Stimulation of pepsinogen release from isolated gastric glands by cholecystokininlike peptides

1983 ◽  
Vol 244 (2) ◽  
pp. G192-G197 ◽  
Author(s):  
S. J. Hersey ◽  
D. May ◽  
D. Schyberg
Keyword(s):  
Acid Formation ◽  
Weak Base ◽  
Gastric Glands ◽  
Cholecystokinin Octapeptide ◽  
Peptide Receptor ◽  
Isolated Gastric Glands ◽  
Pepsinogen Secretion ◽  
Weak Stimulus ◽  
Peptide Stimulation ◽  
Stimulation Of

Gastric glands isolated from rabbit stomach were employed to study the regulation of pepsinogen secretion by peptide hormones. Cholecystokinin octapeptide (CCK-OP) stimulated pepsinogen secretion with an ED50 of about 1 nM. Caerulein was as effective as CCK-OP but less potent (ED50, 10 nM). Gastrin (HG-17) was found to be a weak stimulus, being only about 20% as effective as CCK-OP or caerulein. Sulfation of CCK-OP and caerulein was found to be important for potency but did not alter efficacy. Peptide stimulation of pepsinogen secretion was unaffected by cimetidine, atropine, or propranolol. Combinations of peptides resulted in less-than-additive responses, as did the combination of peptides with carbachol. In contrast, combination of peptides with isoproterenol resulted in additive responses. Accumulation of the weak base aminopyrine was used to measure acid formation by the gastric glands. The peptides gastrin, CCK-OP, and caerulein were found to be equally effective in stimulating acid formation. The peptide stimulation of pepsinogen secretion was inhibited by dibutyryl cGMP, whereas stimulation of acid formation was not inhibited by the cyclic nucleotide. The results indicate that gastric glands contain at least two peptide receptors distinguishable by sensitivity to dibutyryl cGMP. The peptide receptor associated with pepsinogen secretion appears to be selective for CCK relative to gastrin.

Lack of interaction between acid and pepsinogen secretion in isolated gastric glands

1983 ◽  
Vol 245 (6) ◽  
pp. G775-G779
Author(s):  
S. J. Hersey ◽  
M. Miller ◽  
D. May ◽  
S. H. Norris
Keyword(s):  
Cyclic Nucleotides ◽  
Acid Formation ◽  
Dibutyryl Camp ◽  
Gastric Glands ◽  
Isolated Gastric Glands ◽  
Pepsinogen Secretion ◽  
Inhibited Acid ◽  
Weak Stimulation ◽  
Stimulation Of

Gastric glands isolated from rabbit stomach were employed to study the relation between acid and pepsinogen secretion. The effects of adenosine and guanosine nucleotides were examined for both secretory processes. cAMP, dibutyryl cAMP (DBcAMP), and 8-bromo-cAMP (8BrcAMP) were found to stimulate both acid and pepsinogen secretion with a potency sequence of 8BrcAMP greater than DBcAMP greater than cAMP. Adenosine, ATP, and AMP were ineffective, indicating that the responses to adenosine cyclic nucleotides do not involve an adenosine receptor. 8BrcGMP was found to produce a weak stimulation of both acid and pepsinogen secretions, while GMP, cGMP, and DBcGMP were ineffective. DBcGMP was found to inhibit competitively the stimulation of pepsinogen secretion by cholecystokinin (CCK)-like peptides. No inhibition was found with cGMP or 8BrcGMP. Stimulation of pepsinogen secretion by carbachol or isoproterenol was not inhibited by DBcGMP nor was the stimulation of acid formation by CCK-like peptides. Thiocyanate inhibited acid formation but did not affect pepsinogen secretion stimulated by 8BrcAMP or carbachol, indicating that stimulation of pepsinogen secretion does not require simultaneous acid formation. Costimulation of acid formation by histamine and pepsinogen secretion by isoproterenol showed no interaction between the two secretory processes. The results are interpreted to suggest that correlations between acid and pepsinogen secretion observed in vivo do not result from direct interactions between parietal and chief cells.

