The effects of cocaine on responses to supramaximal concentrations of agonists have been studied in preparations of rat vas deferens. Cocaine 10 muM decreased the mean time to peak and increased the mean magnitude of responses to noradrenaline but not to supramaximal field stimulation of sympathetic fibres, to high potassium or to methoxamine. Diphenydramine 10 muM affected responses to noradrenaline similarly. It is proposed that the prejunctional action of cocaine and of diphenhydramine to reduce the rate of neuronal uptake of noradrenaline may provide a sufficient explanation for the enhanced reactivity of the vas deferens to noradrenaline, as this would allow an increased rate of rise of amine concentration at the receptors. Cocaine also enhanced the reactivity of the vas deferens to acetylcholine. The basis of this enhancement by cocaine of the reactivity of the vas deferens to acetylcholine remains to be established, but clearly is not mediated postjunctionally since responses to carbachol were not similarly affected.