title: Long-lasting cholecystokinin(2) receptor blockade after a single subcutaneous injection of YF476 or YM022.
abstract: 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.
authors.affiliation: Department of Pharmacology, University of Lund, Sölvegatan 10, S-223 62 Lund, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Kitano
authors.forename: P
authors.initials: P
authors.lastname: Norlén
authors.forename: X Q
authors.initials: XQ
authors.lastname: Ding
authors.forename: S
authors.initials: S
authors.lastname: Nakamura
authors.forename: R
authors.initials: R
authors.lastname: Håkanson
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001569:Benzodiazepines / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D001570:Benzodiazepinones / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005744:Gastric Acid / Q000378:metabolism; D005753:Gastric Mucosa / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D005755:Gastrins / Q000097:blood / Q000494:pharmacology; D006640:Histidine Decarboxylase / Q000378:metabolism; D006727:Hormone Antagonists / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D007279:Injections, Subcutaneous; D008297:Male; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*; D015430:Weight Gain / Q000187:drug effects
chemical_list: D001570:Benzodiazepinones; D005755:Gastrins; D006727:Hormone Antagonists; D010671:Phenylurea Compounds; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; D001569:Benzodiazepines; C087260:YM 022; D006640:Histidine Decarboxylase; C104428:YF 476