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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 effect of graded oral doses of 16,16-dimethyl-prostaglandin E2 (PG E2) on basal acid secretion in healthy volunteers was tested over a time period of 6 h. In addition, studies were conducted to determine whether pretreatment with this methylated PG-analog could prevent the characteristic fall in human gastric potential difference (PD) associated with intragastric instillation of 50 ml of 4 mmol/l Na-taurocholate. Basal acid output was reduced by 80--90% after 0.5 microgram/kg b.w. 16,16-dimethyl-PG E2. Half maximum inhibition was achieved by 0.1 microgram/kg b.w., whereas a 10 fold lower dose of 16,16-dimethyl-PG E2 (0.01 microgram/kg b.w.) effectively protected human gastric mucosa against the injurious effects of Na-taurocholate. In analogy to findings in animals it is, therefore, concluded that 16,16-dimethyl-PG E2 has two distinct properties in human stomach, antisecretory and protective ones, which were independent of each other.

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.

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.

It has been shown that human gastric mucosa contains a prostaglandin-sensitive adenylate cyclase system. Of the prostaglandins tested the E-type induced an about 3--3.5-fold increase of enzyme activity. The prostaglandin A2 by causing an about 2.5-fold enhancement of cAMP formation and the F-prostaglandins (1.4--2.0-fold stimulation) were less effective in activating the enzyme system. Maximally effective concentrations of histamine and prostaglandin E2 were additive with respect to enzyme activity indicating that both hormones act via individual adenylate cyclases.

The effects of various polypeptide hormones known to inhibit gastric acid secretion were tested on the adenylate cyclase system in human gastric and duodenal mucosal homogenates. Glucagon and secretin failed to stimulate the enzyme system in the stomach. The latter hormone produced a small but significant activation of the duodenal cyclase. The vasoactive intestinal polypeptide (VIP), however, induced a dose-dependent increase of enzyme activity throughout the stomach and the duodenum. Maximal effects (1.8 to 3.0-fold increase) were observed at a VIP-concentration of about 10 microgram per ml. Because the entire physiological role of VIP in gastric function has not been defined, ipt cannot be discerned whether the VIP-stimulated adenylate cyclase is linked to inhibition of gastric acid secretion or to another as yet unrecognized effect of this hormone in human gastric function.

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.

Several prostaglandins prevent ulcer formation (called cytoprotection) by a mechanism other than inhibition of gastric acid secretion. One suggestion is that they increase cyclic AMP in non-parietal cells. A variety of prostaglandins with potent cytoprotective properties were tested for their capacity to modulate adenylate cyclase activity in homogenates of human gastric mucosa. Prostaglandin E2, prostacyclin (PGI2) and 15(S)-methyl-PGE2 stimulated the cyclase in human gastric mucosal biopsy specimens in a dose-dependent manner. Cytoprotective prostaglandins without antisecretory properties such as PGF2 beta were also able to activate the enzyme system dose-dependently. In contrast, cytoprotective prostaglandins such as PGD2, the PGE1-analogue, SC-29333, and the prostaglandin-like compound C83 did not stimulate human gastric adenylate cyclase. Whereas PGD2 did not modulate enzyme activity at all, SC-29333 and C83, at concentrations greater than 10 mumol/l, inhibited basal and PGE2-stimulated enzyme activities. These studies suggest that cyclic AMP is not directly related to the cytoprotective effect of prostaglandins, at least in human gastric mucosa.

The dose-effect relationship of ranitidine, a recently developed selective histamine H2 receptor antagonist was tested on six healthy subjects after oral administration. Ranitidine gave dose-dependent inhibition of pentagastrin-stimulated acid secretion. Half-maximal inhibition occurred at 75 mg. The antisecretory effect was still demonstrable five hours after oral intake. The drug is thus more powerful and has more lasting antisecretory action, even after oral intake, than cimetidine.

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.

Studies during the last few years have revealed evidence of active secretion of HCO3(-) in the gastric mucosa both in vitro and in vivo. This transport process presumably has considerable importance for the protection of the gastric epithelium, disturbance must be considered a causal factor in the pathogenesis of gastric ulcer. The HCO3(-)-transport is subject to autonomic control. It is inhibited by drugs with an ulcerogenic action and stimulated by anti-ulcerogenic prostaglandins. The results available up to now raise the probability of the physiologic and pathophysiologic significance of the HCO3(-)-transport system. Clinical investigations must demonstrate the therapeutic efficacy of control of the alkali secretion in the gastric mucous membrane.

Various prostaglandins posses antisecretory and cytoprotective actions on gastric mucosa. Cytoprotection by prostaglandins is unrelated to the inhibition of gastric acid secretion and can also be detected in small intestinal mucosa of the rat. Prostaglandins protect gastric mucosa against ulcerogenic compounds such as nonsteriod anti-inflammatory agents (NOSAC) as well as against the necrotizing affect produced by alcohol, 25% sodium chloride, 0.2 N solium hydroxide and 0.6 N hydrochloride acid. Prostaglandins protect in doses that are far too small to inhibit gastric acid secretion. At these doses no side-effects have been noted so far. This cytoprotective effect of prostaglandins might be beneficial in the treatment of a variety of diseases in which gastric mucosal injury in present.

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.

The adenylate cyclase system of human fundic gastric mucosa was found to respond to histamine, prostaglandin E 2 and the non-hormonal activators NaF and 5'-guanylyl-imidodiphosphate (GMP(PNP)). Half maximal stimulation of enzyme activity was observed at a histamine concentration of 50 micrometer. Maximal stimulation (about 25%) occurred at a histamine concentration of 1 mM. The stimulatory effect of histamine was competitively inhibited by cimetidine. The stimulatory effect of prostaglandin E 2 was found to be dose-dependent over a concentration range from 0.1 micrometer to 1 mM exerting maximal effects at 0.3 mM. NaF and GMP(PNP) by inducing an about 3.5-fold increase of enzyme activity were more potent in stimulating the human enzyme system than histamine and prostaglandin E 2. Maximal stimulatory doses of prostaglandin E 2 and histamine had an additive effect on the adenylate cyclase activity from fundic gastric mucosa. This implies that histamine acts on an individual adenylate cyclase system. Our results are suggestive for the existence of an adenylate cyclase system in human gastric mucosa coupled to histamine H 2-receptor sites.

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.

The effect of different doses of the newly developed histamine H2 receptor antagonist ranitidine on the sodium taurocholate-induced decrease of the potential difference across the human gastric mucosa was investigated in 18 healthy persons. It was shown that ranitidine protects the human mucosal epithelium against this agent both in acid-inhibitory and non-acid-inhibitory dosages. The results suggest that besides the prostaglandins histamine H2 receptor antagonists possess cytoprotective properties at least against bile acids.

Substituted benzimidazoles inhibit gastric acid secretion stimulated by histamine, pentagastrin and vagal innervation. In contrast to anticholinergic agents and H2-receptor antagonists these compounds also block secretion induced by exogenous cyclic AMP suggesting a more peripheral site of action. Recent data show that these substances inhibit a H+/K+-ATPase which is localized at the secretory surface of the parietal cells and is generally regarded as the proton pump within the gastric mucosa. Because of the unique distribution of H+/K+-ATPase the inhibitory action of substituted benzimidazoles may offer a new therapeutic approach in hypersecretory states.

Human gastric mucosa contains a histamin-sensitive adenylate cyclase system. The activation of this enzyme system by histamine is competititively inhibited by the H2-receptor blocking agent cimetidine. Our results underscore the rational basis for the use 0f H2-receptor antagonists in the therapy of peptic ulcer.