Stimulation of acid formation in permeable gastric glands by valinomycin

1988 ◽  
Vol 255 (3) ◽  
pp. G313-G318 ◽  
Author(s):  
S. J. Hersey ◽  
L. Steiner
Keyword(s):  
Parietal Cells ◽  
Acid Formation ◽  
Dependent Manner ◽  
Weak Base ◽  
Gastric Glands ◽  
Concentration Dependent Manner ◽  
Threefold Increase ◽  
Anion Permeability ◽  
Isolated Gastric Glands ◽  
Stimulation Of

Isolated gastric glands made permeable with digitonin treatment were employed to study the ionic requirements of acid formation. Acid formation was monitored by the accumulation of a novel weak base probe, [14C]benzylamine. ATP-dependent acid formation was found to require K+ in a concentration-dependent manner, with an apparent K0.5 = 7 mM. The anion dependence of acid formation gave a selectivity sequence of Cl = I greater than Br greater than NO3 greater than SO4 = isethionate, with isethionate being approximately 50% as effective as Cl. The dependence of acid formation on [Cl] gave an apparent K0.5 = 6 mM. Addition of the K+ ionophore, valinomycin, to resting glands (cimetidine pretreatment) resulted in a two- to threefold increase in ATP-dependent acid formation. In contrast, stimulated (forskolin pretreated) glands showed a greater accumulation of benzylamine with ATP but significantly less valinomycin stimulation. The valinomycin stimulation required both K+ and Cl- and was inhibited by omeprazole and Sch 28080. The results are interpreted to indicate that major events in the transition from a resting to a stimulated state include changes in both K+ and anion permeability of the secretory membrane of parietal cells.

Stimulation of pepsinogen secretion in permeable isolated gastric glands

1985 ◽  
Vol 249 (3) ◽  
pp. G408-G415
Author(s):  
S. H. Norris ◽  
S. J. Hersey
Keyword(s):  
Lactate Dehydrogenase ◽  
Gastric Glands ◽  
Cholecystokinin Octapeptide ◽  
Chief Cells ◽  
Isolated Gastric Glands ◽  
Pepsinogen Secretion ◽  
Calcium Stimulation ◽  
Intracellular Regulation ◽  
Stimulus Secretion Coupling ◽  
Stimulation Of

Rabbit isolated gastric glands were treated with digitonin so that stimulation of pepsinogen secretion could be studied in a permeable system. Criteria for permeabilization were the release of lactate dehydrogenase in response to digitonin as well as the finding that calcium stimulation and spermine inhibition required the presence of digitonin. Other evidence confirmed that digitonin directly permeabilized chief cells. Pepsinogen secretion was elicited from digitonin-treated gastric glands by a number of agents, including calcium, vanadate, cholecystokinin octapeptide (CCK-OP), 8-bromo-adenosine 3',5'-cyclic monophosphate, and forskolin. Spermine was found to inhibit secretion stimulated by each of these agents only in the presence of digitonin, suggesting an intracellular site of spermine action. We concluded that spermine inhibition of secretion could be used as a marker of secretion elicited from permeable chief cells. The ability to stimulate pepsinogen secretion by such agents as CCK-OP and forskolin suggests that stimulus-secretion coupling is virtually intact even in permeable chief cells. We felt that this preparation should offer unusual opportunities for investigating the mechanisms involved in the intracellular regulation and activation of pepsinogen secretion.

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.

Ontogeny of pepsin secretory response to secretagogues in isolated rat gastric glands

1986 ◽  
Vol 250 (2) ◽  
pp. G200-G204 ◽  
Author(s):  
J. Yahav ◽  
P. C. Lee ◽  
E. Lebenthal
Keyword(s):  
Term Neonate ◽  
Ionophore A23187 ◽  
Newborn Rats ◽  
Dibutyryl Camp ◽  
Gastric Glands ◽  
Cholecystokinin Octapeptide ◽  
Rat Pups ◽  
Isolated Gastric Glands ◽  
Old Rats ◽  
Isolated Rat

By use of isolated gastric glands from rats at various ages, we demonstrated that full-term neonate and 1-day-old rats showed no response to cholecystokinin octapeptide (CCK-OP), carbachol, or Ca2+ ionophore. The same glands, however, were responsive to dibutyryl cAMP. A mature response was not found until the pups were 2 days old. Injection of hydrocortisone into newborn rats led to an increase in pepsinogen concentrations in gastric glands and also an increased responsiveness to CCK-OP, carbachol, and Ca2+ ionophore A23187 24 h after administration. Hydrocortisone thus caused precocious maturation of both pepsinogen accumulation and pepsinogen secretory responsiveness of gastric glands in rat pups.

