Various compounds with different blocking potencies on histamine H2-receptors were administered to rats both into the carotid (ia) and into the brain ventricles (icv) and their effects on PRL release were evaluated. The drugs were cimetidine, as reference compound, ranitidine, 5 to 7 times as potent, and oxmetidine, 8 to 10 times as potent. PRL was measured in blood samples collected at -15, 0 and +5, +10, +20 and +40 min after treatment. Cimetidine (80 mg/kg) and ranitidine (30 mg/kg), when injected ia as a single bolus, induced prompt increases (P less than 0.01) in PRL. On the contrary, oxmetidine (the most potent H2 antagonist), even at the high dose of 80 mg/kg ia, had no effect on PRL release. When the drugs were given icv (0.2 mumol/rat or 0.8 mumol/rat), none of them caused any significant PRL release. These results suggest that histamine H2-blocking potency is not correlated with PRL release. Furthermore, the PRL-releasing activity of the drugs seems not to be due to any action on the central neural control of PRL secretion. This comparative study shows that it is possible (as with oxmetidine) to achieve complete dissociation of the H2-receptor blocking action from the unwanted PRL-release stimulating effect.