Gastroprokinetic activity of nizatidine, a new H2-receptor antagonist, and its possible mechanism of action in dogs and rats

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 264; no. 1; pp. 152 - 157
• Main Authors: UEKI, S, SEIKI, M, YONETA, T, AITA, H, CHAKI, K, HORI, Y, MORITA, H, TAGASHIRA, E, ITOH, Z
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Pharmacology and Experimental Therapeutics 01.01.1993
• Subjects: Animals; Biological and medical sciences; Cholinesterase Inhibitors - pharmacology; Cimetidine - pharmacology; Digestive system; Digestive System - drug effects; Digestive System Physiological Phenomena; Dogs; Dose-Response Relationship, Drug; Famotidine - pharmacology; Fasting - physiology; Gastric Acid - secretion; Gastric Emptying - drug effects; Gastrointestinal Motility - drug effects; Histamine H2 Antagonists - pharmacology; Humans; Male; Medical sciences; Motor Activity - drug effects; Nizatidine - pharmacology; Pharmacology. Drug treatments; Pylorus - physiology; Rats; Rats, Sprague-Dawley; Fissipedia; Carnivora; Motility; Intravenous administration; Rat; Serotonin antagonist; Rodentia; Antiulcer agent; Gastrointestinal; Vertebrata; Mammalia; H2 receptor; Animal; Anticholinesterase agent; Mechanism of action; Dog
• ISSN: 0022-3565; 1521-0103

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.