.

Original languageEnglish
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume268
Issue number6 31-6
Publication statusPublished - 1995

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Keywords

  • carbachol
  • cholecystokinin
  • leukotriene B
  • prostaglandin E
  • secretin
  • vasointestinal peptide

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Physiology
  • Gastroenterology

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