Atrial natriuretic peptide (ANP), released upon pulmonary vasoconstriction, modulates pulmonary vascular tone through an increase of cellular guanosine 3',5'-cyclic monophosphate. In patients with cardiopulmonary disease, however, the plasma levels of ANP are relatively low, considering the high pulmonary arterial pressure. To evaluate the release mechanism of the hormone, plasma ANP levels were studied by the manipulation of right atrial stretch with different body postures. In healthy young subjects, the plasma ANP concentration significantly increased when posture changed from an upright to a supine position (p < 0.01). In contrast, plasma ANP concentrations were significantly higher in patients with chronic obstructive pulmonary disease and elderly subjects (p < 0.01), but the plasma levels did not increase upon the change in posture. Consistent with in vitro findings, the data indicate that chronic ANP stimulation attenuates the secretory response to acute stimuli. In addition, it was demonstrated that the ratio of guanosine 3',5'-cyclic monophosphate to ANP, reflecting the biologic effect of the hormone, was significantly lower in patients with chronic obstructive pulmonary disease as well as in the elderly (p < 0.05). This decreased biologic activity aggravated the blunted ANP response and may contribute to the development of pulmonary hypertension.