Acid Secretion In Animals Research Articles

The renal H,K-ATPases

We integrate recent evidence that demonstrates the importance of the gastric (HKalpha1) and nongastric (HKalpha2)-containing hydrogen potassium adenosine triphosphatases (H,K-ATPases) on physiological function and their role in potassium (K), sodium (Na), and acid-base balance. Previous studies focused on the primary role of H,K-ATPases as a mechanism of K conservation during states of K deprivation. Both isoforms function in H secretion and K absorption in vivo during K deprivation, but recent findings show that these pumps also function in acid secretion in animals fed normal K-replete diets. The complicated pharmacological inhibition of both pumps is reviewed. Interestingly, HKalpha2-null mice have a reduced expression and activity of the renal epithelial Na channel alpha subunit in the colon. When the human nongastric isoform was studied in a heterologous expression system with its cognate beta subunit (NaKbeta1), the pump exhibited substantial Na affinity at the 'K'-binding site. Evidence cited herein raises the possibility that either directly or indirectly the renal HKalpha2-containing H,K-ATPase may affect Na balance. Both H,K-ATPase isoforms are active in normal animals and not just under conditions of K depletion. The possibility that either one or both isoforms contribute to Na absorption, particularly in humans, raises important clinical implications for these pumps in the kidney.

W1091 Effects of Tak-438, a Novel Potassium-Competitive Acid Blocker (P-Cab), on Gastric Acid Secretion in Animals

moderate/severe GERD symptoms on ≥ 1 day a week). Sample-size weighted means and 95% confidence intervals (CI) were calculated for all pooled prevalence data. Potential determinants of partialand non response were examined in Poisson regression analysis. Results: Eighteen studies, including 18 667 individuals, were eligible for inclusion. Most studies had a minimum duration of PPI therapy of 4 weeks, and reported only combined data for partialand non-response. In interventional, non-randomized primary care trials, 27% (95% CI: 17-37%) of patients with GERD had any heartburn and 25% (95% CI: 1535%) had any regurgitation while on PPI therapy; troublesome heartburn or regurgitation was reported by 12% (95% CI: 4-20%) and 29% (one study) of patients, respectively. In interventional, randomized primary care trials, 52% (95% CI: 47-57%) of patients had any heartburn and 52% (95%CI: 43-61%) had any regurgitation despite PPI therapy; troublesome heartburn or regurgitation was reported by 32% (95% CI: 26-38%) and 28% (95% CI: 2630%) of patients, respectively. Observational communityand primary care-based studies had a higher prevalence of partialand non-response to PPI therapy (any GERD symptoms 50%; 95% CI: 42-58%; troublesome GERD symptoms 62%; 95% CI: 61-63%). Studies that had > 60% female participants (vs < 60%) and those that were conducted in North America (vs Europe or Australia) reported higher rates of partialor non-response. Partialor non-response to PPI therapy was associated with decreased psychological and physical well-being. Conclusions: At least 30% of patients on PPI therapy in primary care trials, and 50-60% of individuals using PPIs in the community, have troublesome GERD symptoms despite PPI therapy. Alternative approaches to management are required.

Roxatidine Acetate

Roxatidine acetate is a histamine H2-receptor antagonist which, after almost complete oral absorption (greater than 95%), is rapidly converted to its active metabolite, roxatidine, by esterases in the small intestine, plasma and liver. Roxatidine is a potent inhibitor of basal and stimulated gastric acid secretion in animals and humans and, like most other H2-receptor antagonists, has no anti-androgenic effects and does not interfere with the hepatic metabolism of other drugs. Large-scale trials have shown that roxatidine acetate 150mg per day is as effective as standard doses of cimetidine and ranitidine in the treatment of patients with duodenal or gastric ulcer, and that roxatidine acetate 75mg in the evening is likely to become a 'standard' regimen for the prevention of peptic ulcer recurrence. Preliminary data also suggest that roxatidine acetate may be useful in the treatment of reflux oesophagitis and stomal ulcer, and in the prevention of pulmonary acid aspiration. Roxatidine acetate is an H2-receptor antagonist which has been well tolerated in clinical trials. However, broader experience is required before definitive statements about tolerability relative to other H2-receptor antagonists can be made, and before the role of roxatidine acetate in the treatment of reflux oesophagitis and stomal ulcer, and the prophylaxis of acid aspiration pneumonitis, can be clearly defined.

