The effects of an oral water load and iv administration of isotonic glucose, hypertonic saline, mannitol and furosemide on release of human atrial natriuretic peptide (hANP) were examined in normal subjects to determine the main factors causing its release. In addition, the influence of age on hANP secretion was investigated. The mean plasma hANP level in normal subjects, 0\p=n-\89 years old, was 20.6 \m=+-\1.1 ng/l (mean \m=+-\sem) and showed age-related change. The plasma hANP level did not change significantly after a water load or infusion of isotonic glucose, but rose significantly from 11.4 \m=+-\1.4 to 15.6 \m=+-\3.2 ng/l after infusion of hypertonic saline and from 10.9 \m=+-\1.6 to 17.8 \m=+-\ 4.1 ng/l after infusion of 20% mannitol in parallel with the increase in plasma volume. The plasma hANP level decreased from 17.3 \ m=+-\2.5 to 9.0 \ m=+-\2.5 ng/l after injection of 40 mg of furosemide. A positive correlation was found between change in the plasma hANP level and percent change in the plasma volume (P < 0.001) on these treatments. The response of plasma hANP to hypertonic saline infusion was greater in older than in young men. These results indicate that 1) the secretion of hANP shows an age-related change and 2) increase in the circulating plasma volume is an important factor regulating hANP secretion.-, ß-and -human atrial natriuretic peptides (h AN ) were first isolated from human atria by Kangawa and coworkers (Kangawa & Matsuo 1984; Kangawa et al. 1985). -hANP, consisting of 28 amino acids, has been shown to have potent diuretic, natriuretic and vasorelaxant actions in man (Richards et al. 1985). Radioimmunoassays of plasma hANP have been developed by several groups including us (Nishiuchi et al. 1986) and used to measure the plasma hANP concentrations in normal subjects and patients with various di¬ seases (Hasegawa et al. 1986;Tikkanen et al. 1985). We previously reported that patients with congestive heart failure, renal failure and liver cirrhosis had higher concentrations of plasma hANP than normal subjects (Nishiuchi et al. 1986). It was also reported that hANP is secreted in response to volume expansion owing to isotonic saline infusion (Ogihara et al. 1986), but that other factors regulating ANP secretion were not fully known. There are some reports on the relation between age and plasma hANP concen¬ tration, in children (Weil et al. 1986) and in adults (Ohashi et al. 1987a,b). Therefore, in this work we examined the effects of plasma volume, plasma osmolality and serum sodium concentration on hANP secretion in normal subjects by measuring the plasma hANP concentration after intravenous infusion of isotonic glucose, hypertonic saline or mannitol and after a bolus injection of furosemide. In addition, we measured the plasma levels of hANP in young and older men in the basal state and after infusion of hypertonic saline.