POTENTIATION OF NATRIURETIC PEPTIDES BY NEUTRAL ENDOPEPTIDASE INHIBITORS

1. Inhibitors of neutral endopeptidase (NEP) EC 3.4.24.11 were develop ed to regulate endogenous levels of the natriuretic and vasodilatory h ormone atrial natriuretic peptide (ANP), The selective NEP inhibitor S Q 28603 enhanced the increases in plasma ANP and urinary excretion of ANP, cyclic GMP and sodium stimulated by infusion of human ANP in cons cious monkeys. SQ 28603 also potentiated the renal and depressor respo nses 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 de gradation in vivo and enhanced their biological activities. 2. Selecti ve NEP inhibitors lowered blood pressure in conscious DOCA/salt hypert ensive 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 capto pril significantly reduced blood pressure and systemic vascular resist ance while sustaining sodium excretion and increasing cardiac output, glomerular filtration rate and renal blood flow, Therefore, combined N EP and ACE inhibition produced a unique haemodynamic and renal profile in dogs with pacing-induced heart failure. 4. The novel dual metallop rotease inhibitor BMS-182657 potentiated the renal responses to exogen ous ANP and suppressed the presser response to angiotensin I in consci ous monkeys, indicating in vivo inhibition of both NEP and ACE, EMS-18 2657 also reduced blood pressure and stimulated natriuresis in conscio us 1-kidney 1-dip hypertensive dogs, demonstrating efficacy in a hyper tensive model characterized by normal circulating levels of ANP and re nin activity. Therefore, a dual metalloprotease inhibitor may offer a unique therapeutic approach for treatment of cardiovascular disorders.