Histamine (HA) was found to be present in the sympathetic nerve terminals of guinea pig hearts and vasa deferentia in our previous study; however, little is known about the functions of this neurogenic HA. In this study, we used guinea pig vasa deferentia to investigate the pre- and post-synaptic functions of HA evoked by different frequencies of sympathetic nerve stimulation. We found that sympathetic nerve stimulation could evoke HA release, which was independent to mast cell degranulator compound 48/80 and mast cell stabilizer cromolyn, but was highly sensitive to Na(+) channel blocker tetrodotoxin and chemical sympathectomy with 6-hydroxydopamine. The neurogenically released HA evoked by 12.5 Hz of nerve stimulation activated only pre-synaptic H(3) receptors and mediated pre-synaptic inhibitory effects, while under 25 or 50 Hz stimulation condition, HA simultaneously activated both pre-synaptic H(3) receptors and post-synaptic H(1) receptors. However, the direct contractile responses evoked by sympathetic HA via H(1) receptors were observed at 50 Hz. HA release and HA-mediated contractile responses upon sympathetic nerve stimulation were significantly inhibited by pre-treatment of histidine decarboxylase inhibitor alpha-fluoromethylhistidine. Furthermore, application of exogenous HA could mimic these pre- and post-synaptic effects. Our findings indicate that HA in sympathetic neurons acts as a neurotransmitter and its functions vary from pre-synaptic inhibition, to post-synaptic facilitation, to direct post-synaptic contractile responses according to sympathetic nerve stimulation frequencies.