The effects of the histamine H2-receptor antagonists ranitidine and famotidine on acetylcholine release have been studied in the guinea pig myenteric plexus longitudinal muscle preparation incubated with [3H]-choline. Ranitidine (3 x 10(-5)-3 x 10(-4) M) dose-dependently increased the resting release of acetylcholine and that evoked by electrical stimulation. The effect was present only in strips perfused with 10(-5) M physostigmine. The effect of ranitidine was inhibited by tetrodotoxin and hexamethonium. Famotidine (10(-5)-3 x 10(-4) M) was totally ineffective in modifying both the resting release and that evoked by field stimulation. Ranitidine did not antagonize the inhibitory effect of oxotremorine, which specifically activates negative feedback mechanisms via presynaptic muscarinic receptors.