Neurochemical and circulatory effects of fenoldopam were studied in pithed rabbits with electrically stimulated sympathetic outflow and in strips of the rabbit pulmonary artery. In pithed rabbits, fenoldopam (1-30 micrograms/kg/min) decreased the arterial blood pressure. Fenoldopam (3-30 microgram/kg/min) also increased the norepinephrine spillover rate (the rate at which endogenous norepinephrine enters into the plasma after having been released from postganglionic sympathetic nerves) and decreased the [3H]norepinephrine plasma clearance. The selective dopamine (DA)1 antagonist SCH 23390 (bolus injection of 10 micrograms/kg followed by infusion of 2 micrograms/kg/hr) antagonized markedly and the DA2-selective antagonist domperidone (bolus injection of 200 micrograms/kg followed by infusion of 50 micrograms/kg/hr) antagonized slightly the hypotensive effect. The increase in the norepinephrine spillover rate was enhanced after treatment with desipramine. Clonidine (0.3 microgram/kg/min) reduced the spillover of norepinephrine, and this effect was abolished by fenoldopam (30 micrograms/kg/min). In pulmonary artery strips preincubated with [3H]norepinephrine, fenoldopam (10(-7) and 10(-6) M) increased the electrically evoked overflow of tritium. The effect of fenoldopam (10(-6) M) was prevented in the presence of a supramaximal concentration of clonidine (10(-5) M). The results suggest that fenoldopam lowers blood pressure mainly by activation of vascular smooth muscle DA1 receptors. In addition, however, it blocks prejunctional alpha-2 autoreceptors at postganglionic sympathetic axons.