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Simultaneous inhibition of neutral endopeptidase EC 3.4.24.11 (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.

Combined neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE) inhibition produces greater acute hemodynamic effects than either treatment alone. We investigated whether BMS-182657 (BMS), which bears inhibitory activities against both NEP and ACE, elicited similar enhanced effects. BMS inhibited NEP and ACE, in vitro (IC50 = 6 and 12 nM, respectively) and the pressor response to Ang I in rats. In deoxycorticosterone acetate (DOCA)-salt hypertensive rats sensitive to NEP inhibition but not to ACE inhibition, BMS at 100 mumol/kg i.v. lowered mean arterial pressure (MAP) from 180 +/- 6 to 151 +/- 5 mm Hg. In sodium-depleted, spontaneously hypertensive rats (SHR) sensitive to ACE inhibition but not to NEP inhibition, BMS at 100 mumol/kg p.o. lowered MAP from 151 +/- 4 to 123 +/- 5 mm Hg. Cardiomyopathic hamsters with heart failure were administered vehicle or one of the following (30 mumol/kg i.v.): the ACE inhibitor enalaprilat; the NEP inhibitor SQ-28603; or BMS. Enalaprilat and SQ-28603 had minimal hemodynamic effects. BMS decreased left ventricular end-diastolic pressure by 12 +/- 2 and 10 +/- 1 mm Hg and left ventricular systolic pressure by 27 +/- 2 and 23 +/- 3 mm Hg at 30 and 60 min, respectively (P.05 vs. each other group). These changes were associated with a 40% increase in cardiac output, a 47% decrease in peripheral vascular resistance and a lowering of MAP by 21 +/- 3 mm Hg at 60 min (P.05 vs. each other group). There were no significant differences in the changes in heart rate or left ventricular stroke work index among the four groups. Hence, BMS-182657 is a dual inhibitor of NEP and ACE, is antihypertensive irrespective of the activity of the renin-angiotensin system and has acute hemodynamic effects in hamsters with heart failure greater than those produced by selective inhibition of NEP or ACE. The NEP and ACE inhibitory activities of BMS-182657 act synergistically and mimic the interaction resulting from combining selective inhibitors of these enzymes.

Inhibition of the metallopeptidase neutral endopeptidase 3.4.24.11 (NEP) protects endogenous natriuretic peptides and potentiates their vasodepressor effects. Inhibition of angiotensin converting enzyme (ACE) attenuates the formation of angiotensin II and enhances the vasodepressor effect of endogenous kinins. A combination of NEP inhibition and ACE inhibition can potentially interact to shift the balance of vasoactive peptides toward vasodilation. This potential interaction was examined in conscious cardiomyopathic hamsters with low cardiac output and compensated heart failure. Neither the selective NEP inhibitor SQ 28,603 nor the selective ACE inhibitor enalaprilat (each at 30 mumol/kg, i.v.) caused significant changes in left ventricular end diastolic pressure or left ventricular systolic pressure when administered separately. However, the combination of these inhibitors, each at that dose, caused significant peak decreases in left ventricular end diastolic pressure and left ventricular systolic pressure of -12 +/- 1 and -18 +/- 4 mm Hg, respectively. In separate cardiomyopathic hamsters, this same combination of treatments resulted in significant decreases in mean arterial pressure (-13%) and total peripheral resistance (-37%) and an increase in cardiac output (36%) as compared with vehicle effects (P.05). At 90 min after administration of SQ 28,603 alone, plasma atrial natriuretic peptide concentration was double that in the vehicle group. In the group receiving the combination of inhibitors, plasma atrial natriuretic peptide at 90 min was maintained at the high basal levels associated with this model despite the decrease in cardiac filling pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

The depressor, natriuretic and cyclic GMP responses to several species of brain natriuretic peptide (BNP) were compared to atrial natriuretic peptide (ANP) 99-126 in conscious spontaneously hypertensive rats (SHR) and in conscious cynomolgus monkeys treated with vehicle or the selective neutral endopeptidase (NEP 3.4.24.11) inhibitor N-[2-(mercaptomethyl)-1-oxo-3-phenylpropyl]-beta- alanine (SQ 28,603). In the conscious SHR, the natriuretic and cyclic GMP responses to 3 nmol/kg i.v. rat BNP-32 greater than rat ANP 99-126 greater than pig BNP-26 and were significantly potentiated by 100 mumol/kg i.v. SQ 28,603. Human BNP-32 was inactive in the SHR treated with either vehicle or SQ 28,603. In contrast, 1 nmol/kg i.v. of human BNP-32 stimulated renal and depressor responses in the conscious monkeys that were greater than or equal to those elicited by human ANP 99-126, whereas 3 nmol/kg i.v. rat BNP-32 reduced mean arterial pressure without affecting renal function. Furthermore, SQ 28,603 (100 mumol/kg, i.v.) significantly enhanced the cumulative losses of sodium and cyclic GMP stimulated by each of these peptides. In conclusion, the renal and depressor activities of BNP are highly species specific and are significantly potentiated by an inhibitor of NEP 3.4.24.11 in conscious SHR and monkeys. Therefore, protection of endogenous BNP may contribute importantly to the activity of NEP 3.4.24.11 inhibitors in cardiorenal disorders such as hypertension and congestive heart failure.

The effects of a clearance receptor ligand Arg-Ser-Ser-Cys-Phe-Gly-Gly-Arg-Ile-Asp-Arg-Ile-Gly-Ala-Cys-NH2 with a disulfide bridge between the two cycteines [C-ANF(4-23)] and the potent neutral endopeptidase (NEP) inhibitor SQ 28,603 on mean arterial pressure (MAP), plasma atrial natriuretic factor (ANF) concentration and renal excretion of sodium and cyclic GMP were determined in conscious deoxycorticosterone acetate/salt hypertensive rats and normotensive rats. In the hypertensive rats, i.v. infusion of C-ANF(4-23) produced depressor responses of approximately 25 mm Hg, but did not significantly affect plasma ANF concentration or stimulate cyclic GMP excretion. In contrast, SQ 28,603 (300 mumol/kg i.v.) significantly reduced MAP and increased excretion of sodium and cyclic GMP. When C-ANF(4-23) was administered in combination with SQ 28,603, the depressor activity was additive and plasma ANF concentrations were significantly increased. The excretion of cyclic GMP was slightly enhanced, but, was not significantly different from the effects of SQ 28,603 alone. Neither SQ 28,603 nor C-ANF(4-23) affected MAP or plasma ANF in the normotensive rats. Finally, the in vitro hydrolysis of C-ANF(4-23) by NEP was prevented by SQ 28,603, indicating that inhibition of NEP may protect peptides recognized by the clearance receptors as well as the biological receptors for ANF. Therefore, the additive effects of C-ANF(4-23) and SQ 28,603 may be due to blockade of separate pathways which inactivate ANF or to the inhibition of C-ANF(4-23) degradation by NEP.