In vitro studies have shown that glucocorticoids may increase atrial natriuretic-hormone (ANH) synthesis and/or release. This action of glucocorticoids has also been suggested in vivo in patients with Cushing's syndrome. However, in this circumstance, plasma AH elevation might be due to humoral disturbances associated with cortisol overproduction. We studied 16 patients with endogenous hypercorticism and 11 of them after successful treatment. Plasma levels of ANH, plasma renin activity (PRA), aldosterone, desoxycorticosterone (DOC), angiotensin II (AII), cortisol, osmolarity, sodium and potassium, urinary free cortisol (UFC), and blood pressure were measured. Before treatment the mean plasma ANH concentration in patients with Cushing's syndrome was significantly higher than in controls (11.3 +/- 2.6 vs. 4.9 +/- 2.3 pmol/l; p less than 0.001). ANH was correlated with cortisol and UFC (r = 0.715, r = 0.700; p less than 0.05). There was no significant correlation between plasma ANH, PRA, aldosterone, DOC, AII, osmolarity, sodium or blood pressure. After recovery, ANH concentration decreased in all patients and was not different from that of normal subjects (4.9 +/- 2.3 vs. 4.3 +/- 2.6 pmol/l). These results suggest that in Cushing's syndrome, ANH secretion is mainly dependent on the severity of hypercortisolism and independent of the other associated disturbances that we studied.