The contractile responses to transmural stimulation of, and the overflow of tritium from the rat portal vein prelabelled with 3H-noradrenaline were studied. The contractile responses of the rat portal vein were sustained throughout the period of stimulation. The tension developed did not decline when two consecutive periods of stimulation were compared. In contrast, the tritium overflow decreased during the second period of stimulation. Preincubation with 3 micronM phenoxybenzamine during 30 min increased 3-fold the tritium overflow during stimulation. Phentolamine and phenoxybenzamine were nearly equipotent in reducing the vascular response to stimulation. In contrast, phentolamine was less potent than phenoxybenzamine in increasing the 3H-noradrenaline overflow elicited by stimulation. The results obtained with phentolamine are interpreted in terms of a different potency of phentolamine to produce blockade of prejunctional and postjunctional alpha-adrenoceptors in the rat portal vein. ATP inhibited by 70% the tritium overflow induced by stimulation. The potency of ATP in inhibiting the overflow increased when the prejunction alpha-adrenoceptors were blocked. The purine compounds ATP, ADP, AMP and adenosine were roughly equipotent in inhibiting stimulation-induced tritium overflow. The tritium released by stimulation decreased when uptake and metabolism of adenosine were inhibited. Under physiological conditions, a prejunctional purinergic inhibition of noradrenaline release might be involved in an endogenously mediated negative feed-back regulatory mechanism. It is possible that the purinergic inhibition of the noradrenaline liberation elicited by stimulation plays a physiological role in tissues with both purinergic and adrenergic innervation.