The role of various bioactive peptides in the control of secretion of hypothalamic somatostatin into the hypophysial portal blood was examined in anesthetized rats. Hypophysial portal blood was withdrawn at a rate of 5.0 microliter/min into a chilled tube through a cannula placed over the stump of the pituitary stalk and segmented every 20 min by air bubbles. Immunoreactive somatostatin (IRS) in the plasma was extracted with acetic acid and acetone and quantified by RIA. Basal levels (mean +/- SE) of plasma IRS in the hypophysial portal blood were 646 +/- 36 and 317 +/- 44 pg/ml in urethane- and pentobarbital-anesthetized rats, respectively. Under urethane anesthesia, injection of synthetic neurotensin into the lateral ventricle at various doses in the range of 0.016--2 microgram/rat caused a significant and dose-related increase of plasma IRS levels in the hypophysial portal blood, and this effect of neurotensin was significantly (P less than 0.05) suppressed by pretreatment with diphenhydramine (1 mg/100 g BW, iv), a histamine receptor blocker. Enhancement of IRS release by neurotensin was also observed in pentobarbital-anesthetized rats. Intraventricular injection of substance P (10 microgram/rat), beta-endorphin (1 and 5 microgram/rat), or [Met5]enkephalin had no effect on the level of somatostatin in the hypophysial portal blood of urethane-anesthetized rats. These results suggest a release of hypothalamic somatostatin into the hypophysial portal blood in response to intraventricular administration of neurotensin, probably by a histaminergic mechanism.