Simultaneous inhibition of neutral endopeptidase EC 18.104.22.168 (NEP) and angiotensin converting enzyme (ACE) by equimolar doses (100 mumol/kg i.v.) of SQ 28603 (N-[2-(mercaptomethyl)-1-oxo-3- phenylpropyl]-beta-alanine) and captopril increased sodium excretion by 888 +/- 377 microEq/3 hr and significantly lowered blood pressure by -6 +/- 2 mm Hg in conscious cynomolgus monkeys. This rate of sodium excretion was not significantly different from that elicited by 100 mumol/kg i.v. of SQ 28603 alone (1453 +/- 315 microEq/3 hr). In addition, the natriuretic response to captopril plus SQ 28603 was potentiated by infusion of 10 pmol/kg/min of human atrial natriuretic peptide (hANP 99-126) despite a reduction in renal perfusion pressure from 100 +/- 2 to 86 +/- 2 mm Hg. Lower doses (0.3 to 3 mumol/kg i.v.) of SQ 28603 that had no effect on blood pressure or renal function potentiated the natriuretic, urinary cyclic guanosine monophosphate and atrial natriuretic peptide responses without affecting the depressor activity of 0.3 nmol/kg i.v. of hANP 99-126. The potentiation of the natriuretic activity of 0.3 nmol/kg of hANP 99-126 by 1 or 3 mumol/kg of SQ 28603 was not significantly affected by the addition of equimolar doses of captopril. These results confirmed that the renal responses to the combined inhibitors resulted from NEP inhibition. In contrast, the depressor activity of the combined inhibitors was dependent on the level of ACE inhibition and was not significantly affected by either infusion of hANP 99-126 or prior sodium loading. Therefore, the vascular responses to combined NEP and ACE inhibitors did not necessarily depend upon increases in circulating atrial natriuretic peptide or reductions in angiotensin II levels. The unique profile of renal and vascular responses to combined NEP and ACE inhibition suggested that dual NEP/ACE inhibitors may be useful for the treatment of cardiovascular disorders.