DETERMINANTS OF IN-VIVO ACTIVITY OF NEUTRAL ENDOPEPTIDASE-3.4.24.11 AND ANGIOTENSIN-CONVERTING ENZYME-INHIBITORS

Simultaneous inhibition of neutral endopeptidase EC 3.4.24.11 (NEP) an d angiotensin converting enzyme (ACE) by equimolar doses (100 mu mol/k g i.v.) of SQ 28603 ercaptomethyl)-1-oxo-3-phenylpropyl]-beta-alanine) and captopril increased sodium excretion by 888 +/- 377 mu Eq/3 hr an d significantly lowered blood pressure by -6 +/- 2 mm Hg in conscious cynomolgus monkeys. This rate of sodium excretion was not significantl y different from that elicited by 100 mu mol/kg i.v. of SQ 28603 alone (1453 +/- 315 mu Eq/3 hr). In addition, the natriuretic response to c aptopril plus SQ 28603 was potentiated by infusion of 10 pmol/kg/min o f human atrial natriuretic peptide (hANP 99-126) despite a reduction i n renal perfusion pressure from 100 +/- 2 to 86 +/- 2 mm Hg. Lower dos es (0.3 to 3 mu mol/kg i.v.) of SQ 28603 that had no effect on blood p ressure or renal function potentiated the natriuretic, urinary cyclic guanosine monophosphate and atrial natriuretic peptide responses witho ut 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 mu mol/kg of SQ 28603 was not significantly affected by the addition of equimolar doses of captopril. These results confirm ed that the renal responses to the combined inhibitors resulted from N EP inhibition. In contrast, the depressor activity of the combined inh ibitors was dependent on the level of ACE inhibition and was not signi ficantly affected by either infusion of hANP 99-126 or prior sodium lo ading. Therefore, the vascular responses to combined NEP and ACE inhib itors 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 inhib ition suggested that dual NEP/ACE inhibitors may be useful for the tre atment of cardiovascular disorders.