Peripheral alpha 2 adrenoceptor stimulation contributes to the sympatholytic effect of guanfacine in humans

Guanfacine 3 mg was infused into six volunteers over 1 h on two occasions to investigate whether its sympatholytic effect is centrally or peripherally mediated. On one occasion, the central effects of guanfacine were blocked by prior administration of idazoxan 0.2 mg/kg i.v. (45 min preguanfacine); central alpha 2-blockade was confirmed by inhibition of the guanfacine-induced rise in plasma growth hormone. Rapid disappearance of idazoxan from the circulation prevented antagonism of peripheral alpha 2 receptor effects of guanfacine (confirmed by suppression of plasma insulin by guanfacine on both occasions). Idazoxan elevated plasma noradrenaline concentration by 0.26 +/- 0.018 ng/ml; however, guanfacine caused a similar (approximately 30%) reduction in plasma noradrenaline after both idazoxan and vehicle. Idazoxan elevated systolic and diastolic blood pressure, but no change was observed after guanfacine on either occasion. Thus, the reduction in plasma noradrenaline caused by guanfacine appears to be peripherally mediated but is not due to baroreceptor activation. This is consistent with stimulation of presynaptic alpha 2 receptors.