To evaluate direct secretion from the left atrium and pulmonary extraction of human atrial natriuretic peptide (hANP), we measured plasma hANP levels in the pulmonary artery, pulmonary vein, and left atrium in patients with either mitral stenosis or atrial septal defect. Left atrial pressure in patients with mitral stenosis was significantly higher than that in patients with atrial septal defect (7.5 +/- 1.0 mm Hg vs 3.1 +/- 0.5 mm Hg, p less than 0.01). The significant increase in the hANP level in the left atrium was recognized only in patients with mitral stenosis (149 +/- 33 pg/ml in the left atrium vs 130 +/- 28 pg/ml in the pulmonary vein, p less than 0.05). The plasma hANP level in the pulmonary vein was significantly lower than that in the pulmonary artery in both patients with mitral stenosis and those with atrial septal defect, which suggests that hANP is extracted in the lung. We conclude that hANP is secreted not only through the coronary sinus but also directly from the left atrium, stimulated by high left atrial pressure, and that circulating hANP is partially extracted in the pulmonary circulation.