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Vol. 287, Issue 2, 567-577, November 1998
St. Vincent's Institute of Medical Research, 41 Victoria Parade,
Fitzroy, Victoria 3065, Australia
The combination of neutral endopeptidase 24.11 (NEP) and angiotensin
converting enzyme (ACE) inhibition is a candidate therapy for
hypertension and cardiac failure. Given that NEP and ACE metabolize angiotensin (Ang) and bradykinin (BK) peptides, we investigated the
effects of NEP inhibition and combined NEP and ACE inhibition on the
levels of these peptides. We administered the NEP inhibitor ecadotril
(0, 0.1, 1, 10, 100 mg/kg per day), either alone or together with the
ACE inhibitor perindopril (0.2 mg/kg per day), to rats by 12 hourly
gavage for 7 days. Ecadotril produced diuresis, natriuresis, increased
urine cyclic guanosine monophosphate and BK-(1-9) levels, increased
Ang II and Ang I levels in plasma, and increased Ang I levels in heart.
Perindopril reduced Ang II levels in kidney, and increased BK-(1-9)
levels in blood, kidney and aorta. Combined NEP/ACE inhibition produced
the summation of these effects of separate NEP and ACE inhibition. In
addition, perindopril potentiated the ecadotril-mediated diuresis,
natriuresis and decrease in urine BK-(1-7)/BK-(1-9) ratio, which is
an index of BK-(1-9) metabolism. Moreover, combined NEP/ACE inhibition increased Ang II levels in plasma and lung. These data indicate that
summation of the effects of separate NEP and ACE inhibition provides
the basis for the therapeutic efficacy of their combination. Whereas
potentiation by perindopril of the diuretic and natriuretic effects of
ecadotril may contribute to the therapeutic effects, increased Ang II
levels in plasma and lung may compromise the therapeutic effects of
combined NEP/ACE inhibition.
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