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

1 Histamine-forming ECL cells in the rat stomach operate under the control of gastrin. They represent a convenient target for studying cholecystokinin-B/gastrin (CCK2) receptor antagonists in vivo. 2 We examined the effectiveness and duration of action of two CCK2 antagonists, YM022 and YF476, with respect to their effect on ECL-cell histidine decarboxylase (HDC) activity in the rat. 3 Oral administration of subcutaneous deposition of YF476 or YM022 reduced the HDC activity. The maximum/near-maximum dose for both drugs and for both modes of administration was 300 mu mol kg(-1) (effects measured 24 h after dose). At this dose and time the serum concentration of YF476 was 20-40 nmol l(-1). The dose 300 mu mol kg(-1) was used in all subsequent studies. 4 A single subcutaneous injection of YF476 inhibited the HDC activity for 8 weeks. The circulating concentration of YF476 remained high for the same period of time (greater than or equal to 15 nmol l(-1)). Subcutaneous YM022 suppressed the HDC activity for 4 weeks. A single oral dose of YF476 or YM022 inhibited the HDC activity for 2-3 days. 5 Chronic gastric fistula rats were used to study the effect of subcutaneous YF476 on gastrin-stimulated acid secretion. A single injection of YF476 prevented gastrin from causing an acid response for at least 4 weeks (the longest time studied). 6 We conclude that a single subcutaneous injection of 300 mu mol kg(-1) YF476 causes blockade of CCK2 receptors in the stomach of the rat for 8 weeks thus providing a convenient method for studies of the consequences of long-term CCK2 receptor inhibition.