Time-course of deactivation of rat stomach ECL cells following cholecystokinin B/gastrin receptor blockade.
1 The so-called enterochromaffin-like (ECL) cells constitute 65-75% of the endocrine cells in the acid-producing part of the rat stomach. They produce and secrete histamine and pancreastatin, a chromogranin A (CGA)-derived peptide, in response to gastrin, Cholecystokinin (CCK)B/gastrin receptor blockade is known to suppress their activity. 2 We have examined the time course of the deactivation of the ECL cells following treatment with the selective CCKB receptor antagonists RP73870 and YM022. The drugs were given by continuous subcutaneous infusion for a time span of 1 h to 3 weeks and the serum gastrin concentration and various ECL cell parameters were measured (oxyntic mucosal histidine decarboxylase (HDC) activity, histamine and pancreastatin concentrations, HDC mRNA and CGA mRNA levels, and circulating pancreastatin concentration). 3 The two antagonists caused a prompt and dramatic decline in the oxyntic mucosal HDC activity and HDC mRNA level. The HDC activity started to decline after 1-2 h, was reduced by 60-70% after 6 h and was maximally suppressed (80-90%) after 24-48 h. The HDC mRNA level was reduced after 12 h and was at about 20% of the pretreatment level after 2-4 days of infusion. The ECL cell histamine concentration was lowered by about 50% after 7-10 days. 4 RP73870 and YM022 lowered the serum pancreastatin concentration and the oxyntic mucosal CGA mRNA level. The serum pancreastatin concentration was reduced by 40% after 6 h and the reduction was maximal after 2-3 days. A decline in the oxyntic mucosal CGA mRNA level was noted after 12 h with a maximal reduction after 2-4 days of infusion. The ECL cell pancreastatin concentration was reduced by 30-40% after 3 weeks. 5 The infusion of RP73870 and YM022 induced hypergastrinaemia. The serum gastrin concentration started to rise after 2-4 h, there was a 2 fold increase after 6 h and maximal increase (3-4 fold) after 2-3 days of treatment. 6 In conclusion, CCKB/gastrin receptor blockade promptly deactivates the ECL cells. Deactivation, manifested in a greatly reduced HDC activity, was apparent after 1-2 h of the infusion. The serum pancreastatin concentration and the oxyntic mucosal HDC mRNA and CGA mRNA levels were greatly reduced after 1-2 days. The ECL cell concentrations of histamine and pancreastatin declined quite slowly by comparison.
Ding
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XQ
Department of Pharmacology, University of Lund, Sweden.
Lindström
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E
Håkanson
R
R
D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology*; D001835:Body Weight; D053379:Chromogranin A; D004759:Enterochromaffin Cells / Q000187:drug effects* / Q000502:physiology*; D005753:Gastric Mucosa / Q000378:metabolism; D005755:Gastrins / Q000097:blood; D006632:Histamine / Q000378:metabolism; D006727:Hormone Antagonists / Q000494:pharmacology*; D008297:Male; D010187:Pancreatic Hormones / Q000097:blood / Q000378:metabolism; D010671:Phenylurea Compounds / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*; D013270:Stomach / Q000166:cytology* / Q000187:drug effects; D013997:Time Factors
D000897:Anti-Ulcer Agents; D053379:Chromogranin A; D005755:Gastrins; D006727:Hormone Antagonists; D010187:Pancreatic Hormones; D010671:Phenylurea Compounds; D012333:RNA, Messenger; C094193:RP 73870; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; C050836:pancreastatin; D001569:Benzodiazepines; C087260:YM 022; D006632:Histamine