Inhibition of acid secretion in isolated gastric glands by substituted benzimidazoles

1982 ◽  
Vol 243 (6) ◽  
pp. G505-G510 ◽  
Author(s):  
E. Fellenius ◽  
B. Elander ◽  
B. Wallmark ◽  
H. F. Helander ◽  
T. Berglindh
Keyword(s):  
Oxygen Consumption ◽  
Gastric Gland ◽  
Acid Formation ◽  
Gastric Glands ◽  
New Class ◽  
Weak Bases ◽  
Morphological Studies ◽  
Isolated Gastric Glands ◽  
Dose Dependent ◽  
Distal Site

A new class of gastric acid inhibitors, substituted benzimidazoles (H 83/69 and H 149/94), have been tested in an isolated rabbit gastric gland preparation. Acid formation in the glands was stimulated by histamine, dibutyryl cAMP (DBcAMP), and high extracellular K+ concentrations, and the glandular secretory response was measured by changes in oxygen consumption and in accumulation of the weak base [14C]aminopyrine (AP). The substituted benzimidazoles inhibited AP accumulation induced by all stimulants in a dose-dependent noncompetitive manner. In contrast, cimetidine only inhibited histamine-induced AP accumulation. Basal AP accumulation, not affected by cimetidine, was also inhibited by the substituted benzimidazoles, as was the increase in glandular oxygen consumption produced by the addition of histamine and DBcAMP. Basal oxygen consumption was inhibited by about 15%. The substituted benzimidazoles, like AP, are weak bases and were also found to accumulate in the glands. Semiquantitative morphological studies of glands stimulated by histamine plus theophylline did not show any change in the enlarged secretory surface area after stimulation in the presence of inhibitory concentrations of H 149/94 (10(-4) M). The results suggest that substituted benzimidazoles have a mechanism of action different from that of H2-receptor antagonists and indicate a very distal site of action in the events leading to acid formation.

Acid formation by permeable gastric glands: enhancement by prestimulation

1985 ◽  
Vol 248 (5) ◽  
pp. G561-G568 ◽  
Author(s):  
S. J. Hersey ◽  
L. Steiner
Keyword(s):  
Proton Transport ◽  
Gastric Gland ◽  
Lactic Dehydrogenase ◽  
Acid Formation ◽  
Gastric Glands ◽  
Mitochondrial Inhibitors ◽  
Isolated Gastric Glands ◽  
Exogenous Substrate ◽  
Local Supply

Digitonin was used to render isolated gastric glands permeable. This procedure was found to release cellular lactic dehydrogenase without disrupting the parietal cell's ability to generate proton gradients. Optimal conditions for permeabilizing the glands were found to depend on the ratio of digitonin to gland concentration. Stimulation of the glands with histamine, forskolin, or 8-bromo-cAMP prior to digitonin treatment resulted in a marked enhancement of the subsequent ATP-dependent acid formation. This enhancement was not found with the cholinergic agonist carbachol. These results indicate that preservation of the active secreting state does not require the continued presence of soluble factors. Characterization of the ATP-dependent acid formation in prestimulated permeable glands showed a dependence on exogenous substrate and inhibition by the mitochondrial inhibitors oligomycin and atractyloside. Moreover, it was found that ADP could replace ATP in promoting acid formation. These results are interpreted to show that mitochondrial oxidative phosphorylation can serve as an in situ ATP-recycling system to provide a local supply of ATP for proton transport. The overall study demonstrates that the digitonin-permeabilized gastric gland preparation is a valuable model system for studying mechanisms of gastric proton transport.

Function and structure of parietal cells after H+-K+-ATPase blockade

1988 ◽  
Vol 254 (3) ◽  
pp. G399-G407 ◽  
Author(s):  
J. Fryklund ◽  
H. F. Helander ◽  
B. Elander ◽  
B. Wallmark
Keyword(s):  
Single Dose ◽  
Oxygen Uptake ◽  
Gastric Content ◽  
Inhibitory Action ◽  
Gastric Gland ◽  
Volume Density ◽  
Gastric Glands ◽  
Morphological Studies ◽  
Biopsy Specimens ◽  
Isolated Gastric Glands

