Angiotensin converting enzyme (ACE) and
neutral endopeptidase (NEP), are two mechanistically similar
enzymes involved in the metabolism of several vasoactive
peptides. Selective inhibitors of ACE are effective
antihypertensive agents in high-
renin, renovascular rats and normal-
renin, spontaneously hypertensive rats (SHR), but are not effective in the low-
renin,
deoxycorticosterone acetate (
DOCA)-
salt hypertensive rats. In contrast, NEP inhibitors are only effective in the low-
renin model of
hypertension. Treatment with a combination of selective inhibitors or with a dual inhibitor of both
enzymes produces an
antihypertensive response regardless of basal plasma
renin activity. In this study, we compared the activities of
MDL 100,173, a novel subnanomolar inhibitor of both ACE and NEP, with those of equimolar doses of
captopril, a selective
ACE inhibitor, following
intravenous administration in these three rat models of
hypertension. Treatment with
MDL 100,173 significantly lowered blood pressure compared to vehicle treatment in all three models, whereas
captopril treatment lowered blood pressure in the renovascular and SHR models only. Administration of
MDL 100,173 also significantly elevated diuresis and natriuresis compared to either vehicle or
captopril treatment in the SHR and
DOCA-
salt rats. Urinary excretion of
atrial natriuretic peptide (
ANP) was increased by
MDL 100,173 treatment in all three models of
hypertension. Treatment with
captopril did not alter urine,
sodium, or
ANP excretion in any of the models. However, plasma-
renin activity was elevated by both
MDL 100,173 and
captopril '''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''' ''''''''