Bicarbonate stimulatory action of nizatidine, a histamine H(2)-receptor antagonist, in rat duodenums.
Nizatidine, a histamine H(2)-antagonist, is known to inhibit acetylcholinesterase (AChE) activity and is used clinically as a gastroprokinetic agent as well as the anti-ulcer agent. We examined whether or not nizatidine stimulates duodenal HCO(3)(-) secretion in rats through vagal-cholinergic mechanisms by inhibiting AChE activity. Under pentobarbital anesthesia, a proximal duodenal loop was perfused with saline, and the HCO(3)(-) secretion was measured at pH 7.0 using a pH-stat method and by adding 10 mM HCl. Nizatidine, neostigmine, carbachol, famotidine or ranitidine was administered i.v. as a single injection. Intravenous administration of nizatidine (3-30 mg/kg) dose-dependently increased the HCO(3)(-) secretion, and the effect at 10 mg/kg was equivalent to that obtained by carbachol at 0.01 mg/kg. The HCO(3)(-) stimulatory action of nizatidine was observed at the doses that inhibited the histamine-induced acid secretion and enhanced gastric motility. This effect was mimicked by neostigmine (0.03 mg/kg) and significantly attenuated by bilateral vagotomy and pretreatment with atropine but not indomethacin. The IC(50) of nizatidine for AChE of rat erythrocytes was 1.4 x 10(-6) M, about 12 times higher than that of neostigmine. Ranitidine showed the anti-AchE activity and increased duodenal HCO(3)(-) secretion, similar to nizatidine, whereas famotidine had any influence on neither AChE activity nor the HCO(3)(-) 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 nizatidine and neostigmine, at the doses that increased the HCO(3)(-) secretion. These results suggest that nizatidine increases HCO(3)(-) secretion in the rat duodenum, mediated by vagal-cholinergic mechanism, the action being associated with the anti-AChE activity of this agent.
Mimaki
H
H
Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8414, Japan.
Kawauchi
S
S
Kagawa
S
S
Ueki
S
S
Takeuchi
K
K
D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D001639:Bicarbonates / Q000378:metabolism*; D004386:Duodenum / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D005744:Gastric Acid / Q000378:metabolism; D005769:Gastrointestinal Motility / Q000187:drug effects; D006635:Histamine H2 Antagonists / Q000494:pharmacology*; D006851:Hydrochloric Acid / Q000494:pharmacology; D008297:Male; D016567:Nizatidine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D001639:Bicarbonates; D006635:Histamine H2 Antagonists; D000110:Acetylcholinesterase; D016567:Nizatidine; D006851:Hydrochloric Acid