Electric spinal cord stimulation (SCS) is widely used as a treatment modality for ischemic pain in peripheral arterial insufficiency. The background for the therapeutic effect may be a temporary inhibition of sympathetically maintained peripheral vasoconstriction. In this series of experiments, the involvement of different types of cholinergic and adrenergic receptor subclasses in the vasodilatory effect was explored in anesthetized rats. The microcirculation in hindlimb skin and hamstring muscle was studied by the laser Doppler technique. The ganglionic blocker hexamethonium as well as the nicotinic receptor antagonist chlorisondamine abolished the effect in both vascular beds, whereas the muscarinic receptor antagonists pirenzepine and atropine were ineffective. Among the adrenergic receptor active compounds, phentolamine, prazosine (an alpha 1-receptor antagonist), and clonidine in high doses suppressed the SCS-induced vasodilation. Yohimbine (an alpha 2-receptor antagonist) did not alter the effect. The beta-adrenergic compounds had a differential effect on muscle and skin perfusion. Atenolol, a beta 1-receptor antagonist, inhibited SCS-induced vasodilation only in the skin, whereas the beta 2-receptor antagonist butoxamine selectively depressed the muscle response. The vasodilatory effect of SCS in the animal model used here seems to a large extent to be mediated by an inhibitory effect on peripheral vasoconstriction maintained via efferent sympathetic activity involving nicotinic transmission in the ganglia and the postganglionic alpha 1-adrenoreceptors. The involvement of beta-receptors seems to be different in skin and muscle, beta 1 being more important for the changes in the skin and beta 2 being more important for those in muscle. The high-intensity antidromic response, earlier believed to explain how SCS exerted its vasodilatory effect, was resistant to cholinergic and adrenergic manipulations and seems to depend on entirely different mechanisms.