The atrial natriuretic factor (ANF) is a circulating peptide, consisting of 24 to 28 amino acids. Atrial natriuretic factor is synthetized in atrial cardiomyocytes and stored in specific cytoplasmatic granules. It possesses potent diuretic, natriuretic, and vasorelexant properties. The possible role of ANF in the pathogenesis of hypertension and heart failure was investigated in animal models and in men. We were able to show that the release of ANF from cardiac atria is positively correlated with atrial pressures in both men and rats. In experimental studies, plasma levels of ANF measured by radioimmunoassay, were increased by up to four-fold after acute blood volume expansion. Atrial natriuretic factor release in response to volume loading was markedly attenuated in four-week-old spontaneously hypertensive rats as compared to age-matched normotensive Wistar-Kyoto rats, but a similar responsiveness was found in 16-week-old rats of both strains. This finding can be reconciled with the hypothesis that ANF plays a pathophysiological role in initiating but not maintaining high blood pressure. Clinical studies demonstrate elevated plasma concentrations of ANF in patients with organic heart disease. Further increments in plasma levels of ANF were obtained during physical exercise and after acute volume loading. In patients with congestive cardiomyopathy, the elevated plasma concentrations of ANF reached almost normal levels following improvement of their hemodynamic disturbances after treatment with converting-enzyme inhibitors. These findings suggest that in patients with organic heart disease, plasma concentrations of ANF reflect the hemodynamic burden of the heart and may, therefore, be used as a noninvasive marker of the efficacy of the current cardiac therapy.