Omeprazole was administered to rabbits as a single dose or daily for 1 wk. H+-K+-ATPase and isolated gastric glands were prepared from the oxyntic corpus mucosa and used for functional and quantitative morphological studies. Both 10 and 100 mumol omeprazole/kg increased the pH of the gastric content when measured at death. The stimulated oxygen uptake and the rate of aminopyrine (AP) uptake were both inhibited in the isolated gastric gland preparations. Morphometric studies of biopsy specimens taken from the corpus mucosa and isolated gastric glands showed that omeprazole treatment increased the volume density of the acid compartments. This expansion provides an increased accumulation space for AP. Therefore, an increased AP uptake might be seen in glands isolated from omeprazole-treated animals. Blockade of the H2-receptor by ranitidine transformed the morphology of the cell into a more resting type and, furthermore, reduced the omeprazole-induced increase in the volume density of the acid compartments in the parietal cell. The H+-K+-ATPase activity measured in membrane fractions from the omeprazole-treated animals was decreased dose dependently and inhibited by 95% after 100 mumol omeprazole/kg. However, the concentration of the enzyme in these fractions did not change. These results indicate a specific inhibitory action of omeprazole on the H+-K+-ATPase.

Inhibition of acid secretion by the nonsteroidal anti-inflammatory drugs diclofenac and piroxicam in isolated gastric glands: analysis of a multifocal mechanism

2004 ◽  
Vol 286 (5) ◽  
pp. G711-G721 ◽  
Author(s):  
María Salvatella ◽  
Irma Rossi ◽  
Juan C. Del Valle ◽  
Yolanda Gutiérrez ◽  
Carmen Pereda ◽  
...  
Keyword(s):  
Acetylsalicylic Acid ◽  
Acid Secretion ◽  
Gastric Gland ◽  
Hydrolytic Activity ◽  
Acid Formation ◽  
Dependent Manner ◽  
Inhibitory Effects ◽  
Gastric Glands ◽  
Microsomal Membranes ◽  
Dose Dependent

In nonstimulated rabbit gastric glands, acetylsalicylic acid (10–500 μM) and indomethacin (3–300 μM) did not significantly modify the basal rate of acid secretion, whereas diclofenac and piroxicam (10–1,000 μM each) caused a marked and dose-dependent inhibitory effect (EC50 = 138 and 280 μM, respectively). In gastric glands stimulated by histamine (100 μM), diclofenac also reduced the rate of acid formation in a dose-dependent manner. In contrast, acetylsalicylic acid, indomethacin, and piroxicam exerted a biphasic effect; thus low concentrations (3–100 μM) of these three agents significantly increased the rate of histamine-stimulated acid secretion (10–20% over the corresponding control value) by a cAMP-independent mechanism, whereas higher concentrations reduced the rate of acid formation. With respect to underlying biochemical mechanisms that could mediate inhibitory effects of NSAIDs on gastric acid formation, it was observed that both diclofenac and piroxicam, but not acetylsalicylic acid or indomethacin, decreased the glandular content of ATP, inhibited hydrolytic activity of gastric gland microsomal H+-K+-ATPase, and reduced the rate of H+-K+-ATPase-dependent proton transport across microsomal membranes in a dose-dependent manner. Furthermore, diclofenac and piroxicam also significantly increased passive permeability of microsomal membranes to protons. In conclusion, our work shows that diclofenac and piroxicam cause a significant reduction in the rate of basal and histamine-stimulated acid formation in isolated rabbit gastric glands at concentrations that can be attained in the gastric lumen of patients treated with these drugs. Mechanisms involved in these inhibitory effects appear to be multifocal and include different steps of stimulus-secretion coupling.

