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Research ArticleArticle

Interaction Between Neutral Endopeptidase and Angiotensin Converting Enzyme Inhibition in Rats with Myocardial Infarction: Effects on Cardiac Hypertrophy and Angiotensin and Bradykinin Peptide Levels

Ann-Maree Duncan, Gail M. James, Frank Anastasopoulos, Athena Kladis, Todd A. Briscoe and Duncan J. Campbell
Journal of Pharmacology and Experimental Therapeutics April 1999, 289 (1) 295-303;
Ann-Maree Duncan
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Gail M. James
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Frank Anastasopoulos
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Athena Kladis
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Todd A. Briscoe
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Duncan J. Campbell
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Abstract

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.

Footnotes

  • Send reprint requests to: Dr. D. J. Campbell, St. Vincent’s Institute of Medical Research, 41 Victoria Parade, Fitzroy, Victoria 3065, Australia. E-mail:J.Campbell{at}medicine.unimelb.edu.au

  • ↵1 This study was funded by grants from the National Health and Medical Research Council of Australia and from Bayer.AG, Wuppertal, Germany.

  • Abbreviations:
    ACE
    angiotensin converting enzyme
    Ang
    angiotensin
    BK
    bradykinin
    ecadotril
    N-(S)-[2-[(acetylthio)methyl]-1-oxo-3-phenylpropyl]-glycine benzylester
    NEP
    neutral endopeptidase 24.11
    RB104
    2-[(3-iodo-4-hydroxy)phenylmethyl]-4-N-[3- (hydroxyamino-3-oxo-1-phenylmethyl)propyl]amino-4-oxobutanoic acid
    RIA
    radioimmunoassay
    • Received June 25, 1998.
    • Accepted December 1, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 289 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 289, Issue 1
1 Apr 1999
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Research ArticleArticle

Interaction Between Neutral Endopeptidase and Angiotensin Converting Enzyme Inhibition in Rats with Myocardial Infarction: Effects on Cardiac Hypertrophy and Angiotensin and Bradykinin Peptide Levels

Ann-Maree Duncan, Gail M. James, Frank Anastasopoulos, Athena Kladis, Todd A. Briscoe and Duncan J. Campbell
Journal of Pharmacology and Experimental Therapeutics April 1, 1999, 289 (1) 295-303;

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Research ArticleArticle

Interaction Between Neutral Endopeptidase and Angiotensin Converting Enzyme Inhibition in Rats with Myocardial Infarction: Effects on Cardiac Hypertrophy and Angiotensin and Bradykinin Peptide Levels

Ann-Maree Duncan, Gail M. James, Frank Anastasopoulos, Athena Kladis, Todd A. Briscoe and Duncan J. Campbell
Journal of Pharmacology and Experimental Therapeutics April 1, 1999, 289 (1) 295-303;
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