Reversibility of cholecystokinin-B/gastrin receptor blockade: A study of the gastrin-ECL cell axis in the rat

Gastrin acts via cholecystokinin-B/gastrin 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 ra t stomach. Cholecystokinin-B receptor blockade is known to suppress the act ivity of ECL cells and to prevent their ability to respond to gastrin stimu lation. The present study examines the reversibility of long-standing chole cystokinin-B receptor blockade of ECL cells. YM022, a potent and selective cholecystokinin-B receptor antagonist, was administered in a maximally effe ctive dose by continuous subcutaneous infusion for 4 weeks (via osmotic min ipumps). The resulting receptor blockade was manifested in elevated serum g astrin concentration (due to the ensuing acid inhibition), while the serum pancreastatin concentration, oxyntic mucosal histidine decarboxylase activi ty, histidine decarboxylase- and chromogranin A- mRNA levels and histamine and pancreastatin concentrations were lowered. After withdrawal of YM022, a ll these parameters returned to normal after varying lengths of time. The s erum gastrin concentration and the oxyntic mucosal histidine decarboxylase activity returned to normal within a week after termination of treatment. T he serum pancreastatin concentration and the mucosal histidine decarboxylas e- and chromogranin A-mRNA levels returned to normal within 2 weeks of drug withdrawal. The mucosal pancreastatin and histamine concentrations remaine d unchanged for about a week before gradually returning to control levels w ithin the next two weeks. Hence, the various effects of cholecystokinin-B r eceptor blockade of the ECL cells are fully reversible within 1-3 weeks of drug withdrawal.