4-Aminopyridine, a K+ channel blocker, evoked phasic contractions in the caudal duct of the rat epididymis. The 4-aminopyridine-induced contractile response was either inhibited or prevented by the alpha 1-adrenoceptor antagonists, prazosin (IC50 = 2.7 nM) and benoxathian (IC50 = 14.6 nM). Blockers (1 microM) of alpha 2-adrenoceptors and purinoceptors but not of beta-adrenoceptors or muscarinic receptors caused a small but statistically significant reduction of the 4-aminopyridine-induced response. 4-Aminopyridine lost its ability to induce contractions after noradrenergic nerves had been destroyed by 6-hydroxydopamine. In addition, protriptyline and xylamine, blockers of noradrenaline uptake, also inhibited the 4-aminopyridine-induced contractile response. However, other putative K+ channel blockers (tetraethylammonium ion, quinine, quinidine and glibenclamide) did not cause the muscle to contract. These findings demonstrate that the 4-aminopyridine-induced release of noradrenaline and adenosine 5'-triphosphate as co-transmitters results from membrane depolarization due to 4-aminopyridine blockade of K+ channels in noradrenergic nerve terminals. The 4-aminopyridine-sensitive K+ channels might thus play a physiological role in regulating the nerve membrane potential and neurotransmission in the rat caudal epididymis.