S. Fiorucci et al., LEUKOTRIENES STIMULATE PEPSINOGEN SECRETION FROM GUINEA-PIG GASTRIC CHIEF CELLS BY A NITRIC OXIDE-DEPENDENT PATHWAY, Gastroenterology, 108(6), 1995, pp. 1709-1719
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.