The effect of the histamine H2-antagonists cimetidine and ranitidine on aminopyrine accumulation stimulated by forskolin was investigated in isolated guinea pig parietal cells. Forskolin (10−5mol/L) caused a 2.2-fold increase in acid production, assessed as [14C]-aminophenazone (aminopyrine) accumulation, and a 19-fold increase in cyclic AMP. The H2-antagonists (10−4mol/L) almost completely inhibited the forskolin-induced aminopyrine accumulation, without affecting the cyclic AMP level. Histamine released by forskolin from contaminated cells into the media was 5.08 ± 0.28 × 10−8mol/L, which was not sufficient to stimulate acid secretion in parietal cells. Therefore, it is suggested that the H2-antagonists may inhibit acid secretion at the step subsequent to the synthesis of cyclic AMP, in addition to antagonism of the histamine receptors.