L-365,260, a potent CCK-B/gastrin receptor antagonist, suppresses gastric acid secretion induced by histamine and bethanechol as well as pentagastrin in rats.
We evaluated the effects of a potent cholecystokinin (CCK)-B/gastrin receptor antagonist, L-365,260 (3R(+)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin - 3-yl)-N'-( 3-methylphenyl) urea); a selective CCK-A receptor antagonist, devazepide (L-364,718); and cimetidine on gastric acid secretion induced by pentagastrin, histamine and bethanechol in anesthetized rats. We also evaluated the effects of L-365,260 and cimetidine on acid secretion in pylorus-ligated rats. Intravenous administration of L-365,260, L-364,718 and cimetidine dose-dependently reduced acid secretion induced by pentagastrin (20 nmol/kg/hr), with ED50 values of 0.63, 19.1 and 2.5 mumol/kg, respectively. Of interest was the finding that L-365,260, like cimetidine, dose-dependently inhibited acid secretion induced by histamine (100 mumol/kg/hr) and bethanechol (5 mumol/kg/hr) with ED50 values of 5.9 and 4.3 mumol/kg, respectively. L-364,718, even at 30 mumol/kg, i.v., had only a slight effect on histamine- or bethanechol-induced acid secretion. Gastric acid secretion was suppressed by treatment with L-365,260 (3-100 mumol/kg, i.v.) and cimetidine (11.9-396.4 mumol/kg, i.v.) in pylorus-ligated rats, with ED50 values of 13.3 and 96.9 mumol/kg, respectively. These results indicate that L-365,260 suppresses acid secretion induced by histamine and bethanechol in rats and that the gastrin receptor plays an important role in acid secretion in pylorus-ligated rats.
Medicinal Research Laboratories I, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan.
A
A
Nishida
H
H
Yuki
R
R
Tsutsumi
K
K
Miyata
T
T
Kamato
H
H
Ito
M
M
Yamano
K
K
Honda
D000818:Animals; D001570:Benzodiazepinones / Q000008:administration & dosage / Q000494:pharmacology*; D018723:Bethanechol; D001626:Bethanechol Compounds / Q000008:administration & dosage / Q000494:pharmacology; D002927:Cimetidine / Q000008:administration & dosage / Q000494:pharmacology; D020109:Devazepide; D004305:Dose-Response Relationship, Drug; D005745:Gastric Acidity Determination; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism*; D006632:Histamine / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D010418:Pentagastrin / Q000008:administration & dosage / Q000494:pharmacology; D010477:Perfusion; D010671:Phenylurea Compounds; D051381:Rats; D011919:Rats, Inbred Strains; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*
D001570:Benzodiazepinones; D001626:Bethanechol Compounds; D010671:Phenylurea Compounds; D011949:Receptors, Cholecystokinin; D018723:Bethanechol; C058121:L 365260; D002927:Cimetidine; D006632:Histamine; D010418:Pentagastrin; D020109:Devazepide