Wy-45,727, structurally similar to ranitidine, was characterized in various models to define its gastric acid antisecretory potency and mechanism of action. In vitro it antagonized the histamine-induced 1) positive chronotropism in isolated guinea pig right atria (pA2 = 8.23, Schild coefficient +/- S.E.M. = 1.09 +/- 0.01), and 2) [14C]aminopyrine uptake in rat isolated gastric mucosal cells. It inhibited acid secretion in dogs (p.o.) prepared with innervated gastric pouches (ED50 = 0.2 mg/kg) and in the pylorus-ligated rat (ED50 = 0.43 mg/kg). ED50 values for ranitidine were 0.9 mg/kg (dog) and 9.97 mg/kg (rat). After an 18-hr pretreatment period with doses up to 300 mg/kg p.o., inhibition of acid secretion in the rat barely exceeded 50%, indicating that the duration of action of Wy-45,727 was not excessive. Wy-45,727 appears to be a selective histamine H2 receptor antagonist.