Arginine-vasopressin (AVP) seems to be involved in the histamine (HA)- and stress-induced release of ACTH and β-endorphin (β-END). We studied the effect of selective AVP V₁- or V₂-receptor blockade on the ACTH and β-END response to HA or restraint stress in conscious male rats. HA (270 nmol) administered intracerebroventricularly or 5 min of restraint stress caused a 3-to 7-fold increase in the plasma levels of ACTH and β-END immunoreactivity (β-ENDir). Pretreatment of the animals with the nonselective V₁₊₂-receptor antagonist [l-Pmp-2-Z)-Phe-4-Ile-8-Arg]vasopressin, which was administered intravenously in a low (23 nmol) or a high dose (90 nmol) inhibited the HA-or restraint stress-induced secretion of ACTH and β-ENDir 60 and 25-70%, respectively. Pretreatment with equipotent doses of the selective V₁-receptor antagonist [l-(p-tBu)Pmp-2-Tyr(0-Me)-8-D-Arg]vasopressin (25 nmol) and/or the selective V₂-receptor antagonist [l-Pmp-2-D-IIe-4-Ile-8-Arg]vasopres-sin (7.0 nmol) attenuated the response of ACTH and β-ENDir to HA or restraint stress by 60-80 and 40-60%, respectively. In general, these doses of antagonists had no effect on basal hormone levels. We conclude that AVP takes part in the mediation of HA- and restraint stress-induced ACTH and β-END secretion. This effect seems to be mediated via both AVP V₁ and V₂-receptors or a less selective receptor with ligand specificity for both V₁- and V₂-receptor antagonists.