Noradrenaline release evoked by a physiological irregular sympathetic discharge pattern is modulated by prejunctional alpha- and beta-adrenoceptors in vivo.

1. Sympathetic nerve stimulation-evoked overflow of endogenous noradrenaline (NA) and vasoconstriction were studied in canine blood-perfused gracilis muscle in situ. Nerves were stimulated at an average frequency of 2 Hz (240 pulses, 120 s) with impulses derived from a recording of the normal irregular sympathetic discharge to human skeletal muscle, with regular bursts of impulses, or with the conventional continuous stimulus mode. 2. Variations in impulse activity were closely paralleled by changes in vascular tone. However, all stimulation patterns evoked the same integrated NA overflow and the same degree of vasoconstriction. 3. Blockade of beta-adrenoceptors by propranolol (0.5 mg kg-1 i.v.) significantly reduced NA overflow and vasoconstriction evoked both by continuous and irregular nerve stimulation, by approximately 15-20%. 4. The enhancement of NA overflow following alpha-adrenoceptor blockade by phenoxybenzamine (0.5 mg kg-1 local i.a.) was significantly greater when evoked by continuous than by irregular nerve discharge (24 vs 14 fold). Effects were similar with irregular and regular burst activity. Half of this enhancement has been shown to be due to blockade of neuronal uptake of NA by phenoxybenzamine. Vasoconstrictor responses to all stimulation patterns were similarly reduced, but not abolished, by phenoxybenzamine. 5. The normal irregular sympathetic discharge seems to evoke a similar integrated NA release and equally pronounced vasoconstriction as stimulation with regular bursts or at constant frequency. We provide additional evidence for a physiological prejunctional alpha-adrenoceptor-mediated inhibition of NA release. This mechanism may be influenced by the discharge pattern. Also prejunctional beta-adrenoceptors seem to modulate NA release under physiological conditions. However, the alpha-adrenoceptor-mediated mechanism is quantitatively more important.