Enhancement by KW-5092, a novel gastroprokinetic agent, of the gastrointestinal motor activity in dogs.
KW-5092 ([1-[2-[[[5-(piperidinomethyl)-2- furanyl]methyl]amino]ethyl]-2-imidazolidinylidene) propanedinitrile fumarate) is a novel gastroprokinetic agent with acetylcholinesterase (AChE) inhibitory activity and acetylcholine (ACh) release facilitatory activity. The present study examined the effects of KW-5092 on gastrointestinal (GI) motor activity in dogs. In anesthetized dogs, KW-5092 at 0.03 to 1 mg/kg, i.v. dose-dependently enhanced the gastric antral and the colonic motor activity. Neostigmine, an AChE inhibitor, enhanced the motor activity at 0.03 and 0.1 mg/kg, i.v. Ranitidine, a histamine H2-receptor antagonist with AChE inhibitory activity and ACh release facilitatory activity, enhanced the motor activity but decreased blood pressure at 1 to 10 mg/kg, i.v. In conscious dogs, KW-5092 at 0.03 to 1 mg/kg, i.v. or 1 to 10 mg/kg, p.o. dose-dependently enhanced the gastric antral, duodenal, ileal and the colonic motor activities. Neostigmine at 0.1 mg/kg, i.v. or 3 mg/kg, p.o. enhanced the duodenal, ileal and colonic motor activities, but induced excitement, slavering, vomiting and diarrhea. Ranitidine at 3 mg/kg, i.v. enhanced the gastric antral and colonic motor activities, but induced collapse or akinesia. The present results suggest that KW-5092 enhances the GI motor activity in a wide range from the gastric antrum to the colon and does not induce behavioral and cardiovascular side effects. KW-5092 may be a useful drug for the treatment of GI motility dysfunctions.
Department of Pharmacology, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan.
N
N
Kishibayashi
A
A
Tomaru
S
S
Ichikawa
T
T
Kitazawa
K
K
Shuto
A
A
Ishii
A
A
Karasawa
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D003106:Colon / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004386:Duodenum / Q000187:drug effects; D005260:Female; D005769:Gastrointestinal Motility / Q000187:drug effects*; D007082:Ileum / Q000187:drug effects; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D007275:Injections, Intravenous; D008297:Male; D009388:Neostigmine / Q000008:administration & dosage / Q000494:pharmacology; D009570:Nitriles / Q000008:administration & dosage / Q000494:pharmacology*; D011706:Pyloric Antrum / Q000187:drug effects; D011899:Ranitidine / Q000008:administration & dosage / Q000494:pharmacology; D012119:Respiration / Q000187:drug effects
D002800:Cholinesterase Inhibitors; D007093:Imidazoles; D009570:Nitriles; C081341:KW 5092; D009388:Neostigmine; D011899:Ranitidine; D000109:Acetylcholine