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Vol. 289, Issue 1, 295-303, April 1999
St. Vincent's Institute of Medical Research, Fitzroy, Victoria,
Australia
Combined inhibition of neutral endopeptidase 24.11 (NEP) and
angiotensin converting enzyme (ACE) 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 Ang
and BK levels in rats with myocardial infarction. We administered the
NEP inhibitor ecadotril (0, 0.1, 1, 10, and 100 mg/kg/day), either
alone or together with the ACE inhibitor perindopril (0.2 mg/kg/day) by
12-hourly gavage from day 2 to 28 after infarction. Ecadotril increased
urine cyclic GMP and BK-(1-9) excretion. Perindopril potentiated the
effect of ecadotril on urine cyclic GMP excretion. Neither perindopril
nor ecadotril reduced cardiac hypertrophy when administered separately,
whereas the combination of perindopril and 10 or 100 mg/kg/day
ecadotril reduced heart weight/body weight ratio by 10%.
Administration of ecadotril to perindopril-treated rats decreased
plasma Ang-(1-7) levels, increased cardiac BK-(1-9) levels, and
increased Ang II levels in plasma, kidney, aorta, and lung. These data
demonstrate interactions between the effects of NEP and ACE inhibition
on remodeling of the infarcted heart and on Ang and BK peptide levels.
Whereas increased cardiac BK-(1-9) levels may contribute to the
reduction of cardiac hypertrophy, the reduction in plasma Ang-(1-7)
levels and increase in Ang II levels in plasma and tissues may
compromise the therapeutic effects of combined NEP/ACE inhibition.
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