Action of epidermal growth factor on acid secretion by rat isolated parietal cells

The site and mechanism of action of epidermal growth factor (EGF) on acid secretion by rat isolated parietal cells were investigated by using the intracellular accumulation of the weak base aminopyrine as an index of secretory activity. When parietal cells were stimulated with histamine (0.5 mM), the concentration of EGF required for half-maximal inhibition of acid secretion was 19 nM, with a maximally effective concentration of EGF producing 38% inhibition of secretory activity. EGF did not inhibit secretion stimulated by 0.1 mM-carbachol, or by 30 microM-, 56 microM-, 100 microM- or 1000 microM-dibutyryl cyclic AMP, low concentrations of which produced a secretory response comparable with that obtained with 0.5 mM-histamine. Addition of 0.1 mM-3-isobutyl-1-methylxanthine (IBMX) substantially increased aminopyrine accumulation in the presence of 0.5 mM-histamine. The inhibitory action of EGF on histamine-stimulated secretion was blocked by 0.1 mM-IBMX, even if low concentrations of histamine were used to generate aminopyrine accumulation ratios similar to those obtained with 0.5 mM-histamine alone. The cyclo-oxygenase inhibitor flurbiprofen (1-100 microM) and the cyclo-oxygenase and lipoxygenase inhibitor nordihydroguaiaretic acid (10-100 microM) did not affect the inhibitory action of EGF. The pattern of inhibition of secretion produced by the activator of Ca2+-sensitive phospholipid-dependent protein kinase, 12-O-tetradecanoylphorbol 13-acetate, was markedly different from that produced by EGF. In conclusion, a major site of the action of EGF on acid secretion in the intact stomach is probably a decrease in the stimulatory effect of histamine by a mechanism which does not involve Ca2+-sensitive phospholipid-dependent protein kinase or the production of prostaglandins, but which might involve enhancement of cyclic AMP phosphodiesterase activity.