Low frequencies of renal sympathetic nerve stimulation increase renal tubular sodium reabsorption without causing renal hemodynamic changes. We tested the hypothesis that the natriuretic responses to synthetic atrial peptides (atriopeptin III [APIII], 24 amino acids) are modulated by the renal tubular actions of the renal nerves. Responses to intravenous infusions of APIII (0.5 and 2.0 micrograms/kg/min) were examined in three groups of chloralose-anesthetized rats. Bilateral renal function studies were done in all three groups in which the right kidney was denervated and the left kidney was either left innervated (group I, n = 10) or the distal portion of the transected left renal nerves was stimulated at 15 V, 1 msec, and 0.5 Hz (group II, n = 8) or 1.0 Hz (group III, n = 8). In groups I, II, and III, diuretic and natriuretic responses to APIII were significantly (p less than 0.05) less in the kidneys with intact innervation or low-frequency (0.5 and 1.0 Hz) renal nerve stimulation than in the denervated kidneys. In conclusion, renal excretory responses to APIII are substantially modulated by the renal tubular actions resulting from low-frequency renal nerve stimulation. We speculate that the decrease in renal excretory responses to atrial peptides in pathophysiologic states such as congestive heart failure, nephrotic syndrome, and cirrhosis may result in part from an increase in the prevailing level of renal sympathetic nerve activity.