Bicarbonate stimulatory action of nizatidine, a histamine H-2-receptor antagonist, in rat duodenums

Nizatidine, a histamine H-2-antagonist, is known to inhibit acetylcholinest erase (AChE) activity and is used clinically as a gastroprokinetic agent as well as the anti-ulcer agent. We examined whether or not nizatidine stimul ates duodenal HCO3- secretion in rats through vagal-cholinergic mechanisms by inhibiting AChE activity. Under pentobarbital anesthesia, a proximal duo denal loop was perfused with saline, and the HCO3- secretion was measured a t pH 7.0 using a pH-stat method and by adding 10 mM HCl. Nizatidine, neosti gmine, carbachol, famotidine or ranitidine was administered i.v. as a singl e injection. Intravenous administration of nizatidine (3-30 mg/kg) dose-dep endently increased the HCO3- secretion, and the effect at 10 mg/kg was equi valent to that obtained by carbachol at 0.01 mg/kg. The HCO3- stimulatory a ction of nizatidine was observed at the doses that inhibited the histamine- induced acid secretion and enhanced gastric motility. This effect was mimic ked by neostigmine (0.03 mg/kg) and significantly attenuated by bilateral v agotomy and pretreatment with atropine but not indomethacin. The IC50 of ni zatidine for AChE of rat erythrocytes was 1.4 x 10(-6) M, about 12 times hi gher than that of neostigmine. Ranitidine showed the anti-AchE activity and increased duodenal HCO3- secretion, similar to nizatidine, whereas famotid ine had any influence on neither AChE activity nor the HCO3- secretion. On the other hand, duodenal damage induced by acid perfusion (100 mM HCl for 4 h) in the presence of indomethacin was significantly prevented by nizatidi ne and neostigmine, at the doses that increased the HCO3- secretion. These results suggest that nizatidine increases HCO secretion in the rat duodenum , mediated by vagal-cholinergic mechanism, the action being associated with the anti-AChE activity of this agent. (C) 2001 Elsevier Science Ltd. All r ights reserved.