Experiments have been conducted to evaluate the effect of neuropeptide Y (NPY) administered at three distinct levels of the nervous system: 1) the posterior hypothalamic nucleus, 2) the spinal cord, and 3) the vascular noradrenergic neuroeffector junction. It was observed that NPY produced varying cardiovascular effects at these three distinct sites of the nervous system. Microinjections into the posterior hypothalamic nucleus resulted in an increase in blood pressure, which was reduced by prior microinjection of a muscarinic or HI-histamine antagonist but not an Ha-histamine antagonist. In addition to the involvement of histaminergic and cholinergic pathways, the pressor effect of NPY appears to result from an increase in sympathetic outflow. NPY was also seen to decrease the potassium-induced release of norepinephrine (NE) from slices obtained from the posterior hypothalamic nucleus. In contrast to what was observed in the hypothalamus, the intrathecal injection of NPY at a level of T4 or TI0 in anesthetized or Tlo in unanesthetized rats resulted in a depressor effect as well as a decrease in heart rate. Both an a2-and P-adrenoceptor antagonist reduced the NPY effect. The depressor effect of intrathecal NPY was attenuated in rats pretreated with reserpine as well as in Spontaneously Hypertensive rats (SHR). These data suggest that the effects of NPY are closely associated with sympathetic preganglionic neurons in the spinal cord. At the vascular noradrenergic neuroeffector junction, NPY decreased the nerve stimulation-induced release of NE while potentiating the contractile response. Moreover, NPY potentiated the increase in perfusion pressure of the perfused mesenteric arterial bed in response to angiotensin, vasopressin, or phenylephrine. The potentiation of smooth muscle contraction produced by NPY was shared by the homologous peptide, peptide YY (PYY) and to a lesser extent, pancreatic polypeptide (PPY). The prejunctional effect of NPY was less and the postjunctional effect greater in SHR compared with that in normotensive rats. The evidence obtained in these studies supports a cotransmitter role of NPY with NE in central and peripheral noradrenergic neurons. Moreover, NPY may be implicated in the development and maintenance of hypertension in the SHR.