In patients with essential hypertension, the vasodilator response in the forearm circulation to postjunctional alpha 1-adrenoceptor blockade with prazosin is enhanced. Besides the effects at classical postjunctional alpha 1-adrenoceptor, postjunctional alpha 2-adrenoceptor-mediated effects contribute to vascular tone, and these may be comparable in magnitude to those observed with prazosin. Owing to the extrajunctional localization of alpha 2-adrenoceptors, they may be preferential targets for circulating catecholamines and adrenaline in particular. No evidence of autoinhibitory noradrenaline feedback system via prejunctional alpha 2-adrenoceptors was found by measuring noradrenaline release from the forearm. Therefore increased sympathetic nerve activity, as demonstrated by increased plasma adrenaline concentrations, plays an important role in the pathophysiology of essential hypertension by contributing to increased vascular resistance. Central prejunctional alpha 2-adrenoceptor-stimulating drugs lower sympathetic nerve activity and thereby peripheral resistance and blood pressure, and this effect seems to override peripheral (pre-) and postjunctional alpha 2-adrenoceptor-stimulating effects.