Tricyclic antidepressants cause orthostatic hypotension and have antiarrhythmic effects that may be partially due to effects on the sympathetic nervous system. We studied the influence of intravenous desipramine hydrochloride on renal (n = 12) and lumbar (n = 5) nerve traffic and mean arterial pressure in alpha-chloralose-anesthetized rabbits with sinoaortic and vagal denervation. Desipramine administration resulted in dose-dependent inhibition of renal and lumbar nerve activity that was markedly reduced or abolished by yohimbine (0.5 mg/kg iv), an alpha 2-blocker that enters the brain rapidly. In contrast, administration of phentolamine (0.75 mg/kg iv), an alpha 1- and alpha 2-blocker with limited access to the brain, failed to alter the responses to desipramine. Because renal nerves are postganglionic and lumbar nerves are preganglionic, desipramine does not act via a ganglionic mechanism. Our results are best explained by an effect of desipramine on the sympathetic nervous system mediated via central alpha 2-receptors. This sympathoinhibitory effect of desipramine may contribute to its postural hypotensive effect and to its efficacy as an antiarrhythmic agent.