Prostaglandin interaction with histamine release and parietal cell activity in isolated gastric glands

1986 ◽  
Vol 250 (5) ◽  
pp. G607-G616 ◽  
Author(s):  
O. Nylander ◽  
T. Berglindh ◽  
K. J. Obrink
Keyword(s):  
Oxygen Consumption ◽  
Parietal Cell ◽  
Cell Activity ◽  
Dependent Manner ◽  
Gastric Glands ◽  
Isolated Gastric Glands ◽  
Dose Dependent Fashion ◽  
Pg E2 ◽  
Opposing Effects ◽  
Dose Dependent

The effects of different prostanoids on parietal cell activity and glandular histamine (Hi) release were examined in isolated rabbit gastric glands. [14C]aminopyrine accumulation and glandular oxygen consumption were used as indices of parietal cell activity, and Hi was determined fluorophotometrically in the supernatant of the glandular suspensions. Both prostaglandins (PG) E2 and E1 dose dependently (10(-8) and 10(-6) M) increased the release of endogenous Hi. Carbacyclin was less effective and PGF2 alpha was almost without effect. Hi release induced by acetylcholine (Ach) and pentagastrin (Pg) was markedly potentiated in the presence of PGE2 (10(-8) to 10(-5) M). The Ach-induced sti ulation of Hi release was also potentiated by arachidonic acid (10(-5) M), an effect that was inhibitable by the cyclooxygenase inhibitor meclofenamate (3 X 10(-5) M). Somatostatin partially inhibited the response to Pg (3 X 10(-9) M) in combination with PGE2 (10(-5) M). Atropine (10(-5) M) strongly reduced the response elicited by Ach (3 X 10(-6) M) combined with PGE2 (10(-6) M). All prostanoids inhibited Hi (10(-4) M)-induced parietal cell activity in a dose-dependent manner (60-70%) but displayed different potency. The stimulatory response to Ach (3 X 10(-6) M) or Pg (3 X 10(-9) M) in combination with isobutylmethylxanthine (IBMX, 10(-5) M) was inhibited by PGE2 in a dose-dependent fashion. PGE2 (10(-6) M) was considerably more effective than cimetidine (10(-5) M) in inhibiting IBMX (10(-4) M)-stimulated oxygen consumption, and the remaining IBMX-PGE2 response (approximately 40%) was dose dependently (10(-8) to 10(-5) M) inhibited by cimetidine. Addition of Hi (10(-7) to 4 X 10(-7) M) or Pg (3 X 10(-10) to 3 X 10(-9) M) counteracted the PGE2 inhibition of the IBMX response. In addition, IBMX (10(-4) M) combined with PGE2 (10(-6) M) gave rise to a threefold increase in Hi release. These results suggest that prostaglandins have two opposing effects, i.e., liberation of endogenous Hi and inhibition of the action of Hi on the parietal cell.

Inhibitory action of somatostatin on isolated gastric glands and parietal cells

1983 ◽  
Vol 245 (2) ◽  
pp. G221-G229 ◽  
Author(s):  
C. S. Chew
Keyword(s):  
Parietal Cell ◽  
Inhibitory Action ◽  
Parietal Cells ◽  
Acid Formation ◽  
Gastric Glands ◽  
Isolated Gastric Glands ◽  
Cell Acid ◽  
Kinetics Of ◽  
Apparent Ic50

The action of somatostatin in vitro was characterized using glands and parietal cells isolated from rabbit gastric mucosa. In the presence of the reducing agent dithiothreitol, somatostatin was found to inhibit gastrin- and histamine-stimulated acid formation in glands as measured by [14C]aminopyrine (AP) accumulation and oxygen consumption, both measurements that appear to be reliable indexes of parietal cell acid formation. In glands the inhibition of the secretory response to gastrin was more potent (60-80%) than that to histamine (15-25%). The kinetics of somatostatin inhibition of responses to both agents were noncompetitive. The apparent IC50 for the partial somatostatin inhibition of histamine-stimulated AP accumulation was similar to that for gastrin (approx 3 X 10(-9) M) when maximum concentrations of histamine (10(-4) M) or gastrin (10(-7) M) were used. The inhibitory action of somatostatin appeared to be specific, inasmuch as this peptide had no significant effect on basal secretion or secretion stimulated by carbachol, dibutyryl cAMP, cholera toxin, or elevated extracellular K+. In purified parietal cell preparations, somatostatin inhibited histamine- but not gastrin-stimulated AP accumulation. Moreover, the inhibition of histamine-stimulated AP accumulation in parietal cells was more pronounced than in glands. These results suggest that somatostatin acts directly on parietal cells to inhibit histamine activation of H+ secretion. Somatostatin also acts indirectly to inhibit gastrin, perhaps by blocking the release of histamine from paracrine- or endocrinelike cells present in the glands.

