Impaired gastric acid secretion in gastrin-deficient mice

1998 ◽  
Vol 274 (3) ◽  
pp. G561-G568 ◽  
Author(s):  
Lennart Friis-Hansen ◽  
Frank Sundler ◽  
Ying Li ◽  
Patrick J. Gillespie ◽  
Thomas L. Saunders ◽  
...  

To further understand the role of the peptide hormone gastrin in the development and function of the stomach, we have generated gastrin-deficient mice by gene targeting in embryonic stem cells. Mutant mice were viable and fertile, without obvious visible abnormalities. However, gastric function was severely affected by the loss of gastrin. Basal gastric acid secretion was abolished and could not be induced by histamine, carbachol, or gastrin. Histological analysis revealed alterations in the two cell types primarily involved in acid secretion, parietal and enterochromaffin-like (ECL) cells. Parietal cells were reduced in number with an accumulation of immature cells lacking H+-K+-adenosinetriphosphatase (H+-K+-ATPase). ECL cells were positioned closer to the base of the gastric glands, with markedly lower expression of histidine decarboxylase. Gastrin administration for 6 days reversed the effects of the gastrin deficiency, leading to an increase in the number of mature, H+-K+-ATPase-positive parietal cells and a partial restoration of acid secretion. The results show that gastrin is critically important for the function of the acid secretory system.

1990 ◽  
Vol 259 (1) ◽  
pp. G41-G47 ◽  
Author(s):  
D. J. Stechschulte ◽  
D. C. Morris ◽  
R. L. Jilka ◽  
D. J. Stechschulte ◽  
K. N. Dileepan

Gastric acid secretion in normal (+/+) C57B1/6J mice and congeneic, mast cell-deficient (mi/mi) C57B1/6J mice was examined. The mast cell-deficient animals had approximately 50% of the normal quantity of gastric histamine and a blunted basal acid level and secretory response. These observations were noted despite the presence of parietal cells, which were normal in number and morphology. The H2-antagonist ranitidine inhibited basal acid secretion in both groups of animals. Exogenous histamine induced a significant secretory response in normal and mast cell-deficient groups, but only the secretory response in normal animals could be blocked by the H2-antagonist. Treatment of mast cell-deficient animals with histamine for seven consecutive days before stimulation did not restore the histamine response to the normal (+/+) levels. The normal animals demonstrated an acid secretory response to pentagastrin. Mast cell-deficient mice also responded to pentagastrin, but the response was less than that observed in the normal animals, and a significant difference was not evident in all experiments. Furthermore, simultaneous injection of mast cell-deficient animals with histamine and pentagastrin did not restore pentagastrin responsiveness to normal levels, although the histamine concentration used was sufficient to raise acid secretion to basal levels of normal mice. These results support the conclusion that non-mast cell histamine only partially contributes to basal gastric acid secretion and is insufficient to facilitate full parietal cell responsiveness. Furthermore, pentagastrin requires the presence of mast cells to elicit a maximal secretory response but can use non-mast cell histamine to activate the parietal cells for acid secretion.


2005 ◽  
Vol 289 (6) ◽  
pp. G1084-G1090 ◽  
Author(s):  
Matthias M. Dufner ◽  
Philipp Kirchhoff ◽  
Christine Remy ◽  
Patricia Hafner ◽  
Markus K. Müller ◽  
...  

Gastric acid secretion is activated by two distinct pathways: a neuronal pathway via the vagus nerve and release of acetylcholine and an endocrine pathway involving gastrin and histamine. Recently, we demonstrated that activation of H+-K+-ATPase activity in parietal cells in freshly isolated rat gastric glands is modulated by the calcium-sensing receptor (CaSR). Here, we investigated if the CaSR is functionally expressed in freshly isolated gastric glands from human patients undergoing surgery and if the CaSR is influencing histamine-induced activation of H+-K+-ATPase activity. In tissue samples obtained from patients, immunohistochemistry demonstrated the expression in parietal cells of both subunits of gastric H+-K+-ATPase and the CaSR. Functional experiments using the pH-sensitive dye 2′,7′-bis-(2-carboxyethyl)-5-(and 6)-carboxyfluorescein and measurement of intracellular pH changes allowed us to estimate the activity of H+-K+-ATPase in single freshly isolated human gastric glands. Under control conditions, H+-K+-ATPase activity was stimulated by histamine (100 μM) and inhibited by omeprazole (100 μM). Reduction of the extracellular divalent cation concentration (0 Mg2+, 100 μM Ca2+) inactivated the CaSR and reduced histamine-induced activation of H+-K+-ATPase activity. In contrast, activation of the CaSR with the trivalent cation Gd3+ caused activation of omeprazole-sensitive H+-K+-ATPase activity even in the absence of histamine and under conditions of low extracellular divalent cations. This stimulation was not due to release of histamine from neighbouring enterochromaffin-like cells as the stimulation persisted in the presence of the H2 receptor antagonist cimetidine (100 μM). Furthermore, intracellular calcium measurements with fura-2 and fluo-4 showed that activation of the CaSR by Gd3+ led to a sustained increase in intracellular Ca2+ even under conditions of low extracellular divalent cations. These experiments demonstrate the presence of a functional CaSR in the human stomach and show that this receptor may modulate the activity of acid-secreting H+-K+-ATPase in parietal cells. Furthermore, our results show the viability of freshly isolated human gastric glands and may allow the use of this preparation for experiments investigating the physiological regulation and properties of human gastric glands in vitro.


