Effects of pyroxamidine and guanethidine on contractile responses to field stimulation and to noradrenaline in the anococcygeus muscle and vas deferens of the rat

The effects of pyroxamidine (EMD 21192) and guanethidine on contractile responses were studied in the anococcygeus muscle and vas deferens of the rat. Pyroxamidine (10^?6 and 10^?5 M) and guanethidine (6 times 10^?6 and 10^?5 M) potentiated the responses to low concentrations of acetylcholine in the rat anococcygeus muscle. Following incubation of the muscle with 6-hydroxydopamine (10^?3M for 3 h), pyroxamidine (10^?5 M) and guanethidine (10^?5 M) had no effect on responses to acetylcholine. This suggests that the potentiating effect of pyroxamidine and guanethidine on responses to acetylcholine is due to the release of subthreshold concentrations of noradrenaline. In the anococcygeus, pyroxamidine (10^?6 and 10^?5 M) and guanethidine (10^?6 and 10^?5 M) inhibited responses to field stimulation and potentiated responses to exogenously applied (?)-noradrenaline. The responses to field stimulation in the vas deferens were also inhibited by 10^?5M pyroxamidine and by 10^?5 M guanethidine. 10^?6 M guanethidine, but not 10^?5 M pyroxamidine, potentiated responses to (?)-noradrenaline in the vas deferens. In the presence of nortriptyline (10^?6 M), a potent inhibitor of neuronal uptake, the inhibitory effects of pyroxamidine and guanethidine on responses to field stimulation were reduced or reversed and these drugs had no effect on responses to (?)-noradrenaline. This suggests that pyroxamidine is a noradrenergic neuron blocker and that its action is dependent on continued neuronal uptake. Following 6-hydroxydopamine incubation, 10^?5 M pyroxamidine and 10^?5 M guanethidine inhibited the responses to (?)-noradrenaline in the rat anococcygeus muscle. Thus it seems likely, at high concentrations, that these compounds have postsynaptic blocking activity.