Modulation of noradrenaline release by peripheral presynaptic alpha 2-adrenoceptors in humans

The existence of a functional presynaptic alpha 2-adrenoceptor that modulates noradrenaline release was studied in 15 volunteers. Noradrenaline spillover was measured in the forearm under basal conditions, during single intraarterial infusions of the alpha-adrenoceptor antagonists yohimbine (alpha 2, 1.0 micrograms/kg/min) and doxazosin (alpha 1, 0.1 microgram/kg/min), and during intraarterial infusion of tyramine (1.25 microgram/kg/min) alone and in combination with either and both alpha-adrenoceptor antagonists. Forearm blood flow (FBF) was measured by plethysmography. Noradrenaline spillover was calculated as the product of FBF and the difference in arterial and venous plasma noradrenaline. The various infusions did not induce systemic hemodynamic effects. Tyramine induced a dose-dependent decrease in FBF (p less than 0.001) which was reduced by yohimbine (p less than 0.01), as well as by doxazosin (p less than 0.01), and abolished by the combination of both alpha-adrenoceptor antagonists (p less than 0.001). During basal conditions noradrenaline spillover was virtually zero, and this was not changed by yohimbine or doxazosin. Local infusion of tyramine increased noradrenaline spillover (p less than 0.05). This tyramine-induced noradrenaline spillover was further increased by yohimbine (p less than 0.01) and by the combination of yohimbine and doxazosin (p less than 0.001). The single infusion of doxazosin only enhanced the tyramine-induced noradrenaline spillover significantly when it was preceded by yohimbine. The present investigation supports the concept of a presynaptic alpha 2-adrenoceptor modulating noradrenaline release from sympathetic nerve endings via a negative feedback mechanism in humans. Stimulation of noradrenaline release might help to reveal this mechanism.