To evaluate the effect of physiologic doses of atrial natriuretic hormone (ANH) on hypertonic saline-induced renin-aldosterone system suppression, nine healthy subjects were studied three times: 1) on a low-salt (LS) diet with a 2 h placebo infusion; 2) on LS with 2 h infusion of human Ser-Tyr28 ANH (0.6 pmol/kg/min)(LS+ANH); and 3) on a high-salt (HS) diet with a 2 h placebo infusion. On each study day during the second hour of infusion, subjects also received 3% saline (0.1 mL/kg/min) infusion. Data from eight subjects were used for analysis because of a sampling error in one subject. During ANH infusion, plasma ANH levels increased about twofold and reached levels similar to ANH levels on HS. Serum sodium increased by 3-4 mEq/L, and serum osmolality increased by 7-8 mOsm/L during 3% saline infusion on all study days. ANH levels remained stable during 3% saline infusion. During the first hour of ANH infusion, plasma renin activity (PRA) decreased by about 24% and aldosterone levels by about 27%. Hypertonic saline caused further suppression of PRA and aldosterone. The extent of the suppression was similar under each condition, and the levels at the end of hypertonic saline infusion reached about 60% of the levels at the beginning of the saline infusion. We conclude that low-dose ANH infusion does not seem to have any major influence on PRA and aldosterone response to hypertonic saline.