Neuropeptide Y is colocalized with norepinephrine in both central and peripheral noradrenergic neurons. In this study, we examined the regulatory mechanisms of neuropeptide Y on norepinephrine release in the medulla oblongata of rats. Neuropeptide Y inhibited the stimulation-evoked [3H]norepinephrine release in a dose-dependent manner in slices of medulla oblongata of Sprague-Dawley rats (1 Hz, S2/S1 ratio, control, 0.946 +/- 0.040 [+/- SEM], n = 6; neuropeptide Y 1 x 10(-8) M, 0.676 +/- 0.022, n = 6, p less than 0.05; neuropeptide Y 1 x 10(-7) M, 0.589 +/- 0.014, n = 6, p less than 0.05). Neuropeptide Y potentiated inhibition of [3H]norepinephrine release by the alpha 2-agonists UK 14,304 and clonidine. The blockade of alpha 2-adrenergic receptors by RX 781,094 diminished inhibitory effects of neuropeptide Y on norepinephrine release. Pretreatment of pertussis toxin (a toxin that interferes with the coupling of inhibitory receptors to adenylate cyclase) attenuated the suppression of norepinephrine release by neuropeptide Y. In spontaneously hypertensive rats, the inhibitory effect of UK 14,304 and neuropeptide Y on norepinephrine release from the medulla oblongata was significantly less than in age-matched Wistar-Kyoto rats. These results show that neuropeptide Y inhibits norepinephrine release partially mediated by alpha 2-adrenergic receptors and the pertussis toxin-sensitive guanosine triphosphate-binding proteins in rat medulla oblongata. Furthermore, less suppression of norepinephrine release by UK 14,304 and neuropeptide Y in spontaneously hypertensive rats suggests that alpha 2-adrenergic receptors and neuropeptide Y might be involved in the regulation of central sympathetic tone in hypertension.