Angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP) are implicated in the metabolism of several peptides involved in blood pressure and sodium homeostasis control, such as angiotensins, atrial natriuretic factor (ANF), bradykinin and endothelin. The effects of a highly selective NEP inhibitor (NEPI), retrothiorphan, of a converting enzyme inhibitor (CEI), enalaprilat, and of the combination, CEI + NEPI, were assessed in deoxycorticosterone acetate (DOCA)-salt hypertensive rats, spontaneously hypertensive rats (SHRs) and renovascular hypertensive rats. NEPI increased diuresis, natriuresis and urinary cyclic GMP (cGMP), ANF and bradykinin in the three models. NEPI decreased blood pressure in DOCA-salt hypertensive rats only, whereas CEI decreased blood pressure in SHRs and renovascular hypertensive rats only and increased plasma renin. CEI had no effect on urinary aldosterone or bradykinin in any of the three models. CEI + NEPI increased diuresis and natriuresis in DOCA-salt hypertensive rats and SHRs, and increased urinary cGMP, ANF and bradykinin and plasma renin levels. CEI and NEPI interacted significantly to decrease blood pressure and to increase urinary cGMP in SHRs only. Hence, NEPI increases diuresis, natriuresis and urinary cGMP, ANF and bradykinin in experimental hypertension, whereas CEI acts on blood pressure and increases in plasma renin in SHRs and renovascular hypertensive rats. The significant interaction between CEI and NEPI to decrease blood pressure in SHRs indicates that simultaneous blockade of the two metallopeptidases results in potentiation of the hypotensive effect and that the SHRs appear to be a good model for studying NEP and ACE coinhibition. Finally, NEP rather than ACE appears to be involved in bradykinin renal catabolism in experimental hypertension.