Inhibition Of Stimulated Acid Secretion Research Articles

Cholecystokinin type A receptors mediate intestinal fat-induced inhibition of acid secretion through somatostatin-14 in dogs.

This study was designed to examine whether one or both principle molecular forms of somatostatin (SLI), somatostatin-28 (S-28) and somatostatin-14 (S-14), mediate inhibition of stimulated gastric acid by intestinal fat and to determine whether the mode of action includes activation of type A cholecystokinin (CCK) receptors in conscious dogs. SLI molecular forms were separated by gel filtration chromatography after extraction of acidified plasma on octadecyl silyl cartridges and quantified by RIA. Basal plasma levels of S-28 and S-14 were 4.1 +/- 0.6 and 3.6 +/- 0.3 fmol/ml, respectively. Intraduodenal perfusion with a 10% fat emulsion increased plasma S-28 by 6.3 +/- 1.2 fmol/ml (P < 0.01) and S-14 by 17.8 +/- 2.6 fmol/ml (P < 0.001), and suppressed by 76 +/- 3% (P < 0.001) gastrin (150 pmol/kg.h)-stimulated gastric acid. Blockade of type A CCK receptors with MK-329 (75 micrograms/kg, i.v.) abolished S-28 and S-14 responses (both P < 0.001) and completely reversed the inhibitory effect of gastric acid produced by intraduodenal fat. Intravenous infusions of S-14 dose-dependently inhibited gastrin-stimulated secretion with an estimated 50% inhibitory dose of 125 pmol/kg.h that achieved an incremental plasma S-14 rise of 40 +/- 2 fmol/ml; infusions of S-28 at 30 pmol/kg.h increased plasma S-28 by 47 +/- 3 fmol/ml without altering acid output. The SLI antagonist cyclo-[7-aminoheptanoly-Phe-D-Trp-Lys-Thr(BZL)] (CyCam) reversed by 89 +/- 4% (P < 0.001) exogenous S-14-induced inhibition of gastrin-stimulated acid secretion, but did not influence gastric acid output after the infusion of S-28. CyCam also reversed by 139 +/- 9% (P < 0.001) the early phase of fat-induced acid inhibition; in the late phase, CyCam treatment was associated with a further 2-fold elevation of plasma peptide-YY (PYY) to 102 +/- 6 fmol/ml (P < 0.001) and a 75 +/- 5% suppression of gastric acid. Simulation of this plasma PYY increment with infusions of PYY at 50 pmol/kg.h inhibited by 44 +/- 5% gastrin-stimulated acid secretion. These results indicate that in conscious dogs, endogenous CCK mediation of intraintestinal fat-induced inhibition of stimulated acid secretion occurs in part through CCK type A receptor activation of S-14 secretion. Modulation of gastric acid by S-14 includes both inhibition and attenuation of further suppression via counterregulation of PYY secretion.

Cholecystokinin type A receptors mediate intestinal fat-induced inhibition of acid secretion through somatostatin-14 in dogs

This study was designed to examine whether one or both principle molecular forms of somatostatin (SLI), somatostatin-28 (S-28) and somatostatin-14 (S-14), mediate inhibition of stimulated gastric acid by intestinal fat and to determine whether the mode of action includes activation of type A cholecystokinin (CCK) receptors in conscious dogs. SLI molecular forms were separated by gel filtration chromatography after extraction of acidified plasma on octadecyl silyl cartridges and quantified by RIA. Basal plasma levels of S-28 and S-14 were 4.1 +/- 0.6 and 3.6 +/- 0.3 fmol/ml, respectively. Intraduodenal perfusion with a 10% fat emulsion increased plasma S-28 by 6.3 +/- 1.2 fmol/ml (P < 0.01) and S-14 by 17.8 +/- 2.6 fmol/ml (P < 0.001), and suppressed by 76 +/- 3% (P < 0.001) gastrin (150 pmol/kg.h)-stimulated gastric acid. Blockade of type A CCK receptors with MK-329 (75 micrograms/kg, i.v.) abolished S-28 and S-14 responses (both P < 0.001) and completely reversed the inhibitory effect of gastric acid produced by intraduodenal fat. Intravenous infusions of S-14 dose-dependently inhibited gastrin-stimulated secretion with an estimated 50% inhibitory dose of 125 pmol/kg.h that achieved an incremental plasma S-14 rise of 40 +/- 2 fmol/ml; infusions of S-28 at 30 pmol/kg.h increased plasma S-28 by 47 +/- 3 fmol/ml without altering acid output. The SLI antagonist cyclo-[7-aminoheptanoly-Phe-D-Trp-Lys-Thr(BZL)] (CyCam) reversed by 89 +/- 4% (P < 0.001) exogenous S-14-induced inhibition of gastrin-stimulated acid secretion, but did not influence gastric acid output after the infusion of S-28. CyCam also reversed by 139 +/- 9% (P < 0.001) the early phase of fat-induced acid inhibition; in the late phase, CyCam treatment was associated with a further 2-fold elevation of plasma peptide-YY (PYY) to 102 +/- 6 fmol/ml (P < 0.001) and a 75 +/- 5% suppression of gastric acid. Simulation of this plasma PYY increment with infusions of PYY at 50 pmol/kg.h inhibited by 44 +/- 5% gastrin-stimulated acid secretion. These results indicate that in conscious dogs, endogenous CCK mediation of intraintestinal fat-induced inhibition of stimulated acid secretion occurs in part through CCK type A receptor activation of S-14 secretion. Modulation of gastric acid by S-14 includes both inhibition and attenuation of further suppression via counterregulation of PYY secretion.

Is the bioavailability of famotidine reduced by an antacid?

