The purpose of these studies was to investigate whether the central nervous system (CNS) can modulate the plasma level of atrial natriuretic factor (ANF). In anesthetized, spontaneously breathing rats, electrical stimulation was stereotaxically applied bilaterally to four medullary nuclei: 1) the rostral nucleus of the solitary tract (rNTS), 2) the intermediate portion of the NTS (iNTS), 3) the ventrolateral nucleus ambiguus (NA) 0.3 mm rostral to obex, and 4) the rostral ventrolateral medulla (RVL). Electrical stimulation of the rNTS and RVL caused a 55 +/- 18% (P < 0.025, n = 6) and 187 +/- 80% (P < 0.001, n = 5) increase in plasma ANF, respectively, compared with baseline (56-88 pg/ml), whereas sham stimulations had no effect on plasma ANF release. In contrast, electrical stimulation of the iNTS and the NA elicited a 35 +/- 6 (P < 0.01, n = 7) and 31 +/- 6% (P < 0.05, n = 5) decrease in plasma ANF, respectively. In artificially ventilated rats, unilateral electrical stimulation of the RVL induced a 94 +/- 39 (left RVL, n = 6, P < 0.01) and 186 +/- 68% (right RVL, P < 0.01, n = 5) increase in plasma ANF over baseline. Unilateral microinjection of L-glutamate into RVL also resulted in a 81 +/- 23% (n = 9, P < 0.01) increase in plasma ANF compared with baseline and vehicle control injections. These results suggest that activation of the central sympathetic system potently stimulates the secretion of cardiac ANF.