Neutral endopeptidase regulates C-type natriuretic peptide metabolism but does not potentiate its bioactivity in vivo

Roland R. Brandt, Michael T. Mattingly, Alfredo L. Clavell, Paul L. Barclay, John C Jr. Burnett

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

C-type natriuretic peptide (CNP) is a newly described 22-amino acid peptide of endothelial and renal cell origin with selective cardiovascular actions. Recent in vitro studies have reported that CNP is the most susceptible of all natriuretic peptides to enzymatic degradation by neutral endopeptidase 24.11 (NEP). The present study was undertaken to define the role of NEP in total and regional CNP metabolism and the modulatory actions of NEP inhibition on the biological actions of CNP. CNP (10 ng · kg-1 · rain-1) followed by candoxatrilat (240 μg · kg-1 bolus and 8 μg · kg-1 · min-1), a potent and selective NEP inhibitor, was administered intravenously to a group of anesthetized mongrel dogs (group 1) to permit calculation of total metabolic clearance rate (MCR); results were compared with those in a group receiving vehicle infusion followed by candoxatrilat (group 2; both groups, n=7). NEP inhibition increased circulating CNP achieved by exogenous infusion and reduced total MCR in group 1. The regional CNP MCRs increased after CNP administration. While the pulmonary MCR did not change during concomitant candoxatrilat infusion, renal MCR was suppressed. Hemodynamic changes were not different between groups. A mild natriuretic and diuretic effect in association with an increase in circulating and urinary ANP levels was not different between groups. Urinary CNP excretion did not change with CNP infusion but markedly increased after NEP inhibition. We conclude that (1) circulating CNP achieved by exogenous CNP infusion is regulated by NEP in vivo, (2) regional MCRs are heterogeneous with NEP inhibition, (3) NEP inhibition does not potentiate acute cardiovascular actions of CNP, and (4) a mild natriuretic and diuretic effect observed with CNP and NEP inhibition may be ANP dependent.

Original languageEnglish (US)
Pages (from-to)184-190
Number of pages7
JournalHypertension
Volume30
Issue number2
StatePublished - Aug 1997

Fingerprint

C-Type Natriuretic Peptide
Neprilysin
Metabolic Clearance Rate
Natriuretic Agents
Atrial Natriuretic Factor
Diuretics
Kidney
Natriuretic Peptides
Rain

Keywords

  • Cyclic GMP
  • Kidney
  • Lung
  • Metabolism
  • Natriuresis
  • Natriuretic peptides

ASJC Scopus subject areas

  • Internal Medicine

Cite this

Neutral endopeptidase regulates C-type natriuretic peptide metabolism but does not potentiate its bioactivity in vivo. / Brandt, Roland R.; Mattingly, Michael T.; Clavell, Alfredo L.; Barclay, Paul L.; Burnett, John C Jr.

In: Hypertension, Vol. 30, No. 2, 08.1997, p. 184-190.

Research output: Contribution to journalArticle

Brandt, Roland R. ; Mattingly, Michael T. ; Clavell, Alfredo L. ; Barclay, Paul L. ; Burnett, John C Jr. / Neutral endopeptidase regulates C-type natriuretic peptide metabolism but does not potentiate its bioactivity in vivo. In: Hypertension. 1997 ; Vol. 30, No. 2. pp. 184-190.
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AU - Burnett, John C Jr.

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AB - C-type natriuretic peptide (CNP) is a newly described 22-amino acid peptide of endothelial and renal cell origin with selective cardiovascular actions. Recent in vitro studies have reported that CNP is the most susceptible of all natriuretic peptides to enzymatic degradation by neutral endopeptidase 24.11 (NEP). The present study was undertaken to define the role of NEP in total and regional CNP metabolism and the modulatory actions of NEP inhibition on the biological actions of CNP. CNP (10 ng · kg-1 · rain-1) followed by candoxatrilat (240 μg · kg-1 bolus and 8 μg · kg-1 · min-1), a potent and selective NEP inhibitor, was administered intravenously to a group of anesthetized mongrel dogs (group 1) to permit calculation of total metabolic clearance rate (MCR); results were compared with those in a group receiving vehicle infusion followed by candoxatrilat (group 2; both groups, n=7). NEP inhibition increased circulating CNP achieved by exogenous infusion and reduced total MCR in group 1. The regional CNP MCRs increased after CNP administration. While the pulmonary MCR did not change during concomitant candoxatrilat infusion, renal MCR was suppressed. Hemodynamic changes were not different between groups. A mild natriuretic and diuretic effect in association with an increase in circulating and urinary ANP levels was not different between groups. Urinary CNP excretion did not change with CNP infusion but markedly increased after NEP inhibition. We conclude that (1) circulating CNP achieved by exogenous CNP infusion is regulated by NEP in vivo, (2) regional MCRs are heterogeneous with NEP inhibition, (3) NEP inhibition does not potentiate acute cardiovascular actions of CNP, and (4) a mild natriuretic and diuretic effect observed with CNP and NEP inhibition may be ANP dependent.

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