Modulation of Noradrenaline Release by Peripheral Presynaptic α2-Adrenoceptors in Humans

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Abstract
The existence of a functional presynaptic a2-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 tx-adrenoceptor antagonists yohimbine (α2, 1.0 μg/kg/min) and doxazosin (α2, 0.1 μg/kg/min), and during intraarterial infusion of tyra-mine (1.25 μg/kg/min) alone and in combination with either and both a-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 < 0.001) which was reduced by yohimbine (p < 0.01), as well as by doxazosin (p << 0.01), and abolished by the combination of both a-adrenoceptor antagonists (p < 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 < 0.05). This tyramine-induced noradrenaline spillover was further increased by yohimbine (p < 0.01) and by the combination of yohimbine and doxazosin (p < 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 α2-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