Omeprazole: Mode of Action and Effect on Acid Secretion in Animals

H+,K+-ATPase constitutes the final step in the acid secretory process that takes place in the parietal cell, and this enzyme has recently been recognized as a target for inhibitors of acid secretion. The gastric H+,K+-ATPase is located in the uniquely acidic environment of the parietal cell. Omeprazole, a weak base, is concentrated within the acid canaliculus of the parietal cell and is rapidly converted to an inhibitor of the H+,K+-ATPase in the acid compartments of the parietal cell. Omeprazole is thus activated close to its target enzyme, where it is present in high concentrations, and binds selectively to the gastric H+,K+-ATPase. Omeprazole is the first H+,K+-ATPase inhibitor to be used in the treatment of acid-related diseases, and inhibition of acid secretion is closely correlated to inhibition of gastric H+,K+-ATPase activity. Both basal and stimulated acid secretion are inhibited by omeprazole in a dose-dependent manner, irrespective of the nature of the stimulus. Omeprazole exerts a prolonged antisecretory effect, and in dogs, 4 days are required for return to normal acid secretion following a maximal inhibitory dose.

Effect of terbutaline, a β2-adrenoreceptor agonist, on gastric acid secretion and serum gastrin concentrations in humans

Because β-adrenoreceptor agonists inhibit gastrinstimulated gastric acid secretion in animals, we postulated that the β2-adrenoreceptor agonist, terbutaline, would inhibit pentagastrin-stimulated acid secretion in humans. Moreover, we hypothesized that terbutaline might inhibit food-stimulated acid secretion, as gastrin is a major mediator of food-stimulated acid secretion. Subcutaneous terbutaline (0.25 mg) reduced acid secretion during intravenous infusion of a submaximal dose of pentagastrin by 30%–40% (p < 0.005), even though terbutaline increased serum gastrin levels (p < 0.05). Furthermore, subcutaneous (0.25 mg) or oral (5 mg) terbutaline, given before a homogenized steak meal was infused into the stomach, lowered mean food-stimulated acid secretion rates, despite enhanced postprandial serum gastrin concentrations. Terbutaline also increased serum gastrin concentrations in patients with Zollinger-Ellison syndrome and in vagotomized individuals. Thus, β2-adrenoreceptor agonists enhance gastrin release while at the same time inhibiting gastrin-stimulated acid secretion in humans.

Pharmacology and toxicology of omeprazole--with special reference to the effects on the gastric mucosa.

Omeprazole is a long acting inhibitor of gastric acid secretion in different species including rat and dog. Due to the long duration of action, steady state inhibition at repeated once daily administration is reaches within 4-5 days in dogs and in about 3 days in rats. Daily dosing at high dose levels results in virtually complete 24-hour inhibition of acid secretion in experimental animals. The elimination of the inhibitory feedback effect of acid on gastrin secretion leads to hypergastrinaemia. Because gastrin has a trophic effect on the oxyntic mucosa, the hypergastrinaemia results in a reversible hypertrophy of the oxyntic mucosa and an increased capacity to produce acid following maximal stimulation with exogenous secretagogues after discontinuing treatment. Despite the increased capacity to produce acid, basal acid secretion seems to be unchanged. The pronounced hypergastrinaemia which occurs during long-term treatment with high doses rapidly normalizes after discontinuing treatment. The hyperplasia of the oxyntic endocrine ECL cells, and the eventual development of gastric ECL cell carcinoids after lifelong treatment of rats with high doses, can also be attributed to the hypergastrinaemia developing after almost complete elimination of gastric acid secretion in these animals.

Effect of Omeprazole on Gastric Emptying in Patients with a History of Duodenal Ulceration

Omeprazole, a substituted benzimidazole, inhibits basal and stimulated gastric acid secretion in animals and humans in a dose dependent fashion, for long periods after oral administration. This antisecretory effect is probably due to non-competitive inhibition of the H+K+ATPase proton pump which has been identified in the secretory membrane of the parietal cell. Preliminary data from animal experiments have indicated that oral omeprazole, 400 μmol/kg, also delays gastrin emptying but intravenous omeprazole, 80 μmol/kg, does not, As the plasma concentrations of omeprazole following administration by both routes were similar, a local rather than a systemic effect was suggested. Therefore, in this study the effect has been evaluated of a single oral dose of omeprazole, 90 mg, given as a buffered, uncoated granulate, on gastric emptying of a mixed liquid and solid meal in patients with duodenal ulcer disease.

A new PGE 1 analogue (CL115,574) III. Effects on gastric acid and mucus secretion in man

CL115,574, an analogue of PGE 1, is a potent inhibitor of gastric acid secretion in animals. The effects of this compound on gastric acid and mucus secretion were studied in 8 male volunteers. The compound was well tolerated, and its maximally effective antisecretory dose (750 μg) inhibited pentagastrin stimulated acid secretion by approximately 40% over a 2-hour period, with stimulation beginning one hour after the drug was orally administered. CL115,574 proved to have a significant and sustained effect upon the stimulation of mucus secretion into gastric juice. Considering the possible role that mucuse may play in mucosal cytoprotection, CL115,574 because of its antisecretory and mucogenic actions may prove to be an important clinical anti-ulcer compound.