scholarly journals Impairment of H+-K+-ATPase-dependent proton transport and inhibition of gastric acid secretion by ethanol

2001 ◽  
Vol 280 (6) ◽  
pp. G1331-G1340 ◽  
Author(s):  
Juan C. del Valle ◽  
María Salvatella ◽  
Irma Rossi ◽  
Ramón Andrade ◽  
Yolanda Gutiérrez ◽  
...  
Keyword(s):  
Acid Secretion ◽  
Gastric Acid Secretion ◽  
Gastric Acid ◽  
Proton Transport ◽  
Gastric Gland ◽  
Hydrolytic Activity ◽  
Gastric Glands ◽  
Isolated Gastric Glands ◽  
Low Concentrations ◽  
Camp Levels

Ethanol (1–20% vol/vol) caused a dose-dependent reduction in the basal rate of acid formation in isolated rabbit gastric glands with a calculated EC50 value of 4.5 ± 0.2%. Ethanol also reduced ATP levels in isolated gastric glands and in cultured parietal cells (EC50: 8.8 ± 0.4% and 8.5 ± 0.2%, respectively) and decreased both basal and forskolin-stimulated cAMP levels. In studies carried out in gastric gland microsomes, ethanol inhibited the hydrolytic activity of H+-K+-ATPase (EC50: 8.5 ± 0.6%), increased passive proton permeability (EC50: 7.9%), and reduced H+-K+-ATPase-dependent proton transport (EC50: 3%). Our results show that the inhibition of gastric acid secretion observed at low concentrations of ethanol (≤5%) is mainly caused by the specific impairment of H+-K+-ATPase-dependent proton transport across cell membranes rather than inhibition of the hydrolytic activity of H+-K+-ATPase, reduction in the cellular content of ATP, or increase in the passive permeability of membranes to protons, although these changes, in combination, must be relevant at concentrations of ethanol ≥7%.

Calyculin A, a phosphoprotein phosphatase inhibitor, stimulates acid secretion in isolated gastric glands

1996 ◽  
Vol 270 (1) ◽  
pp. G103-G112 ◽  
Author(s):  
T. Urushidani ◽  
T. Nagao
Keyword(s):  
Protein Kinase ◽  
Acid Secretion ◽  
Protein Kinase A ◽  
Gastric Gland ◽  
Calyculin A ◽  
Gastric Glands ◽  
Isolated Gastric Glands ◽  
Protein Kinase C Inhibitor ◽  
Kinase A

The effects of pkadaic acid (OKA) and calyculin A (CLA), inhibitors of protein phosphatases type 1 (PrPase1) and type 2A (PrPase2A), an acid secretion were examined in rabbit isolated gastric gland, CLA, but not OKA, strongly stimulated acid secretion by itself without affecting glandular adenosine 3',5'-cyclic monophosphate (cAMP) contents. CLA-induced secretion was suggested to be mainly due to the increase in the phosphorylation of protein kinase A substrates via the inhibition of PrPase1 in the parietal cell, since 1) CLA-induced secretion was not inhibited by cimetidine or atropine, 2) a protein kinase A inhibitor inhibited the secretion, whereas a protein kinase C inhibitor did not, 3) CLA augmented dibutyryl cAMP-induced secretion in some cases, and 4) OKA, which is 100 times more selective to PrPase2A than to PrPase1, was not a secretagogue. Unexpectedly, CLA did not augment the secretion by histamine, possibly because the inhibitor augmented the phosphorylation-mediating negative feedback pathway as well. Both CLA and OKA markedly increased phosphorylation of ezrin, a putative protein kinase A substrate, in the course of secretory activation.

