The effects of neuropeptide Y (NPY) on systemic arterial blood pressure and heart rate were studied in anesthetized intact and pithed rats. I.v. doses of NPY (0.3-30 nmol/kg) raised the mean arterial blood pressure dose dependently. At doses of greater than or equal to 3.0 nmol/kg, the initial pressor response was followed by a dose-dependent fall in blood pressure in intact and pithed rats. The depressor response was accompanied 1-2 min after the NPY injection by a slight increase in heart rate in pithed rats but not in intact rats, and 10 min after the injection by a decrease in heart rate in intact rats. After repeated injections of NPY, the depressor effect vanished, whereas the integrated pressor response over time was markedly enhanced. After pretreatment with the histamine H1-receptor antagonist, mepyramine, or with the histamine liberator, compound 48/80, the pressor response to NPY remained but the depressor response disappeared. We suggest that the marked fall in blood pressure can be attributed to NPY-evoked histamine release from mast cells.