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Effect of Cholecystokinin-B/Gastrin Receptor Antagonists on Rat Stomach ECL Cells

Ding, Xi-Qin LU (1997)
Abstract
The histamine- and pancreastatin- containing ECL cells in the acid-producing mucosa of the rat stomach operate under the control of circulating gastrin. The present work examines how cholecystokinin (CCK)-B/gastrin receptors regulate the activity of the ECL cells. The oxyntic mucosal histidine decarboxylase (HDC) activity and the circulating pancreastatin concentration are two markers for the activity of the ECL cells. A series of candidate CCK-B/gastrin receptor antagonists was screened for their potency and selectivity in vivo with particular emphasis on their effect on the gastrin-evoked ECL-cell HDC activation. YF476, YM022, RP73870, JB93182 and AG041R were found to be potent and selective antagonists of the ECL-cell CCK-B/gastrin... (More)
The histamine- and pancreastatin- containing ECL cells in the acid-producing mucosa of the rat stomach operate under the control of circulating gastrin. The present work examines how cholecystokinin (CCK)-B/gastrin receptors regulate the activity of the ECL cells. The oxyntic mucosal histidine decarboxylase (HDC) activity and the circulating pancreastatin concentration are two markers for the activity of the ECL cells. A series of candidate CCK-B/gastrin receptor antagonists was screened for their potency and selectivity in vivo with particular emphasis on their effect on the gastrin-evoked ECL-cell HDC activation. YF476, YM022, RP73870, JB93182 and AG041R were found to be potent and selective antagonists of the ECL-cell CCK-B/gastrin receptors, while the dipeptoid compounds PD136450, PD135158 and PD134308 were found to be partial agonists rather than antagonists. YM022 and RP73870 were selected for further studies. Sustained CCK-B/gastrin receptor blockade (7 days) impaired the functional activity of the ECL cells and prevented the adaptation of the ECL cells to hypergastrinemia as manifested in the reduced oxyntic mucosal HDC activity, histamine concentration and HDC mRNA and chromogranin A (CGA) mRNA concentrations and in the reduced serum pancreastatin concentration and the hypergastrinemia. CCK-B/gastrin receptor blockade deactivated the ECL cells according to a complex time pattern in which histamine and pancreastatin secretion and protein synthesis were promptly inhibited (hours to days) while longer times (days to weeks) were required to lower their histamine and pancreastatin contents. In addition, YM022 and RP73870 abolished the gastrin-induced gastric acid secretion without affecting the basal and vagally stimulated acid secretion. The results support the view that CCK-B/gastrin receptors are essential for the maintenance and adaptation of the ECL cells and for gastrin-stimulated gastric acid secretion. (Less)
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author
opponent
  • Professor Schmidt, Wolfgang E, Kiel, Germany
organization
publishing date
type
Thesis
publication status
published
subject
keywords
pharmacognosy, Pharmacological sciences, vävnadskultur, histokemi, cytokemi, Histologi, tissue culture, histochemistry, gastrin, cholecystokinin (CCK) receptors, ECL cells, CCK-B/gastrin receptor antagonists, histidine decarboxylase (HDC), histamine, pancreastatin, chromogranin A (CGA), gastric acid secretion., cytochemistry, Histology, pharmacy, toxicology, Farmakologi, farmakognosi, farmaci, toxikologi
pages
156 pages
publisher
Department of Pharmacology, Lund University
defense location
Department of Pharmacology
defense date
1997-05-27 10:15
external identifiers
  • Other:ISRN: LUMEDW/MEFA--1034--SE
ISBN
91-628-2498-8
language
English
LU publication?
yes
id
cf7480c2-1d90-4054-84fd-1510cbf1221c (old id 29280)
date added to LUP
2007-06-14 09:02:04
date last changed
2016-09-19 08:45:02
@misc{cf7480c2-1d90-4054-84fd-1510cbf1221c,
  abstract     = {The histamine- and pancreastatin- containing ECL cells in the acid-producing mucosa of the rat stomach operate under the control of circulating gastrin. The present work examines how cholecystokinin (CCK)-B/gastrin receptors regulate the activity of the ECL cells. The oxyntic mucosal histidine decarboxylase (HDC) activity and the circulating pancreastatin concentration are two markers for the activity of the ECL cells. A series of candidate CCK-B/gastrin receptor antagonists was screened for their potency and selectivity in vivo with particular emphasis on their effect on the gastrin-evoked ECL-cell HDC activation. YF476, YM022, RP73870, JB93182 and AG041R were found to be potent and selective antagonists of the ECL-cell CCK-B/gastrin receptors, while the dipeptoid compounds PD136450, PD135158 and PD134308 were found to be partial agonists rather than antagonists. YM022 and RP73870 were selected for further studies. Sustained CCK-B/gastrin receptor blockade (7 days) impaired the functional activity of the ECL cells and prevented the adaptation of the ECL cells to hypergastrinemia as manifested in the reduced oxyntic mucosal HDC activity, histamine concentration and HDC mRNA and chromogranin A (CGA) mRNA concentrations and in the reduced serum pancreastatin concentration and the hypergastrinemia. CCK-B/gastrin receptor blockade deactivated the ECL cells according to a complex time pattern in which histamine and pancreastatin secretion and protein synthesis were promptly inhibited (hours to days) while longer times (days to weeks) were required to lower their histamine and pancreastatin contents. In addition, YM022 and RP73870 abolished the gastrin-induced gastric acid secretion without affecting the basal and vagally stimulated acid secretion. The results support the view that CCK-B/gastrin receptors are essential for the maintenance and adaptation of the ECL cells and for gastrin-stimulated gastric acid secretion.},
  author       = {Ding, Xi-Qin},
  isbn         = {91-628-2498-8},
  keyword      = {pharmacognosy,Pharmacological sciences,vävnadskultur,histokemi,cytokemi,Histologi,tissue culture,histochemistry,gastrin,cholecystokinin (CCK) receptors,ECL cells,CCK-B/gastrin receptor antagonists,histidine decarboxylase (HDC),histamine,pancreastatin,chromogranin A (CGA),gastric acid secretion.,cytochemistry,Histology,pharmacy,toxicology,Farmakologi,farmakognosi,farmaci,toxikologi},
  language     = {eng},
  pages        = {156},
  publisher    = {ARRAY(0xa0f6c88)},
  title        = {Effect of Cholecystokinin-B/Gastrin Receptor Antagonists on Rat Stomach ECL Cells},
  year         = {1997},
}