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 H-2-antagonist, nizatidine, in in vitro experiments and its gastroprokinetic action in the dog and rat in comparison with other H-2-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 much greater than famotidine. The inhibition of AChE by nizatidine was noncompetitive, with a K(i) 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 H-2-antagonists had no such effect. The ED50 and ED90 values of nizatidine for inhibition of gastric acid secretion were 0. 1 8 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. These effects of nizatidine are considered to be due mainly to its anti-AChE activity. Nizatidine may have another new efficacy not found with the other two H-2-antagonists in the stimulation of GI motility.