1. Inhibitors of
neutral endopeptidase (NEP) EC 3.4.24.11 were developed to regulate endogenous levels of the natriuretic and vasodilatory
hormone atrial natriuretic peptide (
ANP). The selective NEP inhibitor
SQ 28603 enhanced the increases in plasma
ANP and urinary excretion of
ANP,
cyclic GMP and
sodium stimulated by infusion of human
ANP in conscious monkeys.
SQ 28603 also potentiated the renal and depressor responses to rat
brain natriuretic peptide (BNP) in conscious spontaneously hypertensive rats (SHR) and human BNP in conscious monkeys. Therefore, selective NEP inhibitors protected both
natriuretic peptides from degradation in vivo and enhanced their
biological activities. 2. Selective NEP inhibitors lowered blood pressure in conscious
DOCA/
salt hypertensive rats and SHR with
antihypertensive activity similar to that of exogenous
ANP. Furthermore, simultaneous treatment with an
angiotensin converting enzyme (
ACE) inhibitor enhanced the depressor activity of the NEP inhibitor in SHR. 3.
SQ 28603 stimulated urinary excretion of
cyclic GMP and
sodium in a dose-related manner in conscious dogs with
tachycardia-induced
heart failure. Addition of the
ACE inhibitor captopril significantly reduced blood pressure and systemic vascular resistance while sustaining
sodium excretion and increasing cardiac output, glomerular filtration rate and renal blood flow. Therefore, combined NEP and ACE inhibition produced a unique haemodynamic and renal profile in dogs with pacing-induced
heart failure. 4. The novel dual
metalloprotease inhibitor
BMS-182657 potentiated the renal responses to exogenous
ANP and suppressed the pressor response to
angiotensin I in conscious monkeys, indicating in vivo inhibition of both NEP and ACE.(ABSTRACT TRUNCATED AT 250 WORDS)