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The localization of the prostaglandin-sensitive adenylate cyclase in the upper gastrointestinal tract in human beings was studied. The prostaglandin-sensitive enzyme was almost evenly distributed throughout the fundic, antral and duodenal mucosa. The enhancement of enzyme activity in the presence of maximally effective prostaglandin concentrations exceeded basal levels by about 200%. The physiological role of the prostaglandin sensitive adenylate cyclase in gastric and duodenal function, however, remains to be established.

The distribution of prostacyclin-(PGI2-)sensitive cyclase in human gastric and duodenal mucosa was studied. Like PGE2, PGI2 induced a dose-dependent increase of enzyme activity throughout the stomach and the duodenum. Maximal effects (about 2.5- to 3.0-fold increase) were observed at a PGI2 concentration of 0.28 mmol/l. The stable breakdown product 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) was much less active. The equal distribution of the PGI2-sensitive adenylate cyclase in the human upper alimentary tract suggests a localization of this enzyme system in cells not directly related to gastric acid secretion.

RMI 12330 A, a compound of the lactamamide series, is a potent inhibitor of vasoactive intestinal polypeptide(VIP)- and prostaglandin (PG)-stimulated colonic secretion in the rat. This substance was tested on the adenylate cyclase system in human colonic mucosa. RMI 12330 A inhibited PGE2-, 16,16-dimethyl-PGE2- as well as VIP-sensitive adenylate cyclases in a dose-related manner. Half-maximal inhibition of hormone-stimulated enzyme activities occurred at a lactamimide concentration of about 0.15 mM. Lactamimide inhibition was non-competitive. Our results are compatible with the concept of RMI 12330 A acting as an inhibitor of colonic secretion via inhibition of hormone-sensitive adenylate cyclase. Since basal, NaF- and guanylyl-imidodiphosphate-stimulated enzyme activities were also affected by this compound, we may conclude that RMI 12330 A is a non-specific inhibitor of the human colonic adenylate cyclase system.

The effects of prostaglandin E2, prostaglandin A2 and their methylated analogues upon the adenylate cyclase in human gastric mucosa were studied. PG E2 and 16,16-dimethyl-PG E2 stimulated the enzyme activity to a greater degree than PG A2 and 16,16-dimethyl-PG A2. 16,16-dimethyl-PG E2 was less potent in activating the enzyme system than its parent compound. The results suggest that the more pronounced antisecretory activity of 16,16-dimethyl-PG E2 is due to its greater resistance against enzymatic degradation.

The effects of meclofenamic acid on basal and hormone-stimulated adenylate cyclase in human colonic mucosa were tested. It is shown that meclofenamic acid is a relatively specific inhibitor of the stimulatory action of prostaglandins on the level of mucosal adenylate cyclase. This compound did not inhibit significantly the effects of vasoactive intestinal peptide (VIP) on the human enzyme system. VIP18-28 did not act as a partial agonist and did not inhibit the response to the intact VIP. Our studies suggest the existence of distinct receptor sites for both secretagogues (VIP and prostaglandins) in human colonic mucosa.

The effects of various nonsteroid anti-inflammatory compounds on human gastric mucosal adenylate cyclase were tested. It is shown that fenamates, indomethacin and diclofenac-Na were relatively specific inhibitors of prostaglandin E2 action at the level of the mucosal cyclase activity. The results suggest that inhibition of prostaglandin E2-activated adenylate cyclase might at least in part contribute to the ulcerogenic effects of certain nonsteroid anti-inflammatory drugs.

Prostacyclin, its stable metabolite 6-keto-prostaglandin F1 alpha and prostaglandin E2 were tested on the adenylate cyclase system in human gastric mucosa. All three compounds were able to activate human cyclase. Saturating concentrations of prostacyclin, prostaglandin E2 and 6-keto-prostaglandin F1 alpha (each 0.28 mM) increased the enzyme activity 3.0 and 1.6 fold, respectively. The concentrations of prostacyclin and prostaglandin E2 required to produce half maximal activation were in the same range. Prostacyclin is an efficient stimulator of human gastric mucosal adenylate cyclase.

The distribution of histamine- and catecholamine-sensitive adenylate cyclases in human gastric and duodenal mucosa was studied. Basal enzyme activities averaged 155 pmol cAMP/mg prot./15 min in fundic gastric mucosa, 305 pmol cAMP/mg prot./15 min in the antral and 344 pmol cAMP/mg prot./15 min duodenal mucosa. 1 mM histamine induced a more than 2-fold increase of enzyme activity in fundic homogenates, whereas this secretagogue was nearly ineffective in similar preparations from the antral region (1.2-fold increase of enzyme activity). The response towards adrenaline was virtually identical in fundic and antral mucosa preparations. The duodenal enzyme was insensitive toward this catecholamine as well as to histamine. The data are suggestive for a messenger function of cAMP in histamine-stimulated gastric acid secretion.

Human gastric mucosal adenylate cyclase has been shown to be sensitive to histamine and catecholamines. Stimulation of enzyme activity by histamine and catecholamines were selectively blocked by cimetidine and propranolol, respectively. Combination of both hormones at maximally effective concentrations were additive, indicating that human gastric mucosa contains at least two separate hormone-sensitive adenylate cyclases.

Human colonic adenylate cyclase has been shown to be sensitive to vasoactive intestinal polypeptide (VIP) and prostaglandins of the E- and F-type. Maximal activation of enzyme activity averaged 200% for VIP and 300-350% for the E-prostaglandins. Both classes of hormones had an additive effect on enzyme activity indicating the existence of two distinct hormone-sensitive adenylate cyclases in human colonic mucosa.