The present study was undertaken to compare the presynaptic interaction of neuronal noradrenaline uptake inhibitors with imidazoline and phenylethylamine alpha 2-adrenoceptor agonists under two different conditions: at low and high noradrenaline concentrations in the biophase. Isolated mouse vasa deferentia were stimulated with trains of 7 pulses given at 0.2 Hz and the inhibition by the alpha 2-adrenoceptor agonists clonidine, alpha-methylnoradrenaline, and UK-14,304 of twitch responses was measured in the absence and in the presence of either cocaine (12 mumol/l) or desipramine (40 nmol/l). The effects were determined for the first (equivalent to single pulse stimulation) and the last stimulus of each train. Both uptake inhibitors antagonized the presynaptic inhibitory effects of imidazolines (clonidine and UK-14,304) on the last twitch; the effects on the first twitch remained unchanged. In contrast, the uptake inhibitors potentiated the inhibitory effect of the phenylethylamine (alpha-methylnoradrenaline) on both the first and the last twitches. These results support the view that the concentration of noradrenaline in the biophase plays a decisive role in the inhibition by alpha 2-adrenoceptor agonists of the electrically evoked release of noradrenaline. Agonists that are not substrates of neuronal uptake (i.e., clonidine, UK-14,304) become less effective when noradrenaline is present in the biophase while substrates of neuronal uptake (i.e., alpha-methylnoradrenaline) do not. The results argue against the hypothesis that uptake inhibitors interact directly with presynaptic alpha 2-adrenoceptors or act at some link between uptake and receptor sites.