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

被引:16
作者
Kitano, M [1 ]
Norlén, P [1 ]
Ding, XQ [1 ]
Nakamura, S [1 ]
Hakanson, R [1 ]
机构
[1] Univ Lund, Dept Pharmacol, S-22362 Lund, Sweden
关键词
CCK2 receptor antagonist; ECL cell; histidine decarboxylase (HDC); acid output; gastrin;
D O I
10.1038/sj.bjp.0703342
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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.
引用
收藏
页码:699 / 705
页数:7
相关论文
共 38 条
[1]   Gastric acid secretion after depletion of enterochromaffin-like cell histamine - A study with alpha-fluoromethylhistidine in rats [J].
Andersson, K ;
Cabero, JL ;
Mattsson, H ;
Hakanson, R .
SCANDINAVIAN JOURNAL OF GASTROENTEROLOGY, 1996, 31 (01) :24-30
[2]   GASTRIN RECEPTOR GENES ARE EXPRESSED IN GASTRIC PARIETAL AND ENTEROCHROMAFFIN-LIKE CELLS OF MASTOMYS-NATALENSIS [J].
ASAHARA, M ;
KINOSHITA, Y ;
NAKATA, H ;
MATSUSHIMA, Y ;
NARIBAYASHI, Y ;
NAKAMURA, A ;
MATSUI, T ;
CHIHARA, K ;
YAMAMOTO, J ;
ICHIKAWA, A ;
CHIBA, T .
DIGESTIVE DISEASES AND SCIENCES, 1994, 39 (10) :2149-2156
[3]   CHOLECYSTOKININ IN THE CENTRAL NERVOUS-SYSTEM - A MINIREVIEW [J].
BEINFELD, MC .
NEUROPEPTIDES, 1983, 3 (06) :411-427
[4]  
BEL A, 1996, J MED LYON OCT, P5
[5]   REFLECTIONS ON THE ANALYTICAL PHARMACOLOGY OF HISTAMINE H-2-RECEPTOR ANTAGONISTS [J].
BLACK, J .
GASTROENTEROLOGY, 1993, 105 (04) :963-968
[6]  
CHANG RSL, 1989, MOL PHARMACOL, V35, P803
[7]   Effect of cholecystokinin-2 receptor blockade on rat stomach ECL cells -: A histochemical, electron-microscopic and chemical study [J].
Chen, D ;
Zhao, CM ;
Norlén, P ;
Björkqvist, M ;
Ding, XQ ;
Kitano, M ;
Håkanson, R .
CELL AND TISSUE RESEARCH, 2000, 299 (01) :81-95
[8]   ACUTE RESPONSES OF RAT STOMACH ENTEROCHROMAFFIN-LIKE CELLS TO GASTRIN - SECRETORY ACTIVATION AND ADAPTATION [J].
CHEN, D ;
MONSTEIN, HJ ;
NYLANDER, AG ;
ZHAO, CM ;
SUNDLER, F ;
HAKANSON, R .
GASTROENTEROLOGY, 1994, 107 (01) :18-27
[9]   Time-course of deactivation of rat stomach ECL cells following cholecystokinin(B)/gastrin receptor blockade [J].
Ding, XQ ;
Lindstrom, E ;
Hakanson, R .
BRITISH JOURNAL OF PHARMACOLOGY, 1997, 122 (01) :1-6
[10]   Evaluation of the specificity and potency of a series of cholecystokinin-B/gastrin receptor antagonists in vivo [J].
Ding, XQ ;
Hakanson, R .
PHARMACOLOGY & TOXICOLOGY, 1996, 79 (03) :124-130