The present experiments were performed to determine whether digitalis-induced augmentation of cardiac receptor discharge could induce reflex reductions in renal sympathetic nerve activity. Intracoronary injection or epicardial application of acetylstrophanthidin (AS) in chloralose-anesthetized dogs caused large decreases in renal sympathetic nerve activity which were accompanied by modest decreases in heart rate and arterial pressure. Vagotomy prevented these reflex responses. Cholinergic blockade with atropine markedly attenuated the heart rate responses to AS but had little effect on the arterial pressure or renal nerve activity responses. Epicardial application of lidocaine blocked cardiac vagal afferents and the reflex responses to intracoronary AS. In sinoaortic denervated dogs, the relationships between doses of AS and mean arterial pressure, heart rate, and renal nerve activity responses were linear. Decreases in renal nerve activity were evoked by doses of AS which did not reflexly change heart rate or arterial pressure. These data show that AS can evoke reflex bradycardia, hypotension, and withdrawal of renal sympathetic nerve activity solely by augmenting the inhibitory influence of cardiac receptors with vagal afferents. This reflex effect may contribute to the changes in renal function and thus to the diuresis that occurs when heart failure is treated with digitalis. Ore Res 44: 8-15, 1979