Amitriptyline can cause tachycardia and arrhythmia associated with an excessive release of cardiac catecholamines. We have investigated its effects on norepinephrine release from adrenergic nerves by using the dog saphenous vein as a model of the sympathetic neuroeffector junction. Isolated strips of vein were mounted for isometric tension recording or incubated with [3H]norepinephrine and mounted for superfusion, tension recording and the superfusate. Amitriptyline (10(-6); 5 x 10(-6) M) increased the overflow of [3H]norepinephrine but decreased that of [3,4-3H]dihydroxyphenylglycol from electrically stimulated strips. The selective decreased in the overflow of this metabolite indicates that amitriptyline inhibits neuronal uptake. However, the increased overflow of [3H]norepinephrine caused by amitriptyline also occurred when neuronal uptake was blocked by cocaine (3 x 10(-5) M) but was abolished when prejunctional alpha receptors were blockade by phentolamine (10(-5) M). Amitriptyline attenuated the prejunctional inhibitory action of exogenous norepinephrine, this indicates that the drug interacts with prejunctional alpha receptors. Amitriptyline also antagonized the prejunctional inhibitory action of acetylcholine, both in the absence and presence of cocaine and phentolamine. These effects were not due to a nonspecific action of the drug as it did not reduce the prejunctional inhibitory effect of histamine. Thus, amitriptyline can increase the concentration of norepinephrine at the neuroeffector junction by blockade of neuronal uptake and by interacting with prejunctional alpha and muscarinic receptors. Since the cardiac adrenergic nerves also possess these receptors, the results could help to explain the cardiotoxic effects of the drug.