Cl- requirement of acid secretion in isolated gastric glands

1983 ◽  
Vol 245 (4) ◽  
pp. G573-G581 ◽  
Author(s):  
D. H. Malinowska ◽  
J. Cuppoletti ◽  
G. Sachs
Keyword(s):  
Steady State ◽  
Acid Secretion ◽  
Parietal Cell ◽  
Acid Formation ◽  
Dibutyryl Camp ◽  
Steady State Distribution ◽  
State Distribution ◽  
Gastric Glands ◽  
Lateral Membrane ◽  
Isolated Gastric Glands

The dependence of acid formation, as measured by aminopyrine (AP) accumulation, on medium and intracellular Cl- was investigated in resting (10(-4) M cimetidine) and stimulated (10(-3) M dibutyryl cAMP) gastric glands isolated from the rabbit stomach. Intracellular Cl- concentrations (Cli-) were measured by the steady-state distribution of 36Cl-. In Cl- -free conditions AP accumulation was absent. Medium Cl- induced AP accumulation (AP ratio = 125) in stimulated glands with a K0.5 of 10.4 +/- 1.1 mM, equivalent to 18.0 +/- 1.2 mM Cli-, and had a small effect on resting glands (AP ratio = 6). With normal Nai+ and Ki+ maintained, similar results were obtained in stimulated glands treated with 10(-5) M amphotericin (ampho) and 10(-4) M ouabain (ouab), where the basal-lateral membrane was confirmed to be short-circuited with respect to Cl- pathways, i.e., medium Cl- and Cli- were equal. The K0.5 for Cl-i was 17.5 +/- 2.5 mM. In resting glands treated with ampho and ouab, AP accumulation increased linearly (no saturation was observed) with increasing Cl- (AP ratio = 35). These results suggest that stimulation activates a Cl- component in the secretory membrane and not in the basal-lateral membrane of the parietal cell. The K+ requirement of AP accumulation at a physiological Cl-i of 60 mM was also investigated in ampho- and ouab-treated glands. On stimulation the K0.5 for Ki+ decreased from 19.5 to 12 mM, coupled with a large increase in AP accumulation, indicating that stimulation also activates a K+ component in the secretory membrane.(ABSTRACT TRUNCATED AT 250 WORDS)

Pepsinogen release from isolated gastric glands

1982 ◽  
Vol 243 (3) ◽  
pp. G218-G225 ◽  
Author(s):  
H. R. Koelz ◽  
S. J. Hersey ◽  
G. Sachs ◽  
C. S. Chew
Keyword(s):  
Adenylyl Cyclase ◽  
Cyclase Activity ◽  
Dependent Manner ◽  
Adrenergic Stimulation ◽  
Adenylyl Cyclase Activity ◽  
Gastric Glands ◽  
Beta Adrenergic ◽  
Camp Content ◽  
Isolated Gastric Glands ◽  
Dose Dependent

The in vitro release of pepsinogen was studied using a preparation of isolated gastric glands from rabbits. The pepsinogen content of the glands was estimated to be about 700 U/mg dry wt. Spontaneous release of pepsinogen was found to be less than 1% of the total per hour and relatively constant for at least 2 h. Pepsinogen release was stimulated in a dose-dependent manner by both carbachol and isoproterenol. The cholinergic and beta-adrenergic stimulation was selectively inhibited by atropine and propranolol, respectively. Removal of external calcium inhibited the responses to both isoproterenol (partially) and carbachol (completely). Several agents, including histamine, prostaglandin (E2), and synthetic secretin, were found not to stimulate pepsinogen release. However, a crude secretin preparation (Boots) was found to produce significant stimulation. Dibutyryl cAMP increased pepsinogen release in a dose-dependent manner. Isoproterenol was found to increase the cAMP content of gastric glands and to stimulate adenylyl cyclase activity in homogenates. The beta-adrenergic stimulation of adenylyl cyclase was found to be selective for a population of gastric cells that was relatively depleted of parietal cells and distinct from the histamine-stimulated adenylyl cyclase activity. The results indicate that pepsinogen secretion by the gastric chief cell is regulated, in part, by separate cholinergic and beta-adrenergic mechanisms and that both calcium and cAMP play a role in this regulation.

Effects of Secretagogues on Oxygen Consumption, Aminopyrine Accumulation and Morphology in Isolated Gastric Glands

1976 ◽  
Vol 97 (4) ◽  
pp. 401-414 ◽  
Author(s):  
Thomas BERGLINDH ◽  
Herbert F. Helander ◽  
Karl Johan Öbrink
Keyword(s):  
Oxygen Consumption ◽  
Gastric Glands ◽  
Isolated Gastric Glands
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