The present studies were designed to test the hypothesis that hyperprolactinemia modulates target tissue responsiveness to angiotensin-II (AII). Adrenal and pressor responses to AII infusions were determined in six patients with PRL-secreting pituitary microadenomas and in five normal controls during defined electrolyte balance. Hyperprolactinemic and normal subjects had similar mean blood pressures while on a regular Na intake (82.5 +/- 0.5 vs. 81.2 +/- 0.3 mm Hg). However, after 4 days of Na loading (200 meq/day), the mean blood pressure in hyperprolactinemic subjects was higher than that in normal (86.6 +/- 1 vs. 83.4 +/- 0.8 mm Hg; P less than 0.05). In addition, enhancement of the mean blood pressure response to three doses of AII was noted in hyperprolactinemic subjects (P less than 0.05) compared to that in normal subjects. After 4 days of Na restriction (10 meq/day), the mean blood pressure in hyperprolactinemic subjects was similar to that in normal subjects (79.7 +/- 0.6 vs. 78.9 +/- 1 mm Hg). However, despite adequate Na restriction, the pressor response to AII continued to be enhanced (P less than 0.05) in hyperprolactinemic subjects. There were no differences in plasma or urinary electrolytes or in PRA between hyperprolactinemic and normal subjects. Hyperprolactinemic subjects had higher basal (P less than 0.01), AII-stimulated (P less than 0.05), and ACTH-stimulated (P less than 0.02) aldosterone levels during Na loading, but not during Na restriction. The differences disappeared after the correction of the hyperprolactinemia. The data demonstrate significant alterations in adrenal and pressor responsiveness in hyperprolactinemic subjects and suggest a modulating role for PRL on vascular reactivity and steroid biosynthesis. The precise mechanism has not been determined, but may be secondary to PRL-induced up-regulation of adrenal and vascular AII receptors.