Nizatidine is a potent and selective antagonist of histamine. The histamine-induced relaxation of the KCl-treated rat uterus was inhibited dose-dependently by nizatidine. The inhibition was characterized by displacement of the dose-response to histamine to the right, in parallel, without depression of the maximum. The affinity of nizatidine for the histamine H2-receptor of the rat uterus was about 10 times that of cimetidine. The steady-state dose-response acid outputs stimulated by histamine from the Heidenhain pouch and the gastric fistula were also shifted dose-dependently by nizatidine, in parallel, to the right. The inhibition was consistent with a surmountable antagonism of histamine. At high (10(-4) to 10(-3) M) concentrations, nizatidine increased the motility of the guinea pig stomach and duodenum in vitro; this effect was abolished noncompetitively by atropine (10(-8) M) and pyrilamine (10(-4) M). Both nizatidine and cimetidine administered s.c. showed "cytoprotective" action by reducing the gastric lesions induced by 1) aminoguinidine and pylorus ligation and 2) HCl plus aspirin in the rat. On a weight and molar basis, nizatidine was 4 and 5.25 times as effective as cimetidine, respectively. This cytoprotective action of nizatidine was found when acidity and total acid load in the stomach were not affected by the histamine H2-receptor antagonist.