The involvement of cyclic adenosine 5′-monophosphate as a second messenger for histamine-induced acid secretion was studied in a physiologically active in vitro preparation, piglet gastric mucosa. Transepithelial voltage, resistance, acid secretion, and tissue cAMP content were measured at different times after stimulation with histamine and/or isobutylmethylxanthine. We have found: (a) During the first 5-10 min of stimulation, increases in tissue cAMP content were well-correlated with decreases in resistance; these changes precede acid secretion by 5-10 min. (b) Once the cells had been fully activated (5-30 min), there was no apparent correlation between tissue cAMP content and the secretory events. With histamine alone, cAMP content decreased to low levels after 45 min, but with isobutylmethylxanthine, cAMP content remained high. Secretory parameters were equivalent in the 2 cases. (c) Experiments with graded doses of histamine on top of a low isobutylmethylxanthine content indicated that the transient nature of the histamine-induced cAMP response might be partially accounted for by the presence of an active phosphodiesterase. Measurements of the cAMP content of the mucosal fluid also indicate that the decrease in cAMP content after histamine stimulation is due primarily to synthesis-degradation mechanisms and not the result of a leak of cAMP from the cell. (d) Control experiments with antral mucosa indicated that most of the histamine and isobutylmethylxanthine-induced changes in cAMP content were due to changes in the parietal cells and not the surface epithelial cells. (e) Dibutyryl-cAMP caused increases in acid secretion and decreases in resistance, which were similar to those observed with histamine or isobutylmethylxanthine. (f) In a separate set of experiments we have isolated two cell fractions: One fraction was rich in parietal cells (60%), and the other was rich in surface epithelial cells (95%). The parietal cell-rich fraction contains a histamine (H2)-sensitive adenylate cyclase that has 10-fold higher activity than that of the surface cell-rich fraction (H1). We conclude that cAMP is intimately involved in histamine stimulation of piglet gastric mucosa during initial stages of activation, i.e., the rise in cAMP content is a second messenger for the triggering of acid secretion, but the maintenance of acid secretion is not dependent on sustained increases of cAMP content.
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