Evidence for a presynaptic neuromodulatory effect of atrial natriuretic factor (ANF) has been obtained in rat adrenal pheochromocytoma cells (PC12), a clonal line that differentiates into adrenergic neuron-like cells when treated with nerve growth factor. ANF had no effect on basal norepinephrine (NE) release. In contrast, ANF markedly and significantly inhibited carbachol-induced NE release in a concentration-dependent manner. This result is consistent with the hypothesis that ANF may be an inhibitory neuromodulator.