Participation of presynaptic noradrenergic fibers in the suppression of alpha 2-adrenoceptor activity by substance P at the nucleus reticularis gigantocellularis of the rat.

We applied reverse microdialysis and high performance liquid chromatography (HPLC) analysis to evaluate the participation of presynaptic noradrenergic neurotransmission in the suppression by substance P (SP) of alpha 2-adrenoceptor activity at the nucleus reticularis gigantocellularis (NRGC) in Sprague-Dawley rats anesthetized with pentobarbital sodium. Microinfusion of SP (600 microM/min) into the NRGC through a stereotaxically positioned microdialysis probe attenuated the hypotensive and bradycardiac actions of the alpha 2-adrenoceptor agonist, guanabenz (100 micrograms/kg, i.v.). This inhibitory effect correlated positively with the time course of elevation in the estimated extracellular concentrations of SP and norepinephrine (NE) in the NRGC. Direct microinfusion of NE (50 nM/min) into the NRGC also lessened the cardiosuppressant effects of guanabenz. These circulatory and NE responses to SP were, however, significantly blunted in rats in which the noradrenergic innervation in the NRGC was depleted with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP4) pretreatment. Microinfusion of NE into the NRGC of DSP4-pretreated animals restored the attenuation of guanabenz-induced cardiovascular suppression. These results suggest that SP may depress the activity of alpha 2-adrenoceptor at the NRGC that are involved in circulatory regulation by increasing the extracellular concentration of NE via a presynaptic modulation of noradrenergic neurotransmission.