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Under non-exercise conditions, atrial natriuretic peptide (ANP) elevation suppresses plasma renin activity (PRA) and aldosterone (PA). A similar effect of ANP on PRA-PA during exercise has been suggested but not demonstrated. We measured ANP, PRA, PA, plasma potassium (K+), and changes in plasma volume (PV) and blood volume (BV) at rest and during incremental cycle ergometer exercise to exhaustion in ten healthy males. Plasma concentrations (X ± SE) of hormones and electrolytes increased (P < 0.05) during exercise: ANP (68 ± 14 to 207 ± 48 pg·ml−1), PA (11.2 ± 2.2 to 18.8 ± 3.4 ng·dl−1), PRA (5.1 ± 1.1 to 8.2 ± 1.6 ng·ml−1 −90 min−1), and K+ (4.2 ± 0.1 to 5.5 ± 0.1 mEq). PV and BV declined, reaching maximal deflections from baseline during the 100% stage (12.9 ± 1.5 and 8.4 ± 0.8% decreases, respectively). There were positive correlations between ANP and PRA (r = 0.58; P < 0.01), ANP and PA (r = 0.56; P < 0.01), and PRA and PA (r = 0.80; P < 0.001). Increases in K+ did not correlate with increases in PA. The fall in PV correlated with elevations in PRA (r = −0.67; P < 0.01) and PA (r = −0.58; P < 0.01), and the fall in BV correlated with elevations in PRA (r = −0.62; P < 0.01) and PA (r = −0.44; P < 0.02). ANP production was related to exercise intensity (gauged by heart rate response; r = 0.58; P < 0.01). In conclusion, vigorous exercise induces increases in ANP, PRA, and PA, with no ANP suppression of the PRA-PA axis noted, although suppression could be masked by the complex interplay of various stimulators of PRA and PA during exercise. These systems appear to be responding to independent stimuli: ANP to increases in venous return, with consequent atrial distention and increases in heart rate; PRA-PA to decreases in PV and BV, decreases in renal perfusion pressure, and increases in sympathetic activity.