Gastroprokinetic activity of nizatidine, a new H2-receptor antagonist, and its possible mechanism of action in dogs and rats.
We studied the anti-acetylcholinesterase (AChE) activity of a new H2-antagonist, nizatidine, in in vitro experiments and its gastroprokinetic action in the dog and rat in comparison with other H2-antagonists, neostigmine and cisapride. The IC50 of nizatidine for AChE was 6.7 x 10(-6) M, and this activity was reversible. The relative anti-AChE potency was in the following order: neostigmine > nizatidine > cimetidine >> famotidine. The inhibition of AChE by nizatidine was noncompetitive, with a Ki value of 7.4 x 10(-6) M. Gastrointestinal (GI) motility was examined during the interdigestive state in dogs with chronically implanted force transducers. Nizatidine (0.3-3 mg/kg, i.v.) significantly increased the motor index in a dose-dependent manner. It was of interest that the contractile response of the GI tract to nizatidine was similar to the interdigestive migrating contractions-like activity. At the doses used in this study, neither cimetidine nor famotidine had a significant effect on the motor index. Neostigmine at a higher dose of 0.06 mg/kg and cisapride at 0.3 mg/kg were found to stimulate GI contractions. Gastric emptying was determined in rats given phenol red as a liquid test meal. Nizatidine (3 mg/kg, i.p., or above) significantly increased gastric emptying, whereas the other H2-antagonists had no such effect. The ED50 and ED90 values of nizatidine for inhibition of gastric acid secretion were 0.18 and 3.22 mg/kg in dogs, and 2.94 and 19.6 mg/kg in rats, respectively. These findings suggest that nizatidine stimulates GI contractions and accelerates gastric emptying at gastric antisecretory doses.(ABSTRACT TRUNCATED AT 250 WORDS)
Ueki
S
S
Department of Pharmacology, Zeria Pharmaceutical Co., Ltd., Saitama, Japan.
Seiki
M
M
Yoneta
T
T
Aita
H
H
Chaki
K
K
Hori
Y
Y
Morita
H
H
Tagashira
E
E
Itoh
Z
Z
D000818:Animals; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D002927:Cimetidine / Q000494:pharmacology; D004064:Digestive System / Q000187:drug effects; D004068:Digestive System Physiological Phenomena; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D015738:Famotidine / Q000494:pharmacology; D005215:Fasting / Q000502:physiology; D005744:Gastric Acid / Q000378:metabolism; D005746:Gastric Emptying / Q000187:drug effects; D005769:Gastrointestinal Motility / Q000187:drug effects*; D006635:Histamine H2 Antagonists / Q000494:pharmacology; D006801:Humans; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D016567:Nizatidine / Q000494:pharmacology*; D011708:Pylorus / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley
D002800:Cholinesterase Inhibitors; D006635:Histamine H2 Antagonists; D015738:Famotidine; D002927:Cimetidine; D016567:Nizatidine