Reversibility of Cholecystokinin‐B/Gastrin Receptor Blockade: A Study of the Gastrin‐ECL Cell Axis in the Rat

Abstract

Absfract: Gastrin acts via cholecystokinin-Blgastrin receptors to control histamine-and chromogranin A-producing ECL cells, which constitute the quantitatively predominant endocrine cell population in the acid-producing part of the rat stomach. Cholecystokinin-B receptor blockade is known to suppress the activity of ECL cells and to prevent their ability to respond to gastrin stimulation. The present study examines the reversibility of long-standing cholecystokinin-B receptor blockade of ECL cells. YM022, a potent and selective cholecystokinin-B receptor antagonist, was administered in a maximally effective dose by continuous subcutaneous infusion for 4 weeks (via osmotic minipumps). The resulting receptor blockade was manifested in elevated serum gastrin concentration (due to the ensuing acid inhibition), while the serum pancreastatin concentration, oxyntic mucosal histidine decarboxylase activity, histidine decarboxylase-and chromogranin A-mRNA levels and histamine and pancreastatin concentrations were lowered. After withdrawal of YM022, all these parameters returned to normal after varying lengths of time. The serum gastrin concentration and the oxyntic mucosal histidine decarboxylase activity returned to normal within a week after termination of treatment. The serum pancreastatin concentration and the mucosal histidine decarboxylase-and chromogranin A-mRNA levels returned to normal within 2 weeks of drug withdrawal. The mucosal pancreastatin and histamine concentrations remained unchanged for about a week before gradually returning to control levels within the next two weeks. Hence, the various effects of cholecystokinin-B receptor blockade of the ECL cells are fully reversible within 1-3 weeks of drug withdrawal.

Effects of CCK2 Receptor Blockade on Growth Parameters in Gastrointestinal Tract and Pancreas in Rats

“…Also gastrin-deficient or CCK 2 receptor-de- ficient (knock-out) mice exhibit morphological and functional changes (Nagata et al 1996;Koh et al 1997;Langhans et al 1997;Friis-Hansen et al 1998) that may be directly and/or indirectly related to the lack of gastrin or CCK 2 receptor, at times perhaps reflecting compensatory adjustments rather than gastrin or CCK 2 receptor deficiency per se. We suggest that pharmacological CCK 2 receptor blockade in comparison with for instance antrectomy, parenteral nutrition or targeted gene disruption may represent a less invasive and perhaps also more specific way (less likely to be associated with compensatory effects) to identify the trophic effects of endogenous gastrin, an approach which has the additional advantage that it is reversible (Norlén et al 1999) and can be applied to many different species.…”

Long‐lasting cholecystokinin2 receptor blockade after a single subcutaneous injection of YF476 or YM022

“…Hence, the long effect duration of YF476 and YM022 can be explained best by slow absorption of the drug from a subcutaneous deposit. It is unlikely that it reflects an irreversible or unsurmountable blockade of the CCK 2 receptors since stopping the continuous subcutaneous infusion of YM022 after 4 weeks led to the prompt reversal of the CCK 2 receptor blockade ( Norlén et al ., 1999 ). The measured serum concentration of YF476 ranged from 20–40 nmol l −1 1 day after administration to about 15 nmol l −1 8 weeks after administration.…”