Renal response to acute neutral endopeptidase inhibition in mild and severe experimental heart failure

Horng Haur Chen, John A. Schirger, William L. Chau, Michihisa Jougasaki, Ondrej Lisy, Margaret May Redfield, Paul T. Barclay, John C Jr. Burnett

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

Background - Neutral endopeptidase 24.11 (NEP) is a metalloprotease that is localized in the greatest abundance in the kidney and degrades natriuretic peptides, such as atrial natriuretic peptide (ANP). Mild congestive heart failure (CHF) is characterized by increases in circulating ANP without activation of the renin-angiotensin-aldosterone system (RAAS) or sodium retention. In contrast, severe CHF is characterized by sodium retention and coactivation of both ANP and the RAAS. Methods and Results - We defined the acute cardiorenal actions of the NEP inhibitor candoxatrilat (8 μg·kg - 1·min -1) in 4 groups of anesthetized dogs (normal, n=8; mild CHF, n=6; severe CHF, n=5; and severe CHF with chronic AT 1 receptor antagonism, n=5). Mild CHF was produced by rapid ventricular pacing at 180 bpm for 10 days and severe CHF at 245 bpm for 10 days. In mild CHF, urinary sodium excretion and glomerular filtration rate were greatest in response to acute NEP inhibition compared with the response in either control animals or those with severe CHF. Furthermore, an increase in glomerular filtration rate was observed only in mild CHF in association with increases in renal blood flow and decreases in renal vascular resistance and distal tubular sodium reabsorption. Urinary ANP and cGMP excretion, markers for renal biological actions of ANP, were greatest in mild CHF. The renal actions observed in mild CHF were attenuated in severe CHF and not restored by chronic AT 1 receptor antagonism. Conclusions - The results of the present study demonstrate that acute NEP inhibition in mild CHF results in marked increases in renal hemodynamics and sodium excretion that exceed that observed in control animals and severe CHF. These studies underscore the potential therapeutic role for NEP inhibition to enhance renal function in mild CHF, an important phase of CHF that is marked by selective activation of endogenous ANP in the absence of an activated RAAS.

Original languageEnglish (US)
Pages (from-to)2443-2448
Number of pages6
JournalCirculation
Volume100
Issue number24
StatePublished - Dec 14 1999

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Neprilysin
Heart Failure
Kidney
Atrial Natriuretic Factor
Sodium
Renin-Angiotensin System
Glomerular Filtration Rate
Natriuretic Peptides
Renal Circulation

Keywords

  • Kidney
  • Metalloprotease
  • Natriuretic peptides
  • Neurohormones
  • Ventricles

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Renal response to acute neutral endopeptidase inhibition in mild and severe experimental heart failure. / Chen, Horng Haur; Schirger, John A.; Chau, William L.; Jougasaki, Michihisa; Lisy, Ondrej; Redfield, Margaret May; Barclay, Paul T.; Burnett, John C Jr.

In: Circulation, Vol. 100, No. 24, 14.12.1999, p. 2443-2448.

Research output: Contribution to journalArticle

Chen, HH, Schirger, JA, Chau, WL, Jougasaki, M, Lisy, O, Redfield, MM, Barclay, PT & Burnett, JCJ 1999, 'Renal response to acute neutral endopeptidase inhibition in mild and severe experimental heart failure', Circulation, vol. 100, no. 24, pp. 2443-2448.
Chen, Horng Haur ; Schirger, John A. ; Chau, William L. ; Jougasaki, Michihisa ; Lisy, Ondrej ; Redfield, Margaret May ; Barclay, Paul T. ; Burnett, John C Jr. / Renal response to acute neutral endopeptidase inhibition in mild and severe experimental heart failure. In: Circulation. 1999 ; Vol. 100, No. 24. pp. 2443-2448.
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AU - Chen, Horng Haur

AU - Schirger, John A.

AU - Chau, William L.

AU - Jougasaki, Michihisa

AU - Lisy, Ondrej

AU - Redfield, Margaret May

AU - Barclay, Paul T.

AU - Burnett, John C Jr.

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N2 - Background - Neutral endopeptidase 24.11 (NEP) is a metalloprotease that is localized in the greatest abundance in the kidney and degrades natriuretic peptides, such as atrial natriuretic peptide (ANP). Mild congestive heart failure (CHF) is characterized by increases in circulating ANP without activation of the renin-angiotensin-aldosterone system (RAAS) or sodium retention. In contrast, severe CHF is characterized by sodium retention and coactivation of both ANP and the RAAS. Methods and Results - We defined the acute cardiorenal actions of the NEP inhibitor candoxatrilat (8 μg·kg - 1·min -1) in 4 groups of anesthetized dogs (normal, n=8; mild CHF, n=6; severe CHF, n=5; and severe CHF with chronic AT 1 receptor antagonism, n=5). Mild CHF was produced by rapid ventricular pacing at 180 bpm for 10 days and severe CHF at 245 bpm for 10 days. In mild CHF, urinary sodium excretion and glomerular filtration rate were greatest in response to acute NEP inhibition compared with the response in either control animals or those with severe CHF. Furthermore, an increase in glomerular filtration rate was observed only in mild CHF in association with increases in renal blood flow and decreases in renal vascular resistance and distal tubular sodium reabsorption. Urinary ANP and cGMP excretion, markers for renal biological actions of ANP, were greatest in mild CHF. The renal actions observed in mild CHF were attenuated in severe CHF and not restored by chronic AT 1 receptor antagonism. Conclusions - The results of the present study demonstrate that acute NEP inhibition in mild CHF results in marked increases in renal hemodynamics and sodium excretion that exceed that observed in control animals and severe CHF. These studies underscore the potential therapeutic role for NEP inhibition to enhance renal function in mild CHF, an important phase of CHF that is marked by selective activation of endogenous ANP in the absence of an activated RAAS.

AB - Background - Neutral endopeptidase 24.11 (NEP) is a metalloprotease that is localized in the greatest abundance in the kidney and degrades natriuretic peptides, such as atrial natriuretic peptide (ANP). Mild congestive heart failure (CHF) is characterized by increases in circulating ANP without activation of the renin-angiotensin-aldosterone system (RAAS) or sodium retention. In contrast, severe CHF is characterized by sodium retention and coactivation of both ANP and the RAAS. Methods and Results - We defined the acute cardiorenal actions of the NEP inhibitor candoxatrilat (8 μg·kg - 1·min -1) in 4 groups of anesthetized dogs (normal, n=8; mild CHF, n=6; severe CHF, n=5; and severe CHF with chronic AT 1 receptor antagonism, n=5). Mild CHF was produced by rapid ventricular pacing at 180 bpm for 10 days and severe CHF at 245 bpm for 10 days. In mild CHF, urinary sodium excretion and glomerular filtration rate were greatest in response to acute NEP inhibition compared with the response in either control animals or those with severe CHF. Furthermore, an increase in glomerular filtration rate was observed only in mild CHF in association with increases in renal blood flow and decreases in renal vascular resistance and distal tubular sodium reabsorption. Urinary ANP and cGMP excretion, markers for renal biological actions of ANP, were greatest in mild CHF. The renal actions observed in mild CHF were attenuated in severe CHF and not restored by chronic AT 1 receptor antagonism. Conclusions - The results of the present study demonstrate that acute NEP inhibition in mild CHF results in marked increases in renal hemodynamics and sodium excretion that exceed that observed in control animals and severe CHF. These studies underscore the potential therapeutic role for NEP inhibition to enhance renal function in mild CHF, an important phase of CHF that is marked by selective activation of endogenous ANP in the absence of an activated RAAS.

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KW - Neurohormones

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