LEUKOTRIENES STIMULATE PEPSINOGEN SECRETION FROM GUINEA-PIG GASTRIC CHIEF CELLS BY A NITRIC OXIDE-DEPENDENT PATHWAY

Background/Aims: Leukotrienes (LTs) are involved in many inflammatory conditions including gastric damage induced by nonsteroidal anti-infla mmatory drugs. Although LTs stimulate acid secretion, the effect they exert on pepsinogen secretion is unknown. The aim of this study was to investigate whether LTs stimulate pepsinogen secretion by isolated ch ief cells and to identify the intracellular messengers that mediate th is action. Methods: Isolated chief cells were incubated with concentra tions of LTB(4), LTC(4), LTD(4), or LTE(4) ranging from 0.1 pmol/L to 10 mu mol/L, and pepsinogen release, intracellular calcium and inosito l (1,4,5)-trisphosphate (IP3) concentrations were measured. Nitric oxi de generation was determined by the amount of citrulline generated dur ing incubation. Results: All four LTs caused a concentration-dependent stimulation of pepsinogen secretion with 50% effective concentration of 0.05-0.1 nmol/L and a dose-dependent increase in cytoplasmic free c alcium and IP3 concentration. The LTB(4) and LTD(4) antagonists caused selective, concentration-dependent inhibition of LTB(4)- and LTD(4)-i nduced pepsinogen secretion, calcium mobilization, and IP3 generation. All four LTs increased NO generation, and the effect was inhibited by LTB(4) and LTD(4) antagonists and an NO synthase inhibitor N-G-monome thyl-L-auginine and reversed by L-arginine. N-G-monomethyl-L-arginine caused a 50%-60% reduction of LT-induced pepsinogen release. Each of t he four LTs caused a fivefold increase in 5'-cyclic guanosine monophos phate. Conclusions: LTs are powerful stimulators of pepsinogen secreti on in isolated chief cells and act via occupancy of specific cell-surf ace receptors.