Long-lasting cholecystokinin(2) receptor blockade after a single subcutaneous injection of YF476 or YM022.

Histamine-forming ECL cells in the rat stomach operate under the control of gastrin. They represent a convenient target for studying cholecystokinin-B/gastrin (CCK(2)) receptor antagonists in vivo. We examined the effectiveness and duration of action of two CCK(2) antagonists, YM022 and YF476, with respect to their effect on ECL-cell histidine decarboxylase (HDC) activity in the rat. 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 micromol 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 micromol kg(-1) was used in all subsequent studies. 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 (>/=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. 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). We conclude that a single subcutaneous injection of 300 micromol kg(-1) YF476 causes blockade of CCK(2) receptors in the stomach of the rat for 8 weeks thus providing a convenient method for studies of the consequences of long-term CCK(2) receptor inhibition.
AuthorsM Kitano, P Norlén, X Q Ding, S Nakamura, R Håkanson
JournalBritish journal of pharmacology (Br J Pharmacol) Vol. 130 Issue 3 Pg. 699-705 (Jun 2000) ISSN: 0007-1188 [Print] ENGLAND
PMID10821801 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Benzodiazepinones
  • Gastrins
  • Hormone Antagonists
  • Phenylurea Compounds
  • Receptor, Cholecystokinin B
  • Receptors, Cholecystokinin
  • YF 476
  • Benzodiazepines
  • YM 022
  • Histidine Decarboxylase
  • Administration, Oral
  • Animals
  • Benzodiazepines (administration & dosage, blood, pharmacology)
  • Benzodiazepinones (administration & dosage, blood, pharmacology)
  • Dose-Response Relationship, Drug
  • Gastric Acid (secretion)
  • Gastric Mucosa (cytology, enzymology, metabolism)
  • Gastrins (blood, pharmacology)
  • Histidine Decarboxylase (metabolism)
  • Hormone Antagonists (administration & dosage, blood, pharmacology)
  • Injections, Subcutaneous
  • Male
  • Phenylurea Compounds (administration & dosage, blood, pharmacology)
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Cholecystokinin B
  • Receptors, Cholecystokinin (antagonists & inhibitors)
  • Weight Gain (drug effects)

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