Cholecystokinin-B/gastrin receptor blockade suppresses the activity of rat stomach ECL cells.
Gastrin controls the histamine- and chromogranin A-producing enterochromaffin-like (ECL) cells, the predominant endocrine cell population in the acid-producing part of the rat stomach. They are responsible for most of the circulating pancreastatin, a chromogranin A-derived peptide. The present study examines the ability of two potent and highly selective cholecystokinin-B/gastrin receptor antagonists, RP73870 and YM022, to incapacitate the ECL cells. The two antagonists were given by continuous subcutaneous infusion to otherwise untreated rats and to hypergastrinaemic rats treated with gastrin-17 (continuous subcutaneous infusion) or omeprazole (orally) for 7 days. Several parameters reflecting ECL cell activity were measured: The oxyntic mucosal histidine decarboxylase activity, the histamine concentration, the histidine decarboxylase mRNA and chromogranin A mRNA concentrations, and the serum pancreastatin concentration. In addition, the serum gastrin concentration was measured. RP73870 and YM022 greatly lowered the oxyntic mucosal histidine decarboxylase activity and the histidine decarboxylase mRNA and chromogranin A mRNA concentrations, and also reduced the oxyntic mucosal histamine concentration and the serum pancreastatin concentration. Moreover, they raised the serum gastrin concentration. With respect to blockade of histidine decarboxylase activity, 1.0 mumol.kg-1.hr-1 was an almost maximally effective dose for both RP73870 and YM022. The corresponding ID50 values were 0.04 and 0.05 mumol.kg-1.hr-1. RP73870 and YM022 inhibited the hypergastrinaemia-evoked rise in all ECL-cell parameters. The results suggest that sustained cholecystokinin-B/gastrin receptor blockade causes lasting deactivation of the ECL cells.
Ding
X Q
XQ
Department of Pharmacology, University of Lund, Sweden.
Lindström
E
E
Håkanson
R
R
D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology*; D053379:Chromogranin A; D002864:Chromogranins / Q000235:genetics; D004759:Enterochromaffin Cells / Q000187:drug effects* / Q000378:metabolism; D005753:Gastric Mucosa / Q000378:metabolism; D005755:Gastrins / Q000097:blood; D006632:Histamine / Q000378:metabolism; D006640:Histidine Decarboxylase / Q000235:genetics / Q000378:metabolism*; D006727:Hormone Antagonists / Q000494:pharmacology*; D008297:Male; D009853:Omeprazole / Q000494:pharmacology; D010187:Pancreatic Hormones / Q000097:blood; D010671:Phenylurea Compounds / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D012337:RNA, Ribosomal, 18S / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*; D013270:Stomach / Q000166:cytology / Q000187:drug effects*
D000897:Anti-Ulcer Agents; D053379:Chromogranin A; D002864:Chromogranins; D005755:Gastrins; D006727:Hormone Antagonists; D010187:Pancreatic Hormones; D010671:Phenylurea Compounds; D012333:RNA, Messenger; D012337:RNA, Ribosomal, 18S; C094193:RP 73870; D011949:Receptors, Cholecystokinin; C050836:pancreastatin; D001569:Benzodiazepines; C087260:YM 022; D006632:Histamine; D006640:Histidine Decarboxylase; D009853:Omeprazole