A significant advance in the field of neurotransmission was made with the discovery of presynaptic release-modulating alpha-adrenoreceptors on noradrenergic nerve terminals. The concept of presynaptic modulation of noradrenaline release developed in parallel with the pharmacological evidence for two subtypes of alpha-adrenoreceptors as defined by a different profile of affinity and relative order of potencies for agonists and for antagonists. The alpha 1-adrenoreceptor is stimulated preferentially by methoxamine and cirazoline and blocked selectively by prazosin or corynanthine. The alpha 2-adrenoreceptor is stimulated preferentially by agonists such as clonidine, TL-99, GHT-933, and UK-14,304, and the responses mediated by these agonists are selectively blocked by the alpha 2-adrenoreceptor antagonist idazoxan. In blood vessels, both the alpha 1- and the alpha 2-adrenoreceptor subtypes are present postsynaptically, where they mediate vasoconstriction, although the alpha 1-adrenoreceptor is the predominant receptor in vascular smooth muscle. Presynaptically on noradrenergic nerve terminals, the stimulation of inhibitory alpha 2-adrenoreceptors reduces the depolarization-evoked release of the transmitter. In most vascular beds, the alpha 1-adrenoreceptor is also the preferentially innervated subtype. In spontaneously hypertensive rats, smooth-muscle alpha 2-adrenoreceptors mediate vasoconstrictor responses to exogenous noradrenaline and to sympathetic nerve stimulation to a greater extent than in the corresponding normotensive Wystar-Kyoto rats, which may point to a pathophysiological role of these alpha 2-adrenoreceptors in hypertension.