Gastric acid secretion inhibitory effect

Effects of acetylcholine, histamine, prostaglandin I2, and E2, and gastrin on gastric acid secretion by the parietal cells of stomach Gs and Gj are membrane proteins that mediate the stimulatory or inhibitory effect of receptor coupling to adenylyl cyclase. 

Glucose-dependent insulinotropic polypeptide is originally known as gastric inhibitory polypeptide (GIP), which is a 42-residue peptide first isolated by Brown and Dryburgh (14). It is secreted from the duodenum and proximal jejunum in response to food. Two major physiological effects of GIP are inhibition of gastric acid secretion and stimulation of insulin release. 

The structure-activity relationship of HVK -ATPase inhibitors of the omeprazole type is based on the balance between chemical stability at neutral pH values and acid-induced conversion into the active sulphenamide. Derivatives, which are too unstable at neutral pH, are very active in the test assay of partly purified HVK" -ATPase. This assay has been performed at pH 7.4 after preincubation at pH 6 of the enzyme protein with the derivative to be tested. The high activity was therefore the result of the conversion of the derivative in solutions of neutral pH values and this does not reflect the situation of high acidity within the secretory compartment of the parietal cell [28]. The derivatives which are very unstable at neutral pH do not inhibit gastric acid secretion in vivo because their transformation had already occurred prior to the active principle reaching the target enzyme. Chemically very stable derivatives do not show any inhibitory effect either in vitro or in vivo. 

Human pharmacology parallels animal pharmacology, especially that of the dog, with respect to the effective dose-range and duration of action. Omeprazole causes dose-dependent inhibition of basal and stimulated gastric acid secretion and reduction of intragastric acidity in healthy volunteers after single administration [96-98] or repeated daily administrations [96]. This was also seen in patients with peptic ulcer disease [99-102]. The inhibitory effect after a single administration lasts 2-3 days [96]. 

The inhibitory effects of verapamil, a calcium channel antagonist, on gastric acid secretion in vitro and in vivo are controversial. There are reports that verapamil causes a significant inhibition of acid secretion in humans [169], and rats [170, 171] but others claim that it has no effect [172, 173]. 

EJeGraf, J., and Wou6sen-Colle, M, (1986). Influence of the stimulation state of the parietal cells on the inhibitory effect of omeprazole on gastric acid secretion in dogs, GffSfnoen-tmlogy 91, 333-337,... 

Coruzzi G, Adami M, Coppelli G, Frati P, Soldani G (1999) Inhibitory effect of the cannabinoid receptor agonist WIN 55,212-2 on pentagastrin-induced gastric acid secretion in the anaesthetized rat. Naunyn Schmiedebergs Arch Pharmacol 360 715-718... 

Inhibitory Effect on Gastric Acid Secretion and H+,K+-A TPase [10-12]... 

SDB and SDC, scopadulan-type diterpenoids, showed cytotoxicity, anti-HSV-1 activity and inhibitory effects on histamine-induced gastric acid secretion and PTH-stimulated bone resorption. 

Inhibitory effects of SDB and SDC on gastric acid secretion were suggested to be mainly attributed to ihibition of gastric proton pump. 

Figure 12. The effect of variations of substituents on the pjn idine ring of H 83/69 on acid-base properties (pX a) and their influence on the inhibitory acton on gastric acid secretion in the dog. Data represent an extract from the chemical synthesis program.

In the mouse, whereas no evidence of H3 receptors was found in isolated gastric glands (Muller et al., 1993), in the whole stomach, (R)a-methylhistamine actually increased, and thioperamide decreased acid secretion, thus indicating a definite stimulatory role for H3 receptors in this species (Table 2). Apparently, this excitatory effect, which contrasts with the observations obtained in other models, was due to an inhibitory effect on somatostatin release from fundic D cells (Schubert et al., 1993 Vuyyuru and Schubert 1993). Also, an inhibitory effect on somatostatin secretion mediated by H3 agonists was observed in other species (rat and dog). However, contrarily to what might have been expected, in these species, the inhibitory effect on somatostatin is not followed by an increase in acid secretion, but it is instead followed by a decrease, owing to the predominant H3-mediated inhibition on the release of excitatory mediators (histamine, acetylcholine) from other sites (ECL, cholinergic nerve terminals)... 

In conclusion, histamine H3 receptors have multiple locations in the gastric mucosa, occurring in different cell types, according to the different animal species however, the final effect on acid secretion seems to be an inhibitory one, although in a particular experimental model of the mouse, a stimulatory effect seems to be predominant. A scheme representing the multiple locations of H3 receptors in the gastric mucosa from available data is reported in Figure 2. 

Intracellular cyclic adenosine monophosphate (cAMP)-stimulated add secretion in the isolated guinea-pig gastric mucosa was not inhibited by administration of an H2-receptor antagonist, as expected, although H 83/69 (timoprazole) induced a dose-dependent inhibition. This was the first experimental evidence for a site of inhibitory action beyond the panel of stimulatory cell membrane receptors. Interestingly, it was found that the initial lead compound (CMN 131), had no inhibitory effect on dibutyryl-cAMP-stimulated acid secretion, nor was it an H2-receptor antagonist [9],... 

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