Inhibition of gastric acid secretion by epidermal growth factor. Effects on cyclic AMP and on prostaglandin production in rat isolated parietal cells

Abstract

Histamine (0.5 mM) stimulated the cyclic AMP content of cell suspensions containing > 80 parietal cells. Epidermal growth factor (EGF) inhibited this stimulatory effect of histamine, but had no effect on basal cyclic AMP content. The half-maximally effective concentration of EGF for inhibition of histaminestimulated cyclic AMP was 3.9 nm. The equivalent measurement for the inhibition of histamine-stimulated aminopyrine accumulation was 3.0 nM. Aminopyrine accumulation was measured because it provides an index of the secretory activity of the cell. The cyclic AMP phosphodiesterase inhibitor 3-isobutyl-Imethylxanthine (IBMX) prevented the inhibitory effect of EGF on cyclic AMP content. This effect of IBMX was not caused by its ability to raise cellular cyclic AMP content in the presence of histamine. Prevention by IBMX of the inhibitory action of EGF on histamine-stimulated aminopyrine accumulation had been shown previously [Shaw, Hatt, Anderson & Hanson (1987) Biochem. J. 244, 699-704]. EGF stimulated prostaglandin E2 (PGE2) production in the cell fraction containing > 800% parietal cells, with the halfmaximally effective concentration being 7.5 nM. EGF was ineffective in stimulating PGE2 production if the cell fraction was depleted of parietal cells (12 %), or if 0.5 mM-histamine was added to the enriched parietalcell fraction. In conclusion, EGF may inhibit histamine-stimulated acid secretion by decreasing the cyclic AMP content of parietal cells. This effect could be mediated by an increase in cyclic AMP phosphodiesterase activity, but it is unlikely to involve an effect of EGF on parietal-cell prostaglandin production. INTRODUCTIONEpidermal growth factor (EGF) is a polypeptide which was first isolated from the mouse submaxillary gland. In the rat, intraperitoneal or intragastric administration of EGF causes a trophic response in the gastroduodenal mucosa (Dembinski et al., 1982). Intravenous or subcutaneous EGF inhibits gastric acid secretion (Bower et al., 1975;Dembinski et al., 1982;Gregory, 1985), but intragastric administration of EGF only inhibits acid secretion when very high doses are used (Konturek et al., 1981). Thus EGF in the gastric lumen could be derived from saliva and might play a role in day-to-day maintenance of the gastric epithelium (Skinner et al., 1984), but luminal EGF is unlikely to regulate gastric acid secretion. Inhibition of acid secretion by EGF might occur during acute damage to the epithelium, and the absence of acid might facilitate the process of repair (Gregory, 1985;Shaw et al., 1987). In such circumstances EGF could be derived from platelets (Shaw et al., 1987 J. F. Hatt and P. J. Hanson about 20 % parietal cells, was resuspended in Eagle's minimum essential medium containing 36 ml of isoosmotic Percoll/100 ml, 12 mM-Hepes, 0.6 mg of bovine serum albumin/ml, 0.3 mM-dithiothreitol and 1.9 mm-EGTA, pH 7.35. This mixture was centrifuged for 13 min at 30000 gayv at 4°C with a 200 angle rotor in a MSE Superspeed 50 centrifuge. The cell fraction removed from the top 20 % of the gr...

Regulation of mucus secretion by cells isolated from the rat gastric mucosa.

“…The relatively poor response of the isolated rat cells to carbachol suggests that some of the effects of carbachol in vivo are indirect, that the machinery effecting the carbachol response may have become partially damaged during cell isolation, or that carbachol may induce the release of a pool of mucus which was not readily labelled in the present protocol. When using a concentration of EGF which causes a near-maximal inhibition of histaminestimulated acid secretion in isolated parietal cells (Hatt & Hanson, 1988) no effect on mucus secretion was detected. Yoshida, Kasuga, Hirao, Fuwa & Nakagawa (1987) claimed that EGF stimulated mucus release by primary cultures of rabbit fundic mucosal cells, but not all of the 3H-labelled material released from the cells was mucous glycoprotein and the increased secretion was not dissociated from the increased incorporation of label into cellular proteins induced by EGF.…”

Intracellular Signalling and Regulation of Gastric Acid Secretion

“…Similar results were reported in an abstract by Chen et al (1984) using dog parietal cells. Epidermal growth factor inhibited the stimulation by histamine of the cyclic AMP content of a rat stomach cell population containing greater than 80 % parietal cells (Hatt & Hanson, 1988). The half-maximally effective concentration of EGF for inhibition of cyclic AMP content was 3 9 nm and the same measurement for inhibition of aminopyrine accumulation was 30 nm.…”

“…Epidermal growth factor inhibited aminopyrine accumulation stimulated by histamine in (Hatt & Hanson, 1988). The half-maximally effective concentration of EGF for inhibition of cyclic AMP content was 3 9 nm and the same measurement for inhibition of aminopyrine accumulation was 30 nm.…”

“…Secondly, the action of PGE2, unlike that of EGF, was not prevented by IBMX (Atwell & Hanson, 1988). Thirdly, the concentration of PGE2 in the medium surrounding enriched parietal cell preparations, and containing 200 nM-EGF, was 84 pM which is substantially below the concentration of PGE2 required for half-maximal inhibition of histamine-stimulated aminopyrine accumulation (24 nM) (Hatt & Hanson, 1988).…”

“…After stimulation with histamine the cyclic AMP content of parietal cells from dog (Wollin, Soll & Samloff, 1979) and rat (Hatt & Hanson, 1988), rose to a plateau and stayed…”