The actions of hydrochloric acid, natural PGE1, PGE2 and a synthetic commercial PGE1 preparation, Enisoprost (Searle) on pepsinogen synthesis and secretion were studied in canine chief cell monolayer cultures. Hydrochloric acid, applied directly to the apical surface of chief cells using culture plate inserts (Millipore) had no effect on secretion, nor did it affect the action of any secretagogue in the basolateral medium. All prostaglandins tested showed significant stimulation of pepsinogen secretion. Basal secretion of pepsinogen after 90 min was 9.4 (1.3)% to total initial monolayer content. At 10(-6) M, PGE1 stimulated secretion was 26.1 (3.8)%; PGE2 27.9 (4)% and Enisoprost 28.8 (4.2)% of initial pepsinogen content. Stimulations by all tested prostaglandins were additive with carbachol (10(-4) M) and CCK (10(-9) M), but not with VIP (10(-6) M), dbcAMP (10(-3) M) or forskolin (10(-6) M) responses. All three prostaglandins stimulated pepsinogen synthesis as measured by 14C labelled amino acid incorporation into pepsinogen. Time course experiments were similar to those for forskolin and showed shorter time delays between stimulus and increased synthesis rate than carbachol but longer than dbcAMP. Stimulated pepsinogen secretion was inhibited by high pepsin concentrations (greater than 800 micrograms/ml) in the medium. The inhibited abolished simultaneous carbachol induced stimulation of synthesis but prostaglandin or forskolin stimulation only after two hours. Combined with the shorter response time, as compared with carbachol, these data support our previous findings that potent stimulators of cAMP production can stimulate pepsinogen synthesis directly by stimulation of mRNA synthesis, independently from an increased secretion. The additivity of effects with carbachol or CCK and similarity with forskolin stimulated synthesis supports the suggestion that the actions of prostaglandins are mediated by cAMP.
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