Depressor and renal activities of atrial natriuretic factor-(99-126) were determined in conscious, unrestrained spontaneously hypertensive rats treated with a neutral endopeptidase inhibitor, SQ 29,amino]heptanoic acid). SQ 29,072 (100 /tmol/kg i.v.) prolonged the transient depressor effects of the peptide for as long as 2 hours. During the first hour after 3, 10, and 30 nmol/kg atrial natriuretic factor, urinary excretion of cyclic 3'5' guanosine monophosphate was significantly increased by 9.2±3.4, 13.0±2.2, and 12.7±4.2 nmol/kg/hr, respectively, in vehicle-treated rats and by 26.9±7.9, 52.1±11.1, and 46.4±12.2 nmol/kg/hr, respectively, in rats given 100 /tmol/kg SQ 29,072. During the first hour after 3 and 10 nmol/kg atrial natriuretic factor-(99-126), the sodium loss was 161±56 and 139±42 /teq/kg/hr in vehicle-treated rats and was significantly greater (694±316 and l,038±135 /teq/kg/hr) in rats given 100 /tmol/kg SQ 29,072. After administration of 3, 10, and 30 /tmol/kg SQ 29,072, the area over the curves of the depressor responses to 3 nmol/kg of the peptide increased from 297±70 to 306±108, 440±143, and 669±186 mm Hgmin, respectively, while the concurrent natriuretic responses rose from 161±56 to 250±88,332±142, 464±164, and 694±316 /teq/kg/hr. In summary, the neutral endopeptidase inhibitor SQ 29,072 increased the magnitudes and especially the durations of the depressor, natriuretic, and cyclic guanosine monophosphate responses to exogenous atria] natriuretic factor-(99-126) in conscious spontaneously hypertensive rats, presumably by inhibition of degradation of atrial natriuretic factor in vivo. In conclusion, neutral endopeptidase inhibition offers an important new technique for enhancement and prolongation of the biological lifetime of atrial natriuretic factor. (Hypertension 1989;14:87-97)