SQ28603 is a potent and selective inhibitor of neutral endopeptidase 3.4.24.11 (NEP), an enzyme that degrades atrial natriuretic peptide (ANP). In conscious deoxycorticosterone acetate (DOCA)/salt hypertensive rats, 300 μmol/kg, i.v., of SQ28603 significantly lowers mean arterial pressure (MAP) from 177±12 to 154±8 mm Hg and increases urinary cyclic guanosine monophosphate (GMP) excretion from 204±70 to 1,068±326 pmol/kg/min within 2 h. SQ28603 also significantly reduces NEP activity by 95% in the kidneys (1.28±0.08 vs. 18.35±0.61 μmol/min after SQ28603 and vehicle respectively) and by 77% in the lungs (0.29±0.03 vs. 0.92±0.14 μmol/kg after SQ28603 and vehicle, respectively). In conclusion, inhibition of NEP activity by SQ28603 significantly decreases MAP and increases plasma ANP concentrations and urinary excretion of cyclic GMP in conscious DOCA/salt hypertensive rats. The potent neutral endopeptidase inhibitor SQ28603 significantly increases excretion of sodium from 4.9±2.3 to 14.3±2.1 muequiv./min and cyclic 3',5'-guanosine monophosphate from 118±13 to 179±18 pmol/min after intravenous administration of 300 μmol/kg (approximately 80 mg/kg) in conscious female cynomolgus monkeys.