Abstract
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.
Footnotes
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Send reprint requests to: Dr. D. J. Campbell, St. Vincent’s Institute of Medical Research, 41 Victoria Parade, Fitzroy, Victoria 3065, Australia.
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1 This study was supported by grants from the National Health and Medical Research Council of Australia and from Bayer.AG, Wuppertal, Germany.
- Abbreviations:
- ACE
- angiotensin converting enzyme
- Ang I
- angiotensin I
- Ang II
- angiotensin II
- ANOVA
- analysis of variance
- ANP
- atrial natriuretic peptide
- B2 receptor
- type 2 bradykinin receptor
- BK-(1–7)
- bradykinin-(1–7)
- BK-(1–8)
- bradykinin-(1–8)
- BK-(1–9)
- bradykinin-(1–9)
- ecadotril
- N-(S)-[2-[(acetylthio)methyl]-1-oxo-3-phenylpropyl]-glycine benzylester
- EDTA
- ethylenediaminetetra-acetate
- GMP
- guanosine monophosphate
- GTC/TFA
- 4 M guanidine thiocyanate, 1% trifluoroacetic acid
- HPLC
- high-performance liquid chromatography
- 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
- SHR
- spontaneously hypertensive rat
- Tris
- tris-(hydroxymethyl)aminomethane
- Received February 24, 1998.
- Accepted June 9, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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