1998 ◽  
Vol 114 ◽  
pp. A1135
Author(s):  
D Chen ◽  
T Koh ◽  
C-M Zhao ◽  
R Håkanson ◽  
TC Wang

2000 ◽  
Vol 82 ◽  
pp. 31
Author(s):  
Satoshi Tanaka ◽  
Satoru Takahashi ◽  
Hiroshi Ohtsu ◽  
Takehiko Watanabe ◽  
Susumu Okabe ◽  
...  

2008 ◽  
Vol 105 (46) ◽  
pp. 17955-17960 ◽  
Author(s):  
Jie Xu ◽  
Penghong Song ◽  
Marian L. Miller ◽  
Frank Borgese ◽  
Sharon Barone ◽  
...  

Slc26a9 is a recently identified anion transporter that is abundantly expressed in gastric epithelial cells. To study its role in stomach physiology, gene targeting was used to prepare mice lacking Slc26a9. Homozygous mutant (Slc26a9−/−) mice appeared healthy and displayed normal growth. Slc26a9 deletion resulted in the loss of gastric acid secretion and a moderate reduction in the number of parietal cells in mutant mice at 5 weeks of age. Immunofluorescence labeling detected the H-K-ATPase exclusively on the apical pole of gastric parietal cells in Slc26a9−/− mice, in contrast to the predominant cytoplasmic localization in Slc26a9+/+ mice. Light microscopy indicated that gastric glands were dilated, and electron micrographs displayed a distinct and striking absence of tubulovesicles in parietal cells and reductions in the numbers of parietal and zymogen cells in Slc26a9−/− stomach. Expression studies indicated that Slc26a9 can function as a chloride conductive pathway in oocytes as well as a Cl−/HCO3− exchanger in cultured cells, and localization studies in parietal cells detected its presence in tubulovesicles. We propose that Slc26a9 plays an essential role in gastric acid secretion via effects on the viability of tubulovesicles/secretory canaliculi and by regulating chloride secretion in parietal cells.


1961 ◽  
Vol 11 (2) ◽  
pp. 349-363 ◽  
Author(s):  
A. W. Sedar ◽  
M. H. F. Friedman

The fine structure of the parietal (oxyntic) cell in the gastric glands (corpus of the stomach) of the dog was examined under conditions of active gastric acid secretion and compared with cellular structure in the non-acid-secretory (basal) state. Animals, in both acute and chronic experiments, were equipped with gastric fistulae so that gastric juice could be collected for analysis of total acidity, free acidity, volume, and pH prior to biopsy of the gastric mucosa. The specimens of mucosa were fixed in buffered OsO4 and embedded in n-butyl methacrylate and the thin sections were stained with lead hydroxide before examination in the electron microscope. A majority of parietal cells showed an alteration of fine structure during stimulation of gastric acid secretion by a number of different techniques (electrical vagal stimulation, histamine administration, or insulin injection). The changes in fine structure affected mainly the smooth surfaced vesicular elements and the intracellular canaliculi in the cytoplasm of the cell. The mitochondria also appeared to be involved to some extent. During acid secretion a greater concentration of smooth surface profiles is found adjacent to the walls of the intracellular canaliculi; other parietal cells exhibited a marked decrease in number of smooth surfaced elements. Intracellular canaliculi, always present in non-acid-secreting oxyntic cells, develop more extensively in cells of acid-secreting gastric glands. The surface area of these canaliculi is greatly increased by the elaboration of a large number of closely approximated and elongated microvilli. Still other parietal cells apparently in a different stage of the secretory cycle exhibit non-patent canaliculi lacking prominence; such cells have very few smooth surfaced vesicular elements. These morphological findings correlated with the acid-secretory state of the stomach provide evidence that the parietal cell participates in the process of acid secretion.


2002 ◽  
Vol 122 (1) ◽  
pp. 145-155 ◽  
Author(s):  
Satoshi Tanaka ◽  
Kiyomi Hamada ◽  
Noboru Yamada ◽  
Yuko Sugita ◽  
Shunsuke Tonai ◽  
...  

2002 ◽  
Vol 120 (3) ◽  
pp. 159-171 ◽  
Author(s):  
Susumu OKABE ◽  
Kazuharu FURUTANI ◽  
Kazuhiko MAEDA ◽  
Takeshi AIHARA ◽  
Teruaki FUJISHITA ◽  
...  

Sign in / Sign up

Export Citation Format

Share Document