Epinephrine, substance P, and glutamate have all been hypothesized as primary chemical mediators in the descending pathway from the brain stem "vasomotor center" to SPNs. Interestingly, lesions of or antagonists to epinephrine, substance P, glutamate, and 5-HT neurons all abolish sympathetic activity and reduce blood pressure to a level similar to that in a spinal-transected animal. However, it is unlikely that all these substances are primary mediators of sympathetic information carried from the brain stem to the spinal cord. How then do we resolve these findings? A plausible explanation is that monoamines and neuropeptides act in the IML, as in other areas of the central nervous system, as neuromodulators, setting the level of excitability of SPNs rather than relaying sympathetic information over a functionally specific pathway from brain stem sympathetic neurons to the IML. For example, the time course of the norepinephrine-mediated slow EPSPs and IPSPs in SPNs is consistent with a gain-setting function. Likewise, the depolarization of SPNs by 5-HT is similar to the depolarization elicited in myenteric and celiac ganglion cells. In these ganglia, 5-HT appears to mediate a slow excitatory potential that enhances incoming fast synaptic potentials. A similar gain-enhancing effect of 5-HT has been demonstrated in facial motoneurons. By analogy, epinephrine is likely to act as a neuromodulator in the IML rather than to serve as the primary mediator of sympathetic information descending from the brain stem. Similarly, it is difficult to imagine that an agent with such a long duration of excitatory action as substance P could serve as the primary descending transmitter in a system where moment to moment changes in activity are essential. It is more likely that substance P aids in setting the excitability of SPNs. Pharmacological antagonism of any of the excitatory neuromodulators (i.e. gain setters) might act to decrease, at least temporarily, the excitability of SPNs to the point where primary sympathetic activity from the brain stem could not excite SPNs. This accounts for the wide variety of pharmacological agents that act to eliminate sympathetic activity and drastically reduce blood pressure. On the basis of the above arguments, the most logical candidate for a transmitter mediating primary excitatory sympathetic information from brain stem "vasomotor centers" would be an excitatory amino acid. Fast EPSPs in SPNs appear to be mediated by glutamate and excitatory amino acid antagonists markedly inhibit sympathetic activity.(ABSTRACT TRUNCATED AT 400 WORDS)