Partial agonism by gastrin for a cholecystokinin receptor mediating pepsinogen secretion

1993 ◽  
Vol 265 (5) ◽  
pp. G865-G872
Author(s):  
L. H. Tang ◽  
M. D. Miller ◽  
J. R. Goldenring ◽  
I. M. Modlin ◽  
S. J. Hersey
Keyword(s):  
Partial Agonist ◽  
Specific Binding ◽  
Receptor Occupancy ◽  
Structural Basis ◽  
Tyrosine Residue ◽  
Gastric Glands ◽  
Cholecystokinin Receptor ◽  
Isolated Gastric Glands ◽  
Pepsinogen Secretion ◽  
Type Receptor

Isolated gastric glands from rabbit were used to characterize the functional cholecystokinin (CCK)-like peptide receptors that mediate pepsinogen secretion. Pepsinogen secretion was stimulated by both CCK octapeptide sulfate (CCK-8) and A-71378, a selective CCK-A-type receptor agonist, with similar mean effective doses (1.0 and 0.8 nM, respectively). Compared with CCK-8, gastrin-17 (G-17-I) showed reduced potency and only partial efficacy for stimulation of pepsinogen secretion while inhibiting the maximal CCK-8-stimulated response. The nonpeptide inhibitors, asperlicin and L-364,718, inhibited pepsinogen secretion with identical pA2 values for antagonism of both CCK and gastrin, indicating that both peptides interact with the same functional receptor. Specific binding of [3H]CCK-8 to isolated chief cell membranes was displaced fully by both CCK and gastrin, indicating full receptor occupancy by both peptides. A novel synthetic peptide analogue, pseudogastrin [(Glu)5-Ala-Tyr-Nle-Gly-Trp-Nle-Asp-Phe-NH2], was used to investigate the structural basis for the lower potency and efficacy of G-17-I. The potency of CCK and gastrin analogues for pepsinogen secretion was found to be dependent on both sulfation of a tyrosine residue and the position of the tyrosine residue relative to the COOH-terminal phenylalanine amide. The efficacy appears to be determined partially by the extended NH2-terminal sequence of G-17-I. The results of the present study are interpreted to show that pepsinogen secretion is mediated by a CCK-A-type receptor and gastrin acts at the same receptor as a partial agonist.

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.

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.

Forskolin stimulation of acid and pepsinogen secretion by gastric glands

1983 ◽  
Vol 755 (2) ◽  
pp. 293-299 ◽  
Author(s):  
S HERSEY ◽  
A OWIRODU ◽  
M MILLER
Keyword(s):  
Gastric Glands ◽  
Pepsinogen Secretion ◽  
Stimulation Of

scholarly journals Targeted disruption of the Lasp-1 gene is linked to increases in histamine-stimulated gastric HCl secretion

2008 ◽  
Vol 295 (1) ◽  
pp. G37-G44 ◽  
Author(s):  
Catherine S. Chew ◽  
Xunsheng Chen ◽  
Roni J. Bollag ◽  
Carlos Isales ◽  
Ke Hong Ding ◽  
...  
Keyword(s):  
Parietal Cell ◽  
Secretory Response ◽  
Actin Binding ◽  
Weak Base ◽  
Targeted Disruption ◽  
Gastric Glands ◽  
Isolated Gastric Glands ◽  
Body Weights ◽  
Hcl Secretion

Lasp-1 (LIM and SH3 domain protein 1) is a multidomain actin-binding protein that is differentially expressed within epithelial tissues and brain. In the gastric mucosa, Lasp-1 is highly expressed in the HCl-secreting parietal cell, where it is prominently localized within the F-actin-rich subcellular regions. Histamine-induced elevation of parietal cell [cAMP]i increases Lasp-1 phosphorylation, which is correlated with activation of HCl secretion. To determine whether Lasp-1 is involved in the regulation of HCl secretion in vivo, we generated a murine model with a targeted disruption of the Lasp-1 gene. Lasp-1-null mice had slightly lower body weights but developed normally and had no overt phenotypic abnormalities. Basal HCl secretion was unaffected by loss of Lasp-1, but histamine stimulation induced a more robust acid secretory response in Lasp-1-null mice compared with wild-type littermates. A similar effect of histamine was observed in isolated gastric glands on the basis of measurements of accumulation of the weak base [14C]aminopyrine. In addition, inhibition of the acid secretory response to histamine by H2 receptor blockade with ranitidine proceeded more slowly in glands from Lasp-1-null mice. These findings support the conclusion that Lasp-1 is involved in the regulation of parietal HCl secretion. We speculate that cAMP-dependent phosphorylation of Lasp-1 alters interactions with F-actin and/or endocytic proteins that interact with Lasp-1, thereby regulating the trafficking/activation of the H+, K+-ATPase (proton pump).

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