The effects of prazosin and yohimbine on the vasopressor response to sympathetic nerve stimulation, and to i.v. administration of norepinephrine were studied in the pithed rat to ascertain whether prazosin and yohimbine would preferentially block pressure responses due to exogenous versus endogenous alpha-adrenergic receptor activation. Prazosin (3 and 10 micrograms/kg, i.v.) was more effective in blocking the response due to sympathetic nerve stimulation than that due to i.v. norepinephrine. On the other hand, yohimbine (0.3 and 1 mg/kg, i.v.) produced greater inhibition of the i.v. norepinephrine response than the sympathetic nerve stimulation response. Yohimbine at the 0.1 mg/kg dose enhanced the nerve stimulation response while at higher doses the response was either unchanged (at 0.3 mg/kg) or substantially reduced (at 1 mg/kg). In this model, prazosin and yohimbine showed dose-related blocking effects on the pressor response of phenylephrine and clonidine, respectively. The results suggest that prazosin and yohimbine preferentially block the pressor responses of postsynaptic alpha-adrenergic receptor activation due to endogenous and exogenous norepinephrine, respectively. The diverse effects of yohimbine on the sympathetic nerve stimulation response may be due to an action on both the presynaptic (low dose) and postsynaptic (high dose) alpha-2 adrenergic receptors in vascular smooth muscle.