title: Effects of KSG-504, a new cholecystokinin-A-receptor antagonist, on pancreatic exocrine and endocrine secretions in rats.
abstract: The effects of KSG-504 ((S)-arginium (R)-4-[N-(3-methoxypropyl)-N-pentylcarbamoyl]-5-(2-naphthylsulf onyl) pentanoate monohydrate), a new cholecystokinin (CCK)-A-receptor antagonist, on pancreatic exocrine secretion in anesthetized rats and endocrine secretion in conscious rats were studied. Intravenous injection of KSG-504 inhibited the pancreatic amylase output stimulated by intravenous infusion of CCK-8 in a dose-dependent manner (ED50: 18 micrograms/kg/min). Moreover, KSG-504 significantly reduced the CCK-8-stimulated increases in pancreatic juice volume and outputs of protein, trypsin and lipase. Intraduodenal infusion of casein increased the plasma CCK concentration and the pancreatic amylase output. KSG-504 significantly inhibited the pancreatic amylase output stimulated by casein. Pancreatic juice volume and bicarbonate output were significantly stimulated by intravenous infusion of secretin, but were not changed by KSG-504. When pancreatic exocrine secretion was stimulated by secretin plus CCK-8, KSG-504 suppressed the increases in juice volume and bicarbonate output to the level stimulated by secretin alone. Basal pancreatic amylase output was decreased by KSG-504. KSG-504 decreased the level of plasma immunoreactive insulin (IRI) stimulated by glucose plus CCK-8, but had no effect on IRI stimulated by glucose alone and the basal IRI. These in vivo studies suggest that KSG-504 has significant inhibitory effects both on the pancreatic exocrine and endocrine secretion stimulated by CCK, but has no effect on the exocrine secretion stimulated by secretin.
authors.affiliation: Central Research Laboratories, Kissei Pharmaceutical Co., Ltd., Nagano, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Yamazaki
authors.forename: M
authors.initials: M
authors.lastname: Akahane
authors.forename: M
authors.initials: M
authors.lastname: Kobayashi
authors.forename: H
authors.initials: H
authors.lastname: Takeda
authors.forename: Y
authors.initials: Y
authors.lastname: Ajisawa
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D006727:Hormone Antagonists / Q000494:pharmacology*; D008297:Male; D009281:Naphthalenes / Q000494:pharmacology*; D010179:Pancreas / Q000187:drug effects*; D010421:Pentanoic Acids / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*; D012844:Sincalide / Q000097:blood
chemical_list: D006727:Hormone Antagonists; D009281:Naphthalenes; D010421:Pentanoic Acids; D011949:Receptors, Cholecystokinin; C085253:KSG 504; D012844:Sincalide