Famotidine is a potent histamine H2-receptor now undergoing clinical trial in Italy, Germany, the UK, France, and the USA, and has just come on the market in Japan. To study the effect of concurrent antacid administration on the oral absorption of famotidine, 10 subjects (8 patients with peptic ulcer, 2 normal adults) received 20 mg (5 subjects) or 40 mg (5 subjects) of famotidine with and without Maalox (aluminum hydroxide and magnesium hydroxide). Slight declines in the maximum plasma concentration and the areas under the plasma concentration time curve of famotidine were observed when an antacid was given simultaneously, indicating that concurrent antacid decreases the bioavailability of this new antisecretory compound. Although the plasma famotidine level was lowered by concurrent administration of antacid, it remained higher than the plasma concentration for 50% inhibition of stimulated acid secretion (IC50) for up to 12 hours.

Ultrastructure of Inhibited Parietal Cells in the Rat

In acutely vagotomized rats, gastric acid secretion was stimulated with a combination of carbachol and pentagastrin, and/or inhibited with picoprazole, cimetidine, or l-hyoscyamine. The animals were killed 1 or 3 h later. Using stereologic electron microscopic methods, the relative area of the secretory surface in the parietal cells and the mean size of these cells were estimated. The parietal cells in the superficial quarter of the oxyntic mucosa were larger than those at deeper levels of the mucosa. Moreover, the secretory surface was proportionally larger in the superficial cells than in the deep cells. Stimulation by carbachol and pentagastrin produced an increase in the secretory surface area. Inhibition of stimulated acid secretion by l-hyoscyamine reduced the secretory surface to the level of the unstimulated controls. Cimetidine, given at doses that inhibited stimulated acid secretion, did not alter the mean size of the secretory membrane. After inhibition by picoprazole, stimulated acid secretion was abolished, but the secretory membrane became significantly larger than after cimetidine inhibition. These divergent patterns of morphologic reactions probably reflect the different mechanisms of inhibition at the cellular level.

Pharmacokinetics of cimetidine after single doses and during continuous treatment.

The plasma concentration-time curve and urinary excretion of cimetidine were followed in 10 patients after single 200mg doses given intravenously, in 9 patients after 400 and 800mg single oral doses, and in 10 patients over a 24-hour period during continuous oral treatment with 1000mg daily. The bioavailability of cimetidine measured as the ratio between the areas under the plasma concentration-time curves (AUC) after oral and intravenous administration was 76%. The mean excretion of cimetidine in the urine as unchanged drug, expressed as a percentage of administered dose, was 58% after 200mg intravenously and between 37 and 41% after single oral doses of 200, 400 and 800mg and during continuous treatment with 1.0g/day. Since there were no significant differences between the oral doses, the relative bioavailability of cimetidine does not appear to be dose-dependent. The AUC after the 800mg dose was 2.1 times that of the 400mg dose. No dose-dependent kinetics were observed. There were also no significant differences in the AUCs after 200 and 400mg doses during continuous treatment compared with the AUCs after the same single doses. Thus, cimetidine does not appear to induce or inhibit its own metabolism during treatment. Following intravenous administration, the mean volume of distribution was 1.39L/kg and the mean total body clearance and the mean plasma renal clearance of cimetidine were 655 and 375ml/min, respectively. A renal clearance of cimetidine more than 3 times higher than the creatinine clearance demonstrates that the renal excretion of cimetidine is mainly by tubular secretion. Plasma concentrations of cimetidine during continuous treatment with 1.0g/day were above 1.0 microgram/ml-the plasma concentration associated with 50% inhibition of stimulated acid secretion in peptic ulcer patients-for 9 out of the 24 hours. A morning plasma concentration above 0.6 microgram/ml before the next morning dose has been taken during treatment with cimetidine 1.0g/day is only seen in patients with some degree of renal failure. Measurement of plasma half-life during continuous treatment shows that the plasma half-life is longer than the mean 1.79 hours estimated after intravenous administration of a single dose.

Role of the small bowel in regulating serum gastrin and gastric inhibitory polypeptide (GIP) levels and gastric acid secretion.

An increase in gastric acid secretion after resection or bypass of the small bowel has been described by several authors in man and dogs1,2,3. Furthermore, a high incidence of peptic ulcer disease has been observed in patients with small bowel resection4,5. The mechanism which induces gastric hypersecretion after exclusion of large parts of the small bowel from food passage is still poorly understood. Several authors have described hypergastrinemia after small bowel exclusion or bypass, which may be caused by either a decrease in catabolism or a diminished release of inhibitors from the small intestine6,7,8. One of the physiologically important inhibitors of gastric acid secretion may be the gastric inhibitory polypeptide (GIP) which is released from the duodenum and jejunum after food intake and shows besides its insulinotropic effect a strong inhibition of stimulated acid secretion in dogs9.

Transmural potential and stimulated acid in innervated rat stomach perfused at pH 3.0.

Abstract : Acid was secreted at high rates, reaching 5 to 13 micro mole/min, promptly after subcutaneous injection of 400 micro g of a semipurified gastrin preparation. Application of the 'pH-stat' principle to a continuous luminal perfusion technic showed that stimulated acid secretion was sharply cut off when the perfusion medium was changed rapidly from pH 2.5 to pH 2.1. Sectioning the vagal trunks and their associated fibers in the forestomach area caused an immediate inhibition of stimulated acid secretion, which could not be restored by gastrin reinjection. Potential differences usually decreased from 41 to 36 mv between resting and stimulated acid rates, but this was not an invariable finding. Atropine at doses sufficient to block all receptor sites for inhibition of gastrin potential had no effect on the stimulation of acid secretion by re-injection of